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Review

Human Induced Pluripotent Stem-Cell-Derived Cardiomyocytes as Models for Genetic Cardiomyopathies

by
Andreas Brodehl
1,*,
Hans Ebbinghaus
1,
Marcus-André Deutsch
2,
Jan Gummert
1,2,
Anna Gärtner
1,
Sandra Ratnavadivel
1 and
Hendrik Milting
1,*
1
Erich and Hanna Klessmann Institute, Heart and Diabetes Center NRW, University Hospital of the Ruhr-University Bochum, Georgstrasse 11, D-32545 Bad Oeynhausen, Germany
2
Department of Thoracic and Cardiovascular Surgery, Heart and Diabetes Center NRW, University Hospital Ruhr-University Bochum, Georgstrasse 11, D-32545 Bad Oeynhausen, Germany
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(18), 4381; https://doi.org/10.3390/ijms20184381
Submission received: 29 July 2019 / Revised: 29 August 2019 / Accepted: 3 September 2019 / Published: 6 September 2019
(This article belongs to the Special Issue From hIPSCs to Adult Cells in a Dish: Promises and Pitfalls)
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Abstract

:
In the last few decades, many pathogenic or likely pathogenic genetic mutations in over hundred different genes have been described for non-ischemic, genetic cardiomyopathies. However, the functional knowledge about most of these mutations is still limited because the generation of adequate animal models is time-consuming and challenging. Therefore, human induced pluripotent stem cells (iPSCs) carrying specific cardiomyopathy-associated mutations are a promising alternative. Since the original discovery that pluripotency can be artificially induced by the expression of different transcription factors, various patient-specific-induced pluripotent stem cell lines have been generated to model non-ischemic, genetic cardiomyopathies in vitro. In this review, we describe the genetic landscape of non-ischemic, genetic cardiomyopathies and give an overview about different human iPSC lines, which have been developed for the disease modeling of inherited cardiomyopathies. We summarize different methods and protocols for the general differentiation of human iPSCs into cardiomyocytes. In addition, we describe methods and technologies to investigate functionally human iPSC-derived cardiomyocytes. Furthermore, we summarize novel genome editing approaches for the genetic manipulation of human iPSCs. This review provides an overview about the genetic landscape of inherited cardiomyopathies with a focus on iPSC technology, which might be of interest for clinicians and basic scientists interested in genetic cardiomyopathies.

Graphical Abstract

1. Introduction

At the beginning of this century, the human genome project was finished [1]. The development of next generation sequencing (NGS) technologies significantly reduced the price and time, allowing for efficient genome and exome analyses, even in clinical routine procedures. However, even 20 years later, the clinical interpretation of genetic sequence variants (GSVs) is still challenging because the functional and structural impact of many variants is unknown. Therefore, multi-disciplinary approaches are often necessary for the interpretation and functional analysis of novel GSVs [2]. At present, in clinical routine procedures, the pathological impact of GSVs is classified due to standards and guidelines of the American College of Medical Genetics and Genomics (ACMG) [3].
Cardiomyopathies are diseases that affect the heart muscle, leading to functional and structural abnormalities [4], and are the main indication for heart transplantation (HTx) [5]. Beside environmental factors, like myocarditis or cardiotoxicity of cancer drugs, non-ischemic cardiomyopathies often have a genetic etiology with dominant inheritance. However, because pathogenic mutations in more than 100 different genes are associated with non-ischemic cardiomyopathies, the interpretation of novel GSVs is still challenging [6]. Moreover, little is currently known on digenic, or even polygenic, etiologies of cardiomyopathies [7]. Incomplete penetrance, different expressivity, and pleiotropy make the clinical interpretation even more challenging.
Functional analyses using adequate cell and animal models can lead to a more sophisticated interpretation of GSVs, which might be not only relevant for genetic counseling but also for the development of personalized therapies. According to the ACMG guidelines, in vitro or/and in vivo functional analyses provide strong criteria (PS3) for the classification of GSVs [3,8]. However, the generation of animal models is still time consuming and expensive. Moreover, in some cases, human cardiomyopathies cannot be modeled using animal models because of species differences. For example, TMEM43-p.S358L is a mutation with full penetrance in several families with arrhythmogenic cardiomyopathy (ACM) [9,10,11]. In contrast, the Tmem43 knock-out, as well as the knock-in mice carrying this specific mutation, do not develop an ACM phenotype [12]. Because of these limitations, human iPSC-derived cardiomyocytes are unprecedented research tools to model and investigate genetic cardiomyopathies.
Here, we provide an overview about the genetic landscape of inherited cardiomyopathies and summarize the development of important human iPSC lines for modelling human cardiomyopathies in vitro. In addition, we review the differentiation into cardiomyocytes and discuss relevant methods used for the cellular and molecular characterization of human iPSC-derived cardiomyocytes.

2. Clinical Background

In clinical cardiology, cardiomyopathies are classified into five major structural subtypes (Figure 1). Dilated cardiomyopathy (DCM, MIM #604145) is mainly characterized by left-ventricular dilation in combination with a decrease of the wall diameter [13]. These structural changes decrease the cardiac ejection fraction. Hypertrophic cardiomyopathy (HCM, MIM #160760) is characterized by the hypertrophy of the ventricular walls and/or the septum [14], leading to a reduced cardiac output. Restrictive cardiomyopathy (RCM, MIM #115210) is caused by an increase in ventricular stiffness, leading to dilated atria and diastolic dysfunction [15]. Hyper-trabeculation of the left ventricular wall is a hallmark for (left-ventricular) non-compaction cardiomyopathy (NCCM, MIM #604169) [16]. It mainly affects the left ventricle, but isolated right ventricular or biventricular forms of NCCM have been reported [17]. Ventricular arrhythmias and predominant right or biventricular dilation are the main clinical symptoms of ACM (MIM #609040) [18]. The fibro fatty replacement of the myocardial tissue is a pathognomonic feature characteristic of ACM [19]. However, at the early stage of the disease, structural changes may be absent or subtle [20]. Because ACM is a progressive disease, left ventricular involvement develops frequently at a later stage [21].

3. Genetic Basis of Inherited Cardiomyopathies

Thirty years ago, Seidmans’ group discovered the first pathogenic mutation in MYH7, encoding for β-myosin heavy chain, in a four-generation family, in which several members developed HCM [22]. At present, genetic variants have been described in more than 100 different genes associated with non-ischemic cardiomyopathies or syndromes with cardiac involvement such as Marfan or Leopard syndrome (for an overview, see Table 1). Of note, the spectrum of affected genes and mutations partially overlaps between the different non-ischemic cardiomyopathies (Figure 1). For example, mutations in DES, encoding the muscle specific intermediate filament protein desmin, might cause DCM [23,24], HCM [25], ACM [26,27], RCM [28], or NCCM [29,30,31]. Similarly, mutations in TTN, encoding the giant sarcomere protein titin, can also cause different types of structural, non-ischemic cardiomyopathies [32,33,34]. However, the molecular reasons why mutations in the same gene can cause different cardiac phenotypes are largely unknown.
From a genetic point of view, non-ischemic cardiomyopathies are quite heterogeneous [35,36,37]. However, the different non-ischemic cardiomyopathies are characterized by an accumulation of mutations in a distinct set of genes encoding for proteins that are essential for cardiomyocyte function. For example, HCM is mainly caused by mutations in genes encoding sarcomeric proteins such as MYH7 or MYBPC3 (Figure 1). Further mutations in other genes, encoding sarcomere proteins, like TPM1 [38], TNNC1 [39], TNNI3 [40], TNNT2 [38], FHL1 [41,42], or ACTC1 [43], have also been identified in patients with HCM (Table 1). In addition, in rare cases, mutations in genes encoding for Z-disc proteins, like ACTN2 [44] or FLNC [45], or genes encoding for proteins involved in the Ca2+-homeostasis like PLN [46], are also known to cause HCM (see Figure 1).
TTN is the most prevalent DCM-related gene with truncating TTN mutations identified in about 20–25% of DCM patients [32,47]. However, several other genes with a lower prevalence can also cause DCM. Besides, mutations have been identified in genes coding proteins of the sarcomere (e.g., MYH7 [48]), the cytoskeleton (e.g., DES [23,24]), the nuclear lamina (e.g., LMNA [49]), ion channels (e.g., SCN5A [50]), and transcription (e.g., EYA4 [51]) or splicing factors (e.g., RBM20 [52]) (Table 1). RBM20 mutations cause an aggressive early onset phenotype including arrhythmias, sudden cardiac death, and DCM, especially in males [53]. In total, mutations associated with DCM have been described in about 80 different genes (see Figure 1 and Table 1).
NCCM is the third most frequent non-ischemic cardiomyopathy [54,55] and can occur as a primary cardiomyopathy or can be part of a syndromic disease like the Barth syndrome (MIM, #302060) [56]. Mutations in over 20 different genes having a significant overlap with HCM- or DCM-associated genes have been described in NCCM patients so far (see Figure 1 and Table 1). Comparable to HCM, the most prevalent NCCM-associated genes are MYH7 and MYBPC3 [57], which encode sarcomeric proteins (Table 1).
ACM is mainly caused by mutations in genes, encoding structural components of the cardiac desmosomes, and adherens junctions [26,58,59]. The cardiac desmosomes are cell–cell junctions mediating the adhesion of the cardiomyocytes [60]. In about 50% of the ACM patients, one or more mutations in desmosomal genes can be identified [26,59,61] (Table 1). Cardiac desmosomes are linked through the intermediate filaments formed mainly by desmin (DES) with several other cell organelles like the Z-bands or the nuclei. Of note, mutations in the DES gene can also cause ACM by abnormal cytoplasmic desmin aggregation [26,62]. In addition, mutations in genes of the nuclear envelope like LMNA [63], TMEM43 [9,10], or LEMD2 [64] are associated with ACM (Table 1). Furthermore, some rare mutations in non-desmosomal and non-nuclear genes like RYR2 [65,66], PLN [67], or ILK [68] have been identified in ACM patients.
Currently, the genetic etiology of RCM is poorly characterized. Recently, Kostareva et al. and Gallego-Delgado et al. genotyped two small cohorts of unrelated RCM index patients and identified likely pathogenic or pathogenic mutations in 50–75% of them [69,70]. The majority of affected RCM genes, which partially overlap with the group of HCM-associated genes, encode for sarcomere or cytoskeleton proteins (see Figure 1 and Table 1). The first RCM-associated mutation was identified in TNNI3, encoding cardiac troponin I [71]. More recently, there is growing evidence that FLNC mutations, encoding the cytolinker protein filamin-C, are frequently associated with RCM [72,73,74,75,76].
In summary, a relevant amount of all non-ischemic cardiomyopathies have a genetic etiology. Although in most cases, cardiomyopathies are inherited monogenetically, the underlying genetic landscape is complex, diverse, and currently only partially known.

4. Generation of Patient-Specific-Induced Pluripotent Stem Cells Via Reprogramming

In the 1960s, Gurdon et al. cloned Xenopus laevis for the first time [274,275]. Consequently, Gurdon was awarded the Nobel Prize in medicine in 2012, together with Yamanaka [276]. The cloning of mammals by nuclear transfer from somatic cells into enucleated unfertilized mammalian eggs over twenty years ago demonstrated that the cellular differentiation can be artificially turned back into a pluripotent state [277]. The next breakthrough was the identification of essential reprogramming factors by the Yamanaka group [278,279]. Initially, reprogramming was performed with 24 candidate transcription factor genes. Out of these, four critical genes were identified to be crucial for iPSC generation: Sox2, Oct4, Klf4, and c-Myc [278]. Depending on the donor cell type, the set of reprogramming factors can vary since specific cell types might endogenously express some of the necessary factors. For example, c-Myc is not required for the reprogramming of fibroblasts [280].
Different delivery methods were developed for reprogramming of somatic cell types like fibroblasts, lymphocytes, keratinocytes, urine-derived, or intestinal cells into iPSCs (see Figure 2). Initially, iPSCs were generated using retroviral transduction [278,279,281]. The Moloney-based retroviral vector system used by the Yamanaka lab has the advantage of undergoing silencing in the iPSCs state but is restricted to dividing cell types. Therefore, lentiviruses were used to improve the transduction efficiency of dividing and non-dividing cell types. However, after lentiviral transduction, the expression of the reprogramming factors are poorly silenced [282,283], leading to difficult differentiation of these iPSCs [284]. Therefore, inducible systems were used, allowing for the silencing of the Yamanaka factors in iPSCs [284,285].
However, usage of integrating viral systems enhances the risk for insertional mutagenesis, limiting their application [286]. Furthermore, the transgene reactivation of c-Myc showed increased tumorigenicity in chimeric mice [280], limiting the usage of iPSCs for clinical approaches. To overcome these limitations, non-integrating delivery methods have been developed. Transient transfection of the PiggyBac transposon with a Cre-mediated excisable system was one of the first non-integrating methods (Figure 2). Minimized genome modification, in combination with silencing of the reprogramming factor expression in the iPSC state, are the main advantages of this system [287]. Another approach is the adenoviral transduction leading to an overexpression of the reprogramming factors in the host cells without genomic integration [288]. Transient transfection or electroporation with episomal plasmids encoding the reprogramming factors is an alternative method to produce virus-free iPSCs [289] (Figure 2). However, the efficiency of this delivery method is quite low [290]. More promising non-inserting delivery methods include the use of Sendai viruses [291], which are RNA viruses that do not enter the nucleus, thereby decreasing the risk of genomic insertion.
Reprogramming using miRNAs that are specifically expressed in embryonic pluripotent stem cells (ESCs) can enhance the reprogramming efficiency [292]. For example, the miR302/367 cluster is highly expressed in pluripotent cells, but not in differentiated cells, and its promoter is transcriptionally regulated by the reprogramming factors Oct4 and Sox2 [293]. This cluster is functionally involved in regulation of the cell cycle and maintenance of pluripotency. Overexpression of the miRNA cluster miR302/367 can promote the reprogramming of somatic cells [294]. In combination with the reprogramming factors, a higher efficiency can be achieved [292]. Although RNA-based reprogramming methods show higher efficiency compared to Sendai virus and episomal methods, the reliability is significantly lower [295]. Non-integrating delivery methods provide iPSCs that are more applicable for clinical disease modeling. Besides the integrating and non-integrating delivery systems, DNA-free approaches with transgene free reprogramming have been established. Small compounds or recombinant reprogramming factors were used (Figure 2) [296,297]. For example, the histone deacetylase inhibitor valproic acid improves the reprogramming efficiency [298,299]. The efficient synthesis of large amounts of purified native recombinant proteins and the permeabilization of the plasma membranes are crucial for this reprogramming method [300]. More recently, the CRISPR-dCas9-based synergistic activation mediator (SAM) system has been developed and applied for reprogramming [301,302]. This system is based on a fusion protein of the enzymatic inactive form of Cas9 (dCas9) and a transcription activator domain forming an artificial transcription factor which, in combination with specific guide RNAs, is able to activate the transcription of endogenous genes with minimal off-target activity. Weltner et al. successfully used this system for the expression of different reprogramming factors to generate iPSCs [302].
In summary, different integrating and non-integrating approaches have been developed for reprogramming different cell types into iPSCs to improve the efficiency and to reduce the risk of further genomic alterations (see Figure 2).

5. Genetic Modification of Induced Pluripotent Stem Cell Lines

Besides the generation of human iPSCs from the primary cells of mutation carriers by direct reprogramming [278,281], specific genetic mutations can also be inserted using genome editing techniques like clustered regularly interspaced short palindromic repeats associated protein 9 (CRISPR-Cas9) [303], CPF1 [304], or transcription activator-like effector nucleases (TALENs) [305,306]. In addition to genome editing approaches, iPSCs or the differentiated cardiomyocytes can be genetically modified by overexpressing specific mutant proteins [307,308] or by decreasing the expression of specific mutant proteins, e.g., by RNA interference [309].
Using patient-derived iPSCs, it is sometimes challenging to correlate directly functional effects in vitro with the specific genetic variants because the genetic and epigenetic background of the cells is largely unknown [310]. In contrast to patient-derived iPSCs, which carry the sum of all genetic sequence variants of the affected patients, genome edited iPSC lines carry specifically inserted mutations. Therefore, the effects of particular mutations can be directly compared with their corresponding isogenic wild-type controls in genome-edited iPSCs.
Genome editing techniques like CRISPR-Cas9 are based on endonuclease activity, which insert double-strand breaks (DSBs) into the DNA double helix at specific sites. Different endogenous cellular repair mechanisms like non-homologous end joining (NHEJ) or homology directed repair (HDR) are used for the repair of these DSBs. However, NHEJ is an imprecise process, which might lead to the insertion, deletion, or substitution of nucleotides [311]. Indel variants frequently cause frameshifts, and consequently, premature termination codons (PTCs). PTCs are recognized by nonsense mediated RNA decay (NMD) degrading the mutant mRNA. Therefore, DSBs can be efficiently used to generate knock-out models. In contrast, HDR uses DNA template molecules for the specific repair of the DSBs. In combination with suitable donor molecules, e.g., single-stranded oligonucleotides or double-stranded DNA templates like PCR products or plasmids, HDR can be used to insert specific point mutations [312], small peptide-encoding tags [313], or even larger fluorescence proteins at specific positions [314,315,316]. Unfortunately, the ratio of HDR to NHEJ is low, limiting the efficiency of knock-in strategies [317]. Therefore, different approaches for inhibiting NHEJ or promoting HDR have been developed (for reviews, see References [317,318,319]). The delivery of donor template molecules in close proximity to the DSBs by coupling Cas9 with the donor molecule might be a promising strategy [320,321,322]. An alternative are dCas9-related base pair editors [323,324,325], which can be used to exchange relevant nucleotides at specific positions.

6. Differentiation of Human Induced Pluripotent Stem Cells into Cardiomyocytes

The human adult heart is a post-mitotic organ with a very limited capacity for regeneration [326]. Beside the murine, atrial cardiomyocytes-related HL-1 cell line [327], no further contracting human cardiomyocytes cell lines are therefore currently available. Because of ethical and technical issues, the isolation of primary human cardiomyocytes from human surgical material and their long-time culture is in most cases impossible. Primary cardiomyocytes isolated from rodent hearts have characteristic differences like a different electrophysiology in comparison to the human ones. Therefore, cardiomyocytes derived from human ESCs or iPSCs are the predominant human cell resource [328,329].
Originally, Zhang et al. described the differentiation of cardiomyocytes from human iPSCs [330]. Comparable to ESCs, human iPSCs form embryonic bodies in suspension that can be further differentiated into cardiomyocytes [330,331,332,333,334]. However, the efficiency of this process was limited. In addition, monolayers of iPSC-derived cardiomyocytes can be generated [335,336]. In vivo, cardiogenesis is a complex cellular and molecular process where different transcription factors, growth factors, and miRNAs are time dependently expressed and regulated [337,338,339,340,341]. Driven by discoveries from development biology, it has been recognized that different recombinant growth factors, e.g., BMP4, can also be used to increase the efficiency of in vitro differentiation into cardiomyocytes [342,343,344]. In addition, modulation of the Wnt pathway by small molecules, e.g., CHIR99021 and IWP2, efficiently increases the differentiation into cardiomyocytes about 90% [344,345]. Furthermore, metabolic selection by glucose depletion, in combination with lactate supplementation, can be applied for further accumulation of cardiomyocytes [346,347]. Recently, Zhao et al. developed a method for the differentiation and generation of heteropolar cardiac tissue with atrial and ventricular ends [348]. Talkhabi et al. has previously reviewed the differentiation of iPSCs into cardiomyocytes in detail [349].

7. Methods for the Functional Analysis of Cardiomyocytes Derived from Induced Pluripotent Stem Cells

Besides general histochemical or molecular methods, e.g., RNA-Seq or proteomics, specific techniques for the functional in vitro analysis of the electrophysiological and contractile properties of iPSC-derived cardiomyocytes are frequently used. Patch clamping and multiple electron arrays (MEAs) are frequently used for the electrophysiological analysis of iPSC-derived cardiomyocyte monolayers [350,351]. The application of Ca2+ specific fluorescence dyes, e.g., Indo1 or Fura-2, allows for the microscopic analysis of Ca2+ transients [352,353,354]. Additionally, voltage-sensitive fluorescence dyes like di-4-ANEPPS can be used for the analysis of the electrophysiological properties [355]. For the analysis of the contractile properties of iPSC-derived cardiomyocytes, microscopic techniques like traction force measurements have also been used [356]. Atomic force microscopy can also be applied for measuring the contraction forces of iPSC-derived cardiomyocytes [357,358]. Feaster and coworkers developed a method to culture iPSC-derived cardiomyocytes on Matrigel mattresses, allowing for the contractility measurement by cell shortening [359].

8. Overview about Existing iPSC Lines Carrying Cardiomyopathy Associated Mutations

In 2010, Carvajal-Vergara and co-workers published a landmark paper about the generation of an iPSC line carrying the heterozygous mutation PTPN11-p.T468M [360]. Mutations in PTPN11 cause the Leopard syndrome [361,362], which is frequently associated with severe HCM [363]. Interestingly, these iPSC-derived cardiomyocytes were larger and presented an abnormal, nuclear localization of NFATc4 [360]. Members of the NFAT family are involved in the calcineurin-NFAT signaling regulating hypertrophy [364]. Since this original report, about 70 different iPSC lines carrying cardiomyopathy-associated mutations in several different genes have been generated (Table 2). The majority of these mutant iPSC lines have been used for phenotypic modeling of genetic cardiomyopathies using electrophysiological and/or contraction measurements (Table 2). Besides modeling genetic cardiomyopathies, iPSC-derived cardiomyocytes were also used for the modeling of non-genetic causes of cardiomyopathies, e.g., doxorubicin cardiotoxicity [263,365], hypoxia [366], peripartum [367], or diabetic cardiomyopathy [368,369,370,371], or even infection with Trypanosoma cruzi [372] or with coxsackievirus B3 [373].
In the beginning, iPSC lines generated from healthy probands were frequently used as controls for experiments. However, because different iPSC lines have a variable genetic background, this approach has limitations. Since the development of efficient genome editing technologies like CRISPR-Cas9 or TALENs [303], it is common to generate isogenic control lines [374]. Interestingly, the reverse approach by inserting specific mutations in iPSCs from healthy control persons is also sometimes used [375]. In some cases, the rationale of these studies is the functional characterization of specific cardiomyopathy-associated mutations, which might contribute to a pathogenicity classification. In addition, iPSC-derived cardiomyocytes were used for the development of therapeutic strategies, e.g., genome editing. An interesting application of iPSC-derived cardiomyocytes is the testing of specific gene therapeutic concepts [376]. For example, Gramlich et al. applied antisense-mediated exon skipping in iPSC-derived cardiomyocytes with a truncating TTN (TTNtv) mutation for restoring the expression of titin [377]. However, at present, it appears that some of the TTNtv do not lead to premature translation termination in failing human hearts [378]. Thus, iPSCs might therefore be useful in future to check and modulate possible read-throughs of TTNtv mutations as well. Similarly, Kyrychenko et al. used CRISPR-Cas9 to delete whole exons within the DMD gene to correct the reading frame [379]. Of note, this strategy restores contractility in the iPSC-derived cardiomyocytes [379]. Hopefully, the combination of iPSC-derived cardiomyocytes with adequate modern genetic engineering tools will contribute in future to the development of therapeutic options in the context of personalized medicine.

9. Limitations of Human Induced Pluripotent Stem-Cell-Derived Cardiomyocytes

Besides cardiomyocytes, the human adult heart consists of several different cell types like fibroblasts, endothelial cells, leukocytes, pericytes, and smooth muscle cells. It has been estimated that the proportion of cardiomyocytes in myocardial tissue is around 25–35%, indicating that the majority of the cardiac cells are non-cardiomyocytes [460]. However, the molecular and cellular interactions and interferences between the different cardiac cell types are poorly understood. In particular, under pathological conditions like inflammation or fibrosis, the cellular composition of the heart of cardiomyopathy patients can vary and might change over time. Therefore, it is in general challenging to model the complex cellular and molecular networks using iPSC-derived cardiomyocytes in vitro, although the artificial generation of cardiac tissue has been impressively improved during the last few years [461,462,463,464,465]. Besides these general limitations, iPSCs and iPSC-derived cardiomyocytes have some specific limitations, which are outlined in the following paragraphs.

9.1. Genomic Instability

Genomic instability of iPSCs can be a fundamental problem limiting the clinical application of iPSC-derived cells because of safety concerns [466]. Mayshar et al. showed that a significant portion of iPSC and ESC lines carry full or partial chromosomal aberrations [467]. However, even for in vitro analysis, genomic instability could be an important issue, especially in the context of modeling genetic diseases like cardiomyopathies. Therefore, novel iPSC lines should be genetically characterized in general. Karyotype analysis using Giemsa staining or comparative genomic hybridization arrays can be used to detect larger chromosomal abnormalities, while next generation sequencing assays can be applied for genetic analysis at the single nucleotide level.
Three different mechanisms contribute to the mutagenesis in iPSCs: besides the existence of genetic variants in the parental somatic donor cells, mutations can be introduced during reprogramming procedure or during the long-time culture of iPSCs [468]. Of note, mutations might accumulate in iPSCs over the culturing time [469]. Therefore, it is advisable to use early passages and to repeat analyses for genetic stability from time to time.

9.2. Heterogeneity of iPSC-Derived Cardiomyocytes

Although cardiac differentiation protocols for iPSCs have been improved significantly over recent years [345,470], it should be kept in mind that iPSC-derived cardiomyocytes are still a heterogeneous cell population. Especially for bulk down-stream applications like proteomics, genomics, or metabolomics, this might have a significant impact.

9.3. Cellular, Molecular, and Functional Differences of Adult Ventricular Cardiomyocytes and iPSC-Derived Cardiomyocytes

Even though human iPSC-derived cardiomyocytes are contractile cell types, there are important cellular, molecular, and functional differences compared to adult cardiomyocytes. The most obvious differences are the size and shape of iPSC-derived cardiomyocytes. Adult ventricular cardiomyocytes have a typical rod-like shape and are relatively large cells with lengths of about 100 µm and diameters of 10–25 µm [471]. In contrast, iPSC-derived cardiomyocytes are much smaller [472] and are morphologically heterogeneous. The geometry of iPSC-derived cardiomyocytes ranges from round to rectangular or polygonal shapes [473,474]. In adult ventricular cardiomyocytes, the sarcomeric structure is highly organized and the Z-bands are in parallel with the intercalated disc. On the contrary, iPSC-derived cardiomyocytes have a more irregular and amorphous sarcomeric organization with diverse orientations [462,475]. In human myocardial tissue, the closed-ends of the plasma membranes connect the cardiomyocytes longitudinally and these ends of the cardiomyocytes “cylinders” are called intercalated discs. Multi-protein complexes mediate the cell–cell interactions at the intercalated discs and are subdivided into desmosomes, adherens, and gap junctions [476]. Although desmosomes and adherens junctions are also formed in iPSC-derived cardiomyocytes [472,477], the cellular distribution of these cell–cell junctions are not conserved [478,479]. Another important difference is the number of nuclei. Whereas a significant number of the human cardiomyocytes in vivo are binuclear cells [480], iPSC-derived cardiomyocytes are mononuclear cells [481]. In addition, there are significant differences in contraction and electrical properties of iPSC-derived cardiomyocytes in comparison to adult ones [474]. In summary, the structural and functional properties of iPSC-derived cardiomyocytes are more similar to fetal cardiomyocytes than to adult cardiomyocytes [482]. To overcome these limitations, different natural engineering approaches were established to drive cardiomyocytes maturation. One method is to stimulate the cardiomyocytes with electrical or mechanical impulses [483]. The composition of the extracellular matrix can also affect the interaction of the CMs, therefore influencing the cellular behavior [484,485]. Another promising approach is the co-culture of iPSC-derived cardiomyocytes with non-cardiomyocytes, enabling a more likely cardiac environment with different cellular interactions [486]. Physical, chemical, electrical, and genetic factors are being tested as stimuli for further maturation [487]. However, maturation of iPSC-derived cardiomyocytes is incompletely understood at the molecular level and more studies are needed in future.

10. Testing of Gene Therapies Using iPSC-Derived Cardiomyocytes as in Vitro Models

An interesting research topic is the development of personalized therapeutic strategies for genetic cardiomyopathies in vitro. Beyond the opportunities that reprogramming technologies offer for therapeutic myocardial regeneration, iPSC-derived cardiomyocytes are a promising platform to develop and test different gene therapies for genetic, non-ischemic cardiomyopathies. In general, the pathomechanisms of inherited cardiomyopathies can be classified into loss of function (LOF) or gain of function (GOF) mechanisms. LOF can be caused by (haplo)insufficiency or by the expression of non-functional proteins. For example, several HCM-associated MYBPC3 mutations cause haploinsufficiency [415,488]. GOF is caused by mutant and toxic proteins such as those shown for several DES missense mutations [489,490].
Genome editing using CRISPR-Cas9 or TALENs has been applied to repair different mutations in iPSC-derived cardiomyocytes. After the insertion of DSBs, iPSCs repair these DSBs using NHEJ or HDR. Template molecules like oligonucleotides, plasmids, PCR products, or even the second chromosome might be used for HDR. Recently, Ma et al. even applied CRISPR-Cas9 for the repair of a pathogenic MYBPC3 mutation in human pre-implanted embryos [491]. However, because the efficiency of HDR is low, the direct repair of mutations in iPSCs via genome editing is challenging. Therefore, single iPSC clones were frequently generated in vitro and the direct translational transfer of this method is consequently limited. A second therapeutic strategy is exon skipping [492]. Exon skipping corrects the open reading frame (ORF) of an affected gene via skipping of the mutant or multiple exons and restores the expression of the truncated, but still functional, protein. For this approach, specific antisense oligonucleotides binding to the mutant exons can be used [493]. Besides its application in iPSC-derived cardiomyocytes carrying mutations in DMD [494] or TTN [377], antisense-mediated exon skipping was also directly applied in human patients with Duchenne’s muscular dystrophy [495]. Recently, Eric Olson’s group applied CRISPR-CPF1 or -Cas9-mediated genome editing for exon skipping in iPSC-derived cardiomyocytes [379,496,497]. Prondzynski et al. applied trans-splicing and total gene replacement for the artificial increased expression of MYBPC3 in iPSC-derived cardiomyocytes carrying a heterozygous frameshift mutation in MYBPC3 [419]. The authors used adeno-associated viruses (serotype 2/9, AAV2/9) for the transduction of iPSC-derived cardiomyocytes with 5′- and 3′-pre-trans-splicing molecules and the total cDNA of MYBPC3. However, the efficiency of the trans-splicing approach was low. In contrast, the total gene replacement strategy increased the MYBPC3 expression to over 80% in comparison with wild-type controls and was able to prevent cellular hypertrophy [419].
The combination of the iPSC-derived cardiomyocytes platform with gene therapy tools is a promising therapeutic approach enabling pre-clinical demonstration of proof-of-principle for inherited cardiomyopathies.

11. Summary

Human iPSC-derived cardiomyocytes represent the only available human cellular model for the direct functional analysis of specific genetic cardiomyopathies and might therefore overcome the limitation of species differences. Impressive progress in the reprogramming and differentiation procedure during the last decade allows, in combination with novel genome editing techniques like CRISPR-Cas9, for the development of defined/patient specific cardiomyocyte models including generation of their isogenic control lines. In summary, iPSC-derived cardiomyocytes have been used for: (a) the characterization of genetic variants of unknown significance, which might be helpful for genetic counseling [375]; (b) analyses of the molecular pathomechanisms [415]; and (c) the development of specific therapies [377,497].
However, the cellular and molecular crosstalk between inflammatory cells, fibroblasts, myoblasts, and cardiomyocytes is difficult to model using iPSC-derived cardiomyocytes. Therefore, in our opinion, iPSC-derived cardiomyocytes should also be combined with animal models or with ex vivo investigations of explanted human myocardial tissue whenever possible to overcome the specific limitations of iPSC-derived cardiomyocytes.
Interestingly, for some genes like DMD, PKP2, MYBPC3, or MYH7, several different iPSC lines have been generated. In contrast, for rare cardiomyopathy genes, e.g., TMEM43, no iPSC lines have been developed yet. The genetic analysis in the past few decades has revealed a high heterogeneity of inherited, non-ischemic cardiomyopathies. In our view, it is therefore important to generate further novel iPSC lines also carrying mutations in rare cardiomyopathy genes to compare the molecular differences and commonalities leading to non-ischemic cardiomyopathies. Hopefully, iPSC-derived cardiomyocytes will contribute to unravelling the pathomechanisms of genetic cardiomyopathies and will help in efficient drug development in future.
Gene names follow the official guidelines of the HUGO Gene Nomenclature Committee (HGNC, https://www.genenames.org/) [498].

Author Contributions

Writing and original draft preparation—A.B., H.E., and S.R; figure preparation—A.B.; review and editing—M.A.D., A.G., J.G., and H.M.

Funding

A.B., J.G., and H.M. are thankful for financial support of the German Foundation for Heart Research (DSHF, F07/17) and by the University of Bielefeld (Forschungsfonds Medizin in der Region OWL). H.E. received a Kaltenbach scholarship from the German Heart Foundation. H.M. received a grant from the German Research Foundation (DFG, MI-1146/2-1).

Conflicts of Interest

The authors declare no conflict of interest.

Abbreviations

ACMGAmerican College of Medical Genetics and Genomics Institute
ACMArrhythmogenic Cardiomyopathy
CMCardiomyopathy
DCMDilated Cardiomyopathy
ESCEmbryonic Stem Cell
HCMHypertrophic Cardiomyopathy
iPSCInduced Pluripotent Stem Cell
HTxHeart Transplantation
NCCMNon-Compaction Cardiomyopathy
MPMyopathy
NMDNonsense Mediated RNA Decay
RCMRestrictive Cardiomyopathy

References

  1. Green, E.D.; Watson, J.D.; Collins, F.S. Human genome project: Twenty-five years of big biology. Nat. News 2015, 526, 29–31. [Google Scholar] [CrossRef] [PubMed]
  2. Brodehl, A.; Ebbinghaus, H.; Gaertner-Rommel, A.; Stanasiuk, C.; Klauke, B.; Milting, H. Functional analysis of DES-p.L398P and RBM20-p.R636C. Genet. Med. 2019, 21, 1246–1247. [Google Scholar] [CrossRef] [PubMed]
  3. Richards, S.; Aziz, N.; Bale, S.; Bick, D.; Das, S.; Gastier-Foster, J.; Grody, W.W.; Hegde, M.; Lyon, E.; Spector, E.; et al. Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genet. and Genomics and the Association for Molecular Pathology. Genet. Med. 2015, 17, 405–424. [Google Scholar] [CrossRef] [PubMed]
  4. Maron, B.J.; Towbin, J.A.; Thiene, G.; Antzelevitch, C.; Corrado, D.; Arnett, D.; Moss, A.J.; Seidman, C.E.; Young, J.B.; American Heart, A.; et al. Contemporary definitions and classification of the cardiomyopathies: An american heart association scientific statement from the council on clinical cardiology, heart failure and transplantation committee; Quality of care and outcomes research and functional genomics and translational biology interdisciplinary working groups; and council on epidemiology and prevention. Circulation 2006, 113, 1807–1816. [Google Scholar] [PubMed]
  5. Alraies, M.C.; Eckman, P. Adult heart transplant: Indications and outcomes. J. Thorac. Dis. 2014, 6, 1120–1128. [Google Scholar] [PubMed]
  6. Minoche, A.E.; Horvat, C.; Johnson, R.; Gayevskiy, V.; Morton, S.U.; Drew, A.P.; Woo, K.; Statham, A.L.; Lundie, B.; Bagnall, R.D.; et al. Genome sequencing as a first-line genetic test in familial dilated cardiomyopathy. Genet. Med. 2019, 21, 650–662. [Google Scholar] [CrossRef] [PubMed]
  7. Kolokotronis, K.; Kuhnisch, J.; Klopocki, E.; Dartsch, J.; Rost, S.; Huculak, C.; Mearini, G.; Stork, S.; Carrier, L.; Klaassen, S.; et al. Biallelic mutation in MYH7 and MYBPC3 leads to severe cardiomyopathy with left ventricular noncompaction phenotype. Hum. Mutat. 2019, 40, 1101–1114. [Google Scholar] [CrossRef] [PubMed]
  8. Hershberger, R.E.; Givertz, M.M.; Ho, C.Y.; Judge, D.P.; Kantor, P.F.; McBride, K.L.; Morales, A.; Taylor, M.R.G.; Vatta, M.; Ware, S.M.; et al. Genetic evaluation of cardiomyopathy: A clinical practice resource of the American College of Medical Genet. and Genomics (ACMG). Genet. Med. 2018, 20, 899–909. [Google Scholar] [CrossRef]
  9. Merner, N.D.; Hodgkinson, K.A.; Haywood, A.F.; Connors, S.; French, V.M.; Drenckhahn, J.D.; Kupprion, C.; Ramadanova, K.; Thierfelder, L.; McKenna, W.; et al. Arrhythmogenic right ventricular cardiomyopathy type 5 is a fully penetrant, lethal arrhythmic disorder caused by a missense mutation in the TMEM43 gene. Am. J. Hum. Genet. 2008, 82, 809–821. [Google Scholar] [CrossRef] [PubMed]
  10. Milting, H.; Klauke, B.; Christensen, A.H.; Musebeck, J.; Walhorn, V.; Grannemann, S.; Munnich, T.; Saric, T.; Rasmussen, T.B.; Jensen, H.K.; et al. The TMEM43 Newfoundland mutation p.S358L causing ARVC-5 was imported from Europe and increases the stiffness of the cell nucleus. Eur. Heart J. 2015, 36, 872–881. [Google Scholar] [CrossRef]
  11. Christensen, A.H.; Andersen, C.B.; Tybjaerg-Hansen, A.; Haunso, S.; Svendsen, J.H. Mutation analysis and evaluation of the cardiac localization of TMEM43 in arrhythmogenic right ventricular cardiomyopathy. Clin. Genet. 2011, 80, 256–264. [Google Scholar] [CrossRef] [PubMed]
  12. Stroud, M.J.; Fang, X.; Zhang, J.; Guimaraes-Camboa, N.; Veevers, J.; Dalton, N.D.; Gu, Y.; Bradford, W.H.; Peterson, K.L.; Evans, S.M.; et al. Luma is not essential for murine cardiac development and function. Cardiovasc. Res. 2018, 114, 378–388. [Google Scholar] [CrossRef]
  13. Figulla, H.R.; Wiegand, V.; Kreuzer, H. Dilated cardiomyopathy. Dtsch. Med. Wochenschr. 1989, 114, 66–70. [Google Scholar] [CrossRef] [PubMed]
  14. Seidman, C.E.; Seidman, J.G. Identifying sarcomere gene mutations in hypertrophic cardiomyopathy: A personal history. Circ. Res. 2011, 108, 743–750. [Google Scholar] [CrossRef] [PubMed]
  15. Muchtar, E.; Blauwet, L.A.; Gertz, M.A. Restrictive cardiomyopathy: Genetics, pathogenesis, clinical manifestations, diagnosis, and therapy. Circ. Res. 2017, 121, 819–837. [Google Scholar] [CrossRef]
  16. Shariati, J.; Schlosser, T.; Erbel, R. Noncompaction cardiomyopathy. Herz 2015, 40, 583–590. [Google Scholar] [CrossRef] [PubMed]
  17. Fazio, G.; Corrado, G.; Novo, G.; Zachara, E.; Rapezzi, C.; Sulafa, A.K.; Sutera, L.; D’Angelo, L.; Visconti, C.; Stollberger, C.; et al. Ventricular dysfunction and number of non compacted segments in non compaction: Non-independent predictors. Int. J. Cardiol. 2010, 141, 250–253. [Google Scholar] [CrossRef] [PubMed]
  18. Gandjbakhch, E.; Redheuil, A.; Pousset, F.; Charron, P.; Frank, R. Clinical diagnosis, imaging, and genetics of arrhythmogenic right ventricular cardiomyopathy/dysplasia: JACC state-of-the-art review. J. Am. Coll. Cardiol. 2018, 72, 784–804. [Google Scholar] [CrossRef]
  19. Basso, C.; Corrado, D.; Marcus, F.I.; Nava, A.; Thiene, G. Arrhythmogenic right ventricular cardiomyopathy. Lancet 2009, 373, 1289–1300. [Google Scholar] [CrossRef]
  20. Marcus, F.I.; Fontaine, G.H.; Guiraudon, G.; Frank, R.; Laurenceau, J.L.; Malergue, C.; Grosgogeat, Y. Right ventricular dysplasia: A report of 24 adult cases. Circulation 1982, 65, 384–398. [Google Scholar] [CrossRef]
  21. Corrado, D.; Basso, C.; Thiene, G.; McKenna, W.J.; Davies, M.J.; Fontaliran, F.; Nava, A.; Silvestri, F.; Blomstrom-Lundqvist, C.; Wlodarska, E.K.; et al. Spectrum of clinicopathologic manifestations of arrhythmogenic right ventricular cardiomyopathy/dysplasia: A multicenter study. J. Am. Coll. Cardiol. 1997, 30, 1512–1520. [Google Scholar] [CrossRef]
  22. Geisterfer-Lowrance, A.A.; Kass, S.; Tanigawa, G.; Vosberg, H.P.; McKenna, W.; Seidman, C.E.; Seidman, J.G. A molecular basis for familial hypertrophic cardiomyopathy: A beta cardiac myosin heavy chain gene missense mutation. Cell 1990, 62, 999–1006. [Google Scholar] [CrossRef]
  23. Li, D.; Tapscoft, T.; Gonzalez, O.; Burch, P.E.; Quinones, M.A.; Zoghbi, W.A.; Hill, R.; Bachinski, L.L.; Mann, D.L.; Roberts, R. Desmin mutation responsible for idiopathic dilated cardiomyopathy. Circulation 1999, 100, 461–464. [Google Scholar] [CrossRef] [PubMed]
  24. Brodehl, A.; Dieding, M.; Biere, N.; Unger, A.; Klauke, B.; Walhorn, V.; Gummert, J.; Schulz, U.; Linke, W.A.; Gerull, B.; et al. Functional characterization of the novel DES mutation p.L136P associated with dilated cardiomyopathy reveals a dominant filament assembly defect. J. Mol. Cell. Cardiol. 2016, 91, 207–214. [Google Scholar] [CrossRef] [PubMed]
  25. Harada, H.; Hayashi, T.; Nishi, H.; Kusaba, K.; Koga, Y.; Koga, Y.; Nonaka, I.; Kimura, A. Phenotypic expression of a novel desmin gene mutation: Hypertrophic cardiomyopathy followed by systemic myopathy. J. Hum. Genet. 2018, 63, 249–254. [Google Scholar] [CrossRef] [PubMed]
  26. Klauke, B.; Kossmann, S.; Gaertner, A.; Brand, K.; Stork, I.; Brodehl, A.; Dieding, M.; Walhorn, V.; Anselmetti, D.; Gerdes, D.; et al. De novo desmin-mutation N116S is associated with arrhythmogenic right ventricular cardiomyopathy. Hum. Mol. Genet. 2010, 19, 4595–4607. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  27. Bermudez-Jimenez, F.J.; Carriel, V.; Brodehl, A.; Alaminos, M.; Campos, A.; Schirmer, I.; Milting, H.; Abril, B.A.; Alvarez, M.; Lopez-Fernandez, S.; et al. Novel desmin mutation p.Glu401Asp impairs filament formation, disrupts cell membrane integrity, and causes severe arrhythmogenic left ventricular cardiomyopathy/dysplasia. Circulation 2018, 137, 1595–1610. [Google Scholar] [CrossRef] [PubMed]
  28. Pruszczyk, P.; Kostera-Pruszczyk, A.; Shatunov, A.; Goudeau, B.; Draminska, A.; Takeda, K.; Sambuughin, N.; Vicart, P.; Strelkov, S.V.; Goldfarb, L.G.; et al. Restrictive cardiomyopathy with atrioventricular conduction block resulting from a desmin mutation. Int. J. Cardiol. 2007, 117, 244–253. [Google Scholar] [CrossRef] [PubMed]
  29. Fan, P.; Lu, C.X.; Dong, X.Q.; Zhu, D.; Yang, K.Q.; Liu, K.Q.; Zhang, D.; Zhang, Y.; Meng, X.; Tan, H.Q.; et al. A novel phenotype with splicing mutation identified in a Chinese family with desminopathy. Chin. Med. J. 2019, 132, 127–134. [Google Scholar] [CrossRef] [PubMed]
  30. Marakhonov, A.V.; Brodehl, A.; Myasnikov, R.P.; Sparber, P.A.; Kiseleva, A.V.; Kulikova, O.V.; Meshkov, A.N.; Zharikova, A.A.; Koretsky, S.N.; Kharlap, M.S.; et al. Non-compaction cardiomyopathy is caused by a novel in-frame desmin (DES) deletion mutation within the 1A coiled-coil rod segment leading to a severe filament assembly defect. Hum. Mutat. 2019. [Google Scholar] [CrossRef] [PubMed]
  31. Brodehl, A.; Gaertner-Rommel, A.; Milting, H. Molecular insights into cardiomyopathies associated with desmin (DES) mutations. Biophys. Rev. 2018, 10, 983–1006. [Google Scholar] [CrossRef] [PubMed]
  32. Gerull, B.; Gramlich, M.; Atherton, J.; McNabb, M.; Trombitas, K.; Sasse-Klaassen, S.; Seidman, J.G.; Seidman, C.; Granzier, H.; Labeit, S.; et al. Mutations of TTN, encoding the giant muscle filament titin, cause familial dilated cardiomyopathy. Nat. Genet. 2002, 30, 201–204. [Google Scholar] [CrossRef] [PubMed]
  33. Taylor, M.; Graw, S.; Sinagra, G.; Barnes, C.; Slavov, D.; Brun, F.; Pinamonti, B.; Salcedo, E.E.; Sauer, W.; Pyxaras, S.; et al. Genetic variation in titin in arrhythmogenic right ventricular cardiomyopathy-overlap syndromes. Circulation 2011, 124, 876–885. [Google Scholar] [CrossRef] [PubMed]
  34. Peled, Y.; Gramlich, M.; Yoskovitz, G.; Feinberg, M.S.; Afek, A.; Polak-Charcon, S.; Pras, E.; Sela, B.A.; Konen, E.; Weissbrod, O.; et al. Titin mutation in familial restrictive cardiomyopathy. Int. J. Cardiol. 2014, 171, 24–30. [Google Scholar] [CrossRef] [PubMed]
  35. Haas, J.; Frese, K.S.; Peil, B.; Kloos, W.; Keller, A.; Nietsch, R.; Feng, Z.; Muller, S.; Kayvanpour, E.; Vogel, B.; et al. Atlas of the clinical genetics of human dilated cardiomyopathy. Eur. Heart J. 2015, 36, 1123–1135. [Google Scholar] [CrossRef] [PubMed]
  36. Pugh, T.J.; Kelly, M.A.; Gowrisankar, S.; Hynes, E.; Seidman, M.A.; Baxter, S.M.; Bowser, M.; Harrison, B.; Aaron, D.; Mahanta, L.M.; et al. The landscape of genetic variation in dilated cardiomyopathy as surveyed by clinical DNA sequencing. Genet. Med. 2014, 16, 601–608. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  37. Klauke, B.; Gaertner-Rommel, A.; Schulz, U.; Kassner, A.; Zu Knyphausen, E.; Laser, T.; Kececioglu, D.; Paluszkiewicz, L.; Blanz, U.; Sandica, E.; et al. High proportion of genetic cases in patients with advanced cardiomyopathy including a novel homozygous Plakophilin 2-gene mutation. PLoS ONE 2017, 12, e0189489. [Google Scholar] [CrossRef] [PubMed]
  38. Thierfelder, L.; Watkins, H.; MacRae, C.; Lamas, R.; McKenna, W.; Vosberg, H.P.; Seidman, J.G.; Seidman, C.E. Alpha-tropomyosin and cardiac troponin T mutations cause familial hypertrophic cardiomyopathy: A disease of the sarcomere. Cell 1994, 77, 701–712. [Google Scholar] [CrossRef]
  39. Landstrom, A.P.; Parvatiyar, M.S.; Pinto, J.R.; Marquardt, M.L.; Bos, J.M.; Tester, D.J.; Ommen, S.R.; Potter, J.D.; Ackerman, M.J. Molecular and functional characterization of novel hypertrophic cardiomyopathy susceptibility mutations in TNNC1-encoded troponin C. J. Mol. Cell. Cardiol. 2008, 45, 281–288. [Google Scholar] [CrossRef]
  40. Kimura, A.; Harada, H.; Park, J.E.; Nishi, H.; Satoh, M.; Takahashi, M.; Hiroi, S.; Sasaoka, T.; Ohbuchi, N.; Nakamura, T.; et al. Mutations in the cardiac troponin I gene associated with hypertrophic cardiomyopathy. Nat. Genet. 1997, 16, 379–382. [Google Scholar] [CrossRef]
  41. Knoblauch, H.; Geier, C.; Adams, S.; Budde, B.; Rudolph, A.; Zacharias, U.; Schulz-Menger, J.; Spuler, A.; Yaou, R.B.; Nurnberg, P.; et al. Contractures and hypertrophic cardiomyopathy in a novel FHL1 mutation. Ann. Neurol. 2010, 67, 136–140. [Google Scholar] [CrossRef] [PubMed]
  42. Gaertner-Rommel, A.; Tiesmeier, J.; Jakob, T.; Strickmann, B.; Veit, G.; Bachmann-Mennenga, B.; Paluszkiewicz, L.; Klingel, K.; Schulz, U.; Laser, K.T.; et al. Molecular autopsy and family screening in a young case of sudden cardiac death reveals an unusually severe case of FHL1 related hypertrophic cardiomyopathy. Mol. Genet. Genom. Med. 2019, 7, e841. [Google Scholar] [CrossRef] [PubMed]
  43. Mogensen, J.; Klausen, I.C.; Pedersen, A.K.; Egeblad, H.; Bross, P.; Kruse, T.A.; Gregersen, N.; Hansen, P.S.; Baandrup, U.; Borglum, A.D. Alpha-cardiac actin is a novel disease gene in familial hypertrophic cardiomyopathy. J. Clin. Investig. 1999, 103, R39–R43. [Google Scholar] [CrossRef] [PubMed]
  44. Haywood, N.J.; Wolny, M.; Rogers, B.; Trinh, C.H.; Shuping, Y.; Edwards, T.A.; Peckham, M. Hypertrophic cardiomyopathy mutations in the calponin-homology domain of ACTN2 affect actin binding and cardiomyocyte Z-disc incorporation. Biochem. J. 2016, 473, 2485–2493. [Google Scholar] [CrossRef] [PubMed]
  45. Valdes-Mas, R.; Gutierrez-Fernandez, A.; Gomez, J.; Coto, E.; Astudillo, A.; Puente, D.A.; Reguero, J.R.; Alvarez, V.; Moris, C.; Leon, D.; et al. Mutations in filamin C cause a new form of familial hypertrophic cardiomyopathy. Nat. Commun. 2014, 5, 5326. [Google Scholar] [CrossRef] [PubMed]
  46. Chiu, C.; Tebo, M.; Ingles, J.; Yeates, L.; Arthur, J.W.; Lind, J.M.; Semsarian, C. Genetic screening of calcium regulation genes in familial hypertrophic cardiomyopathy. J. Mol. Cell. Cardiol. 2007, 43, 337–343. [Google Scholar] [CrossRef] [PubMed]
  47. Herman, D.S.; Lam, L.; Taylor, M.R.; Wang, L.; Teekakirikul, P.; Christodoulou, D.; Conner, L.; DePalma, S.R.; McDonough, B.; Sparks, E.; et al. Truncations of titin causing dilated cardiomyopathy. N. Engl. J. Med. 2012, 366, 619–628. [Google Scholar] [CrossRef] [PubMed]
  48. Daehmlow, S.; Erdmann, J.; Knueppel, T.; Gille, C.; Froemmel, C.; Hummel, M.; Hetzer, R.; Regitz-Zagrosek, V. Novel mutations in sarcomeric protein genes in dilated cardiomyopathy. Biochem. Biophys. Res. Commun. 2002, 298, 116–120. [Google Scholar] [CrossRef]
  49. Fatkin, D.; MacRae, C.; Sasaki, T.; Wolff, M.R.; Porcu, M.; Frenneaux, M.; Atherton, J.; Vidaillet, H.J., Jr.; Spudich, S.; De Girolami, U.; et al. Missense mutations in the rod domain of the lamin A/C gene as causes of dilated cardiomyopathy and conduction-system disease. N. Engl. J. Med. 1999, 341, 1715–1724. [Google Scholar] [CrossRef]
  50. McNair, W.P.; Ku, L.; Taylor, M.R.; Fain, P.R.; Dao, D.; Wolfel, E.; Mestroni, L.; Familial cardiomyopathy registry research, G. SCN5A mutation associated with dilated cardiomyopathy, conduction disorder, and arrhythmia. Circulation 2004, 110, 2163–2167. [Google Scholar] [CrossRef]
  51. Schonberger, J.; Wang, L.; Shin, J.T.; Kim, S.D.; Depreux, F.F.; Zhu, H.; Zon, L.; Pizard, A.; Kim, J.B.; Macrae, C.A.; et al. Mutation in the transcriptional coactivator EYA4 causes dilated cardiomyopathy and sensorineural hearing loss. Nat. Genet. 2005, 37, 418–422. [Google Scholar] [CrossRef] [PubMed]
  52. Brauch, K.M.; Karst, M.L.; Herron, K.J.; de Andrade, M.; Pellikka, P.A.; Rodeheffer, R.J.; Michels, V.V.; Olson, T.M. Mutations in ribonucleic acid binding protein gene cause familial dilated cardiomyopathy. J. Am. Coll. Cardiol. 2009, 54, 930–941. [Google Scholar] [CrossRef] [PubMed]
  53. Hey, T.M.; Rasmussen, T.B.; Madsen, T.; Aagaard, M.M.; Harbo, M.; Molgaard, H.; Moller, J.E.; Eiskjaer, H.; Mogensen, J. Pathogenic RBM20-variants are associated with a severe disease expression in male patients with dilated cardiomyopathy. Circ. Heart Fail. 2019, 12, e005700. [Google Scholar] [CrossRef] [PubMed]
  54. Nugent, A.W.; Daubeney, P.E.; Chondros, P.; Carlin, J.B.; Cheung, M.; Wilkinson, L.C.; Davis, A.M.; Kahler, S.G.; Chow, C.W.; Wilkinson, J.L.; et al. The epidemiology of childhood cardiomyopathy in Australia. N. Engl. J. Med. 2003, 348, 1639–1646. [Google Scholar] [CrossRef] [PubMed]
  55. Jefferies, J.L.; Wilkinson, J.D.; Sleeper, L.A.; Colan, S.D.; Lu, M.; Pahl, E.; Kantor, P.F.; Everitt, M.D.; Webber, S.A.; Kaufman, B.D.; et al. Pediatric cardiomyopathy registry, I. Cardiomyopathy phenotypes and outcomes for children with left ventricular myocardial noncompaction: Results from the pediatric cardiomyopathy registry. J. Card. Fail. 2015, 21, 877–884. [Google Scholar] [CrossRef] [PubMed]
  56. Marziliano, N.; Mannarino, S.; Nespoli, L.; Diegoli, M.; Pasotti, M.; Malattia, C.; Grasso, M.; Pilotto, A.; Porcu, E.; Raisaro, A.; et al. Barth syndrome associated with compound hemizygosity and heterozygosity of the TAZ and LDB3 genes. Am. J. Med. Genet. Part A 2007, 143A, 907–915. [Google Scholar] [CrossRef] [PubMed]
  57. Probst, S.; Oechslin, E.; Schuler, P.; Greutmann, M.; Boye, P.; Knirsch, W.; Berger, F.; Thierfelder, L.; Jenni, R.; Klaassen, S. Sarcomere gene mutations in isolated left ventricular noncompaction cardiomyopathy do not predict clinical phenotype. Circ. Cardiovasc. Genet. 2011, 4, 367–374. [Google Scholar] [CrossRef] [PubMed]
  58. McKoy, G.; Protonotarios, N.; Crosby, A.; Tsatsopoulou, A.; Anastasakis, A.; Coonar, A.; Norman, M.; Baboonian, C.; Jeffery, S.; McKenna, W.J. Identification of a deletion in plakoglobin in arrhythmogenic right ventricular cardiomyopathy with palmoplantar keratoderma and woolly hair (Naxos disease). Lancet 2000, 355, 2119–2124. [Google Scholar] [CrossRef]
  59. Gerull, B.; Heuser, A.; Wichter, T.; Paul, M.; Basson, C.T.; McDermott, D.A.; Lerman, B.B.; Markowitz, S.M.; Ellinor, P.T.; MacRae, C.A.; et al. Mutations in the desmosomal protein plakophilin-2 are common in arrhythmogenic right ventricular cardiomyopathy. Nat. Genet. 2004, 36, 1162–1164. [Google Scholar] [CrossRef]
  60. Patel, D.M.; Green, K.J. Desmosomes in the heart: A review of clinical and mechanistic analyses. Cell Commun. Adhes. 2014, 21, 109–128. [Google Scholar] [CrossRef]
  61. Xu, T.; Yang, Z.; Vatta, M.; Rampazzo, A.; Beffagna, G.; Pilichou, K.; Scherer, S.E.; Saffitz, J.; Kravitz, J.; Zareba, W.; et al. Multidisciplinary study of right ventricular dysplasia, I. Compound and digenic heterozygosity contributes to arrhythmogenic right ventricular cardiomyopathy. J. Am. Coll. Cardiol. 2010, 55, 587–597. [Google Scholar] [CrossRef] [PubMed]
  62. Brodehl, A.; Hedde, P.N.; Dieding, M.; Fatima, A.; Walhorn, V.; Gayda, S.; Saric, T.; Klauke, B.; Gummert, J.; Anselmetti, D.; et al. Dual color photoactivation localization microscopy of cardiomyopathy-associated desmin mutants. J. Biol. Chem. 2012, 287, 16047–16057. [Google Scholar] [CrossRef] [PubMed]
  63. Quarta, G.; Syrris, P.; Ashworth, M.; Jenkins, S.; Zuborne Alapi, K.; Morgan, J.; Muir, A.; Pantazis, A.; McKenna, W.J.; Elliott, P.M. Mutations in the Lamin A/C gene mimic arrhythmogenic right ventricular cardiomyopathy. Eur. Heart J. 2012, 33, 1128–1136. [Google Scholar] [CrossRef] [PubMed]
  64. Abdelfatah, N.; Chen, R.; Duff, H.J.; Seifer, C.M.; Buffo, I.; Huculak, C.; Clarke, S.; Clegg, R.; Jassal, D.S.; Gordon, P.M.K.; et al. Characterization of a unique form of arrhythmic cardiomyopathy caused by recessive mutation in LEMD2. JACC Basic Transl. Sci. 2019, 4, 204–221. [Google Scholar] [CrossRef] [PubMed]
  65. Tiso, N.; Stephan, D.A.; Nava, A.; Bagattin, A.; Devaney, J.M.; Stanchi, F.; Larderet, G.; Brahmbhatt, B.; Brown, K.; Bauce, B.; et al. Identification of mutations in the cardiac ryanodine receptor gene in families affected with arrhythmogenic right ventricular cardiomyopathy type 2 (ARVD2). Hum. Mol. Genet. 2001, 10, 189–194. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  66. Milting, H.; Lukas, N.; Klauke, B.; Korfer, R.; Perrot, A.; Osterziel, K.J.; Vogt, J.; Peters, S.; Thieleczek, R.; Varsanyi, M. Composite polymorphisms in the ryanodine receptor 2 gene associated with arrhythmogenic right ventricular cardiomyopathy. Cardiovasc. Res. 2006, 71, 496–505. [Google Scholar] [CrossRef] [PubMed]
  67. Van der Zwaag, P.A.; van Rijsingen, I.A.; Asimaki, A.; Jongbloed, J.D.; van Veldhuisen, D.J.; Wiesfeld, A.C.; Cox, M.G.; van Lochem, L.T.; de Boer, R.A.; Hofstra, R.M.; et al. Phospholamban R14del mutation in patients diagnosed with dilated cardiomyopathy or arrhythmogenic right ventricular cardiomyopathy: Evidence supporting the concept of arrhythmogenic cardiomyopathy. Eur. J. Heart Fail. 2012, 14, 1199–1207. [Google Scholar] [CrossRef]
  68. Brodehl, A.; Rezazadeh, S.; Williams, T.; Munsie, N.M.; Liedtke, D.; Oh, T.; Ferrier, R.; Shen, Y.; Jones, S.J.M.; Stiegler, A.L.; et al. Mutations in ILK, encoding integrin-linked kinase, are associated with arrhythmogenic cardiomyopathy. Transl. Res. 2019, 208, 15–29. [Google Scholar] [CrossRef]
  69. Kostareva, A.; Kiselev, A.; Gudkova, A.; Frishman, G.; Ruepp, A.; Frishman, D.; Smolina, N.; Tarnovskaya, S.; Nilsson, D.; Zlotina, A.; et al. Genetic spectrum of idiopathic restrictive cardiomyopathy uncovered by next-generation sequencing. PLoS ONE 2016, 11, e0163362. [Google Scholar] [CrossRef]
  70. Gallego-Delgado, M.; Delgado, J.F.; Brossa-Loidi, V.; Palomo, J.; Marzoa-Rivas, R.; Perez-Villa, F.; Salazar-Mendiguchia, J.; Ruiz-Cano, M.J.; Gonzalez-Lopez, E.; Padron-Barthe, L.; et al. Idiopathic restrictive cardiomyopathy Is primarily a genetic disease. J. Am. Coll. Cardiol. 2016, 67, 3021–3023. [Google Scholar] [CrossRef]
  71. Mogensen, J.; Kubo, T.; Duque, M.; Uribe, W.; Shaw, A.; Murphy, R.; Gimeno, J.R.; Elliott, P.; McKenna, W.J. Idiopathic restrictive cardiomyopathy is part of the clinical expression of cardiac troponin I mutations. J. Clin. Investig. 2003, 111, 209–216. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  72. Brodehl, A.; Ferrier, R.A.; Hamilton, S.J.; Greenway, S.C.; Brundler, M.A.; Yu, W.; Gibson, W.T.; McKinnon, M.L.; McGillivray, B.; Alvarez, N.; et al. Mutations in FLNC are associated with familial restrictive cardiomyopathy. Hum. Mutat. 2016, 37, 269–279. [Google Scholar] [CrossRef] [PubMed]
  73. Tucker, N.R.; McLellan, M.A.; Hu, D.; Ye, J.; Parsons, V.A.; Mills, R.W.; Clauss, S.; Dolmatova, E.; Shea, M.A.; Milan, D.J.; et al. Novel mutation in FLNC (Filamin C) causes familial restrictive cardiomyopathy. Circ. Cardiovasc. Genet. 2017, 10, e001780. [Google Scholar] [CrossRef] [PubMed]
  74. Kiselev, A.; Vaz, R.; Knyazeva, A.; Khudiakov, A.; Tarnovskaya, S.; Liu, J.; Sergushichev, A.; Kazakov, S.; Frishman, D.; Smolina, N.; et al. De novo mutations in FLNC leading to early-onset restrictive cardiomyopathy and congenital myopathy. Hum. Mutat. 2018, 39, 1161–1172. [Google Scholar] [CrossRef] [PubMed]
  75. Schubert, J.; Tariq, M.; Geddes, G.; Kindel, S.; Miller, E.M.; Ware, S.M. Novel pathogenic variants in filamin C identified in pediatric restrictive cardiomyopathy. Hum. Mutat. 2018, 39, 2083–2096. [Google Scholar] [CrossRef] [PubMed]
  76. Roldan-Sevilla, A.; Palomino-Doza, J.; de Juan, J.; Sanchez, V.; Dominguez-Gonzalez, C.; Salguero-Bodes, R.; Arribas-Ynsaurriaga, F. Missense mutations in the FLNC gene causing familial restrictive cardiomyopathy. Circ. Genom. Precis. Med. 2019, 12, e002388. [Google Scholar] [CrossRef]
  77. Bienengraeber, M.; Olson, T.M.; Selivanov, V.A.; Kathmann, E.C.; O’Cochlain, F.; Gao, F.; Karger, A.B.; Ballew, J.D.; Hodgson, D.M.; Zingman, L.V.; et al. ABCC9 mutations identified in human dilated cardiomyopathy disrupt catalytic KATP channel gating. Nat. Genet. 2004, 36, 382–387. [Google Scholar] [CrossRef]
  78. Collet, M.; Assouline, Z.; Bonnet, D.; Rio, M.; Iserin, F.; Sidi, D.; Goldenberg, A.; Lardennois, C.; Metodiev, M.D.; Haberberger, B.; et al. High incidence and variable clinical outcome of cardiac hypertrophy due to ACAD9 mutations in childhood. Eur. J. Hum. Genet. 2016, 24, 1112–1116. [Google Scholar] [CrossRef]
  79. Carlus, S.J.; Almuzaini, I.S.; Karthikeyan, M.; Loganathan, L.; Al-Harbi, G.S.; Abdallah, A.M.; Al-Harbi, K.M. Next-generation sequencing identifies a homozygous mutation in ACADVL associated with pediatric familial dilated cardiomyopathy. Eur. Rev. Med. Pharmacol. Sci. 2019, 23, 1710–1721. [Google Scholar]
  80. Monserrat, L.; Hermida-Prieto, M.; Fernandez, X.; Rodriguez, I.; Dumont, C.; Cazon, L.; Cuesta, M.G.; Gonzalez-Juanatey, C.; Peteiro, J.; Alvarez, N.; et al. Mutation in the alpha-cardiac actin gene associated with apical hypertrophic cardiomyopathy, left ventricular non-compaction, and septal defects. Eur. Heart J. 2007, 28, 1953–1961. [Google Scholar] [CrossRef] [Green Version]
  81. Olson, T.M.; Michels, V.V.; Thibodeau, S.N.; Tai, Y.S.; Keating, M.T. Actin mutations in dilated cardiomyopathy, a heritable form of heart failure. Science 1998, 280, 750–752. [Google Scholar] [CrossRef] [PubMed]
  82. Klaassen, S.; Probst, S.; Oechslin, E.; Gerull, B.; Krings, G.; Schuler, P.; Greutmann, M.; Hurlimann, D.; Yegitbasi, M.; Pons, L.; et al. Mutations in sarcomere protein genes in left ventricular noncompaction. Circulation 2008, 117, 2893–2901. [Google Scholar] [CrossRef] [PubMed]
  83. Kaski, J.P.; Syrris, P.; Burch, M.; Tome-Esteban, M.T.; Fenton, M.; Christiansen, M.; Andersen, P.S.; Sebire, N.; Ashworth, M.; Deanfield, J.E.; et al. Idiopathic restrictive cardiomyopathy in children is caused by mutations in cardiac sarcomere protein genes. Heart 2008, 94, 1478–1484. [Google Scholar] [CrossRef] [PubMed]
  84. Chiu, C.; Bagnall, R.D.; Ingles, J.; Yeates, L.; Kennerson, M.; Donald, J.A.; Jormakka, M.; Lind, J.M.; Semsarian, C. Mutations in alpha-actinin-2 cause hypertrophic cardiomyopathy: A genome-wide analysis. J. Am. Coll. Cardiol. 2010, 55, 1127–1135. [Google Scholar] [CrossRef] [PubMed]
  85. Mohapatra, B.; Jimenez, S.; Lin, J.H.; Bowles, K.R.; Coveler, K.J.; Marx, J.G.; Chrisco, M.A.; Murphy, R.T.; Lurie, P.R.; Schwartz, R.J.; et al. Mutations in the muscle LIM protein and alpha-actinin-2 genes in dilated cardiomyopathy and endocardial fibroelastosis. Mol. Genet. Metab. 2003, 80, 207–215. [Google Scholar] [CrossRef]
  86. Bagnall, R.D.; Molloy, L.K.; Kalman, J.M.; Semsarian, C. Exome sequencing identifies a mutation in the ACTN2 gene in a family with idiopathic ventricular fibrillation, left ventricular noncompaction, and sudden death. BMC Med. Genet. 2014, 15, 99. [Google Scholar] [CrossRef] [PubMed]
  87. Waldmuller, S.; Schroeder, C.; Sturm, M.; Scheffold, T.; Imbrich, K.; Junker, S.; Frische, C.; Hofbeck, M.; Bauer, P.; Bonin, M.; et al. Targeted 46-gene and clinical exome sequencing for mutations causing cardiomyopathies. Mol. Cell. Probes 2015, 29, 308–314. [Google Scholar] [CrossRef] [PubMed]
  88. Forleo, C.; D’Erchia, A.M.; Sorrentino, S.; Manzari, C.; Chiara, M.; Iacoviello, M.; Guaricci, A.I.; De Santis, D.; Musci, R.L.; La Spada, A.; et al. Targeted next-generation sequencing detects novel gene-phenotype associations and expands the mutational spectrum in cardiomyopathies. PLoS ONE 2017, 12, e0181842. [Google Scholar] [CrossRef] [PubMed]
  89. Nerakh, G.; Ranganath, P. Alstrom syndrome presenting as isolated dilated cardiomyopathy. Indian J. Pediatr. 2019, 86, 296–298. [Google Scholar] [CrossRef]
  90. Almomani, R.; Verhagen, J.M.; Herkert, J.C.; Brosens, E.; van Spaendonck-Zwarts, K.Y.; Asimaki, A.; van der Zwaag, P.A.; Frohn-Mulder, I.M.; Bertoli-Avella, A.M.; Boven, L.G.; et al. Biallelic truncating mutations in ALPK3 cause severe pediatric cardiomyopathy. J. Am. Coll. Cardiol. 2016, 67, 515–525. [Google Scholar] [CrossRef]
  91. Lopes, L.R.; Syrris, P.; Guttmann, O.P.; O’Mahony, C.; Tang, H.C.; Dalageorgou, C.; Jenkins, S.; Hubank, M.; Monserrat, L.; McKenna, W.J.; et al. Novel genotype-phenotype associations demonstrated by high-throughput sequencing in patients with hypertrophic cardiomyopathy. Heart 2015, 101, 294–301. [Google Scholar] [CrossRef] [PubMed]
  92. Roberts, J.D.; Murphy, N.P.; Hamilton, R.M.; Lubbers, E.R.; James, C.A.; Kline, C.F.; Gollob, M.H.; Krahn, A.D.; Sturm, A.C.; Musa, H.; et al. Ankyrin-B dysfunction predisposes to arrhythmogenic cardiomyopathy and is amenable to therapy. J. Clin. Investig. 2019, 129, 3171–3184. [Google Scholar] [CrossRef] [PubMed]
  93. Arimura, T.; Bos, J.M.; Sato, A.; Kubo, T.; Okamoto, H.; Nishi, H.; Harada, H.; Koga, Y.; Moulik, M.; Doi, Y.L.; et al. Cardiac ankyrin repeat protein gene (ANKRD1) mutations in hypertrophic cardiomyopathy. J. Am. Coll. Cardiol. 2009, 54, 334–342. [Google Scholar] [CrossRef] [PubMed]
  94. Duboscq-Bidot, L.; Charron, P.; Ruppert, V.; Fauchier, L.; Richter, A.; Tavazzi, L.; Arbustini, E.; Wichter, T.; Maisch, B.; Komajda, M.; et al. Mutations in the ANKRD1 gene encoding CARP are responsible for human dilated cardiomyopathy. Eur. Heart J. 2009, 30, 2128–2136. [Google Scholar] [CrossRef] [PubMed]
  95. Moulik, M.; Vatta, M.; Witt, S.H.; Arola, A.M.; Murphy, R.T.; McKenna, W.J.; Boriek, A.M.; Oka, K.; Labeit, S.; Bowles, N.E.; et al. ANKRD1, the gene encoding cardiac ankyrin repeat protein, is a novel dilated cardiomyopathy gene. J. Am. Coll. Cardiol. 2009, 54, 325–333. [Google Scholar] [CrossRef] [PubMed]
  96. Norton, N.; Li, D.; Rieder, M.J.; Siegfried, J.D.; Rampersaud, E.; Zuchner, S.; Mangos, S.; Gonzalez-Quintana, J.; Wang, L.; McGee, S.; et al. Genome-wide studies of copy number variation and exome sequencing identify rare variants in BAG3 as a cause of dilated cardiomyopathy. Am. J. Hum. Genet. 2011, 88, 273–282. [Google Scholar] [CrossRef] [PubMed]
  97. Schanzer, A.; Rupp, S.; Graf, S.; Zengeler, D.; Jux, C.; Akinturk, H.; Gulatz, L.; Mazhari, N.; Acker, T.; Van Coster, R.; et al. Dysregulated autophagy in restrictive cardiomyopathy due to Pro209Leu mutation in BAG3. Mol. Genet. Metab. 2018, 123, 388–399. [Google Scholar] [CrossRef] [PubMed]
  98. Gripp, K.W.; Lin, A.E.; Nicholson, L.; Allen, W.; Cramer, A.; Jones, K.L.; Kutz, W.; Peck, D.; Rebolledo, M.A.; Wheeler, P.G.; et al. Further delineation of the phenotype resulting from BRAF or MEK1 germline mutations helps differentiate cardio-facio-cutaneous syndrome from Costello syndrome. Am. J. Med. Genet. Part A 2007, 143A, 1472–1480. [Google Scholar] [CrossRef] [PubMed]
  99. Shakeel, M.; Irfan, M.; Khan, I.A. Rare genetic mutations in Pakistani patients with dilated cardiomyopathy. Gene 2018, 673, 134–139. [Google Scholar] [CrossRef]
  100. Boczek, N.J.; Ye, D.; Jin, F.; Tester, D.J.; Huseby, A.; Bos, J.M.; Johnson, A.J.; Kanter, R.; Ackerman, M.J. Identification and functional characterization of a novel CACNA1C-mediated cardiac disorder characterized by prolonged QT intervals with hypertrophic cardiomyopathy, congenital heart defects, and sudden cardiac death. Circ. Arrhythm. Electrophysiol. 2015, 8, 1122–1132. [Google Scholar] [CrossRef]
  101. Friedrich, F.W.; Bausero, P.; Sun, Y.; Treszl, A.; Kramer, E.; Juhr, D.; Richard, P.; Wegscheider, K.; Schwartz, K.; Brito, D.; et al. A new polymorphism in human calmodulin III gene promoter is a potential modifier gene for familial hypertrophic cardiomyopathy. Eur. Heart J. 2009, 30, 1648–1655. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  102. Qiu, X.B.; Qu, X.K.; Li, R.G.; Liu, H.; Xu, Y.J.; Zhang, M.; Shi, H.Y.; Hou, X.M.; Liu, X.; Yuan, F.; et al. CASZ1 loss-of-function mutation contributes to familial dilated cardiomyopathy. Clin. Chem. Lab. Med. 2017, 55, 1417–1425. [Google Scholar] [CrossRef] [PubMed]
  103. Guo, J.; Li, Z.; Hao, C.; Guo, R.; Hu, X.; Qian, S.; Zeng, J.; Gao, H.; Li, W. A novel de novo CASZ1 heterozygous frameshift variant causes dilated cardiomyopathy and left ventricular noncompaction cardiomyopathy. Mol. Genet. Genom. Med. 2019, 7, e828. [Google Scholar] [CrossRef] [PubMed]
  104. Hayashi, T.; Arimura, T.; Ueda, K.; Shibata, H.; Hohda, S.; Takahashi, M.; Hori, H.; Koga, Y.; Oka, N.; Imaizumi, T.; et al. Identification and functional analysis of a caveolin-3 mutation associated with familial hypertrophic cardiomyopathy. Biochem. Biophys. Res. Commun. 2004, 313, 178–184. [Google Scholar] [CrossRef] [PubMed]
  105. Rodriguez, G.; Ueyama, T.; Ogata, T.; Czernuszewicz, G.; Tan, Y.; Dorn, G.W., II; Bogaev, R.; Amano, K.; Oh, H.; Matsubara, H.; et al. Molecular genetic and functional characterization implicate muscle-restricted coiled-coil gene (MURC) as a causal gene for familial dilated cardiomyopathy. Circ. Cardiovasc. Genet. 2011, 4, 349–358. [Google Scholar] [CrossRef] [PubMed]
  106. Mayosi, B.M.; Fish, M.; Shaboodien, G.; Mastantuono, E.; Kraus, S.; Wieland, T.; Kotta, M.C.; Chin, A.; Laing, N.; Ntusi, N.B.; et al. Identification of Cadherin 2 (CDH2) mutations in arrhythmogenic right ventricular cardiomyopathy. Circ. Cardiovasc. Genet. 2017, 10, e001605. [Google Scholar] [CrossRef]
  107. Turkowski, K.L.; Tester, D.J.; Bos, J.M.; Haugaa, K.H.; Ackerman, M.J. Whole exome sequencing with genomic triangulation implicates CDH2-encoded N-cadherin as a novel pathogenic substrate for arrhythmogenic cardiomyopathy. Congenit. Heart Dis. 2017, 12, 226–235. [Google Scholar] [CrossRef]
  108. Zhang, L.; Hu, A.; Yuan, H.; Cui, L.; Miao, G.; Yang, X.; Wang, L.; Liu, J.; Liu, X.; Wang, S.; et al. A missense mutation in the CHRM2 gene is associated with familial dilated cardiomyopathy. Circ. Res. 2008, 102, 1426–1432. [Google Scholar] [CrossRef]
  109. Lan, N.S.R.; Fietz, M.; Pachter, N.; Paul, V.; Playford, D. A case of vascular Ehlers-Danlos Syndrome with a cardiomyopathy and multi-system involvement. Cardiovasc. Pathol. 2018, 35, 48–51. [Google Scholar] [CrossRef]
  110. Antonicka, H.; Mattman, A.; Carlson, C.G.; Glerum, D.M.; Hoffbuhr, K.C.; Leary, S.C.; Kennaway, N.G.; Shoubridge, E.A. Mutations in COX15 produce a defect in the mitochondrial heme biosynthetic pathway, causing early-onset fatal hypertrophic cardiomyopathy. Am. J. Hum. Genet. 2003, 72, 101–114. [Google Scholar] [CrossRef]
  111. Inagaki, N.; Hayashi, T.; Arimura, T.; Koga, Y.; Takahashi, M.; Shibata, H.; Teraoka, K.; Chikamori, T.; Yamashina, A.; Kimura, A. αB-crystallin mutation in dilated cardiomyopathy. Biochem. Biophys. Res. Commun. 2006, 342, 379–386. [Google Scholar] [CrossRef] [PubMed]
  112. Brodehl, A.; Gaertner-Rommel, A.; Klauke, B.; Grewe, S.A.; Schirmer, I.; Peterschroder, A.; Faber, L.; Vorgerd, M.; Gummert, J.; Anselmetti, D.; et al. The novel αB-crystallin (CRYAB) mutation p.D109G causes restrictive cardiomyopathy. Hum. Mutat. 2017, 38, 947–952. [Google Scholar] [CrossRef] [PubMed]
  113. Newman, B.; Cescon, D.; Woo, A.; Rakowski, H.; Erikkson, M.J.; Sole, M.; Wigle, E.D.; Siminovitch, K.A. W4R variant in CSRP3 encoding muscle LIM protein in a patient with hypertrophic cardiomyopathy. Mol. Genet. Metab. 2005, 84, 374–375. [Google Scholar] [CrossRef] [PubMed]
  114. Geier, C.; Gehmlich, K.; Ehler, E.; Hassfeld, S.; Perrot, A.; Hayess, K.; Cardim, N.; Wenzel, K.; Erdmann, B.; Krackhardt, F.; et al. Beyond the sarcomere: CSRP3 mutations cause hypertrophic cardiomyopathy. Hum. Mol. Genet. 2008, 17, 2753–2765. [Google Scholar] [CrossRef] [PubMed]
  115. Janin, A.; Bessiere, F.; Chauveau, S.; Chevalier, P.; Millat, G. First identification of homozygous truncating CSRP3 variants in two unrelated cases with hypertrophic cardiomyopathy. Gene 2018, 676, 110–116. [Google Scholar] [CrossRef]
  116. Hershberger, R.E.; Parks, S.B.; Kushner, J.D.; Li, D.; Ludwigsen, S.; Jakobs, P.; Nauman, D.; Burgess, D.; Partain, J.; Litt, M. Coding sequence mutations identified in MYH7, TNNT2, SCN5A, CSRP3, LBD3, and TCAP from 313 patients with familial or idiopathic dilated cardiomyopathy. Clin. Transl. Sci. 2008, 1, 21–26. [Google Scholar] [CrossRef] [PubMed]
  117. Erdmann, J.; Hassfeld, S.; Kallisch, H.; Fleck, E.; Regitz-Zagrose, V. Genetic variants in the promoter (g983G>T) and coding region (A92T) of the human cardiotrophin-1 gene (CTF1) in patients with dilated cardiomyopathy. Hum. Mutat. 2000, 16, 448. [Google Scholar] [CrossRef]
  118. Van Hengel, J.; Calore, M.; Bauce, B.; Dazzo, E.; Mazzotti, E.; De Bortoli, M.; Lorenzon, A.; Li Mura, I.E.; Beffagna, G.; Rigato, I.; et al. Mutations in the area composita protein alphaT-catenin are associated with arrhythmogenic right ventricular cardiomyopathy. Eur. Heart J. 2013, 34, 201–210. [Google Scholar] [CrossRef]
  119. Taylor, M.R.; Slavov, D.; Ku, L.; Di Lenarda, A.; Sinagra, G.; Carniel, E.; Haubold, K.; Boucek, M.M.; Ferguson, D.; Graw, S.L.; et al. Prevalence of desmin mutations in dilated cardiomyopathy. Circulation 2007, 115, 1244–1251. [Google Scholar] [CrossRef]
  120. Towbin, J.A.; Hejtmancik, J.F.; Brink, P.; Gelb, B.; Zhu, X.M.; Chamberlain, J.S.; McCabe, E.R.; Swift, M. X-linked dilated cardiomyopathy. Molecular genetic evidence of linkage to the Duchenne muscular dystrophy (dystrophin) gene at the Xp21 locus. Circulation 1993, 87, 1854–1865. [Google Scholar] [CrossRef]
  121. Ojala, T.; Polinati, P.; Manninen, T.; Hiippala, A.; Rajantie, J.; Karikoski, R.; Suomalainen, A.; Tyni, T. New mutation of mitochondrial DNAJC19 causing dilated and noncompaction cardiomyopathy, anemia, ataxia, and male genital anomalies. Pediatr. Res. 2012, 72, 432–437. [Google Scholar] [CrossRef] [PubMed]
  122. Rush, E.T.; Baker, C.V.; Rizzo, W.B. Dolichol kinase deficiency (DOLK-CDG): Two new cases and expansion of phenotype. Am. J. Med. Genet. Part A 2017, 173, 2428–2434. [Google Scholar] [CrossRef] [PubMed]
  123. Svahn, J.; Laforet, P.; Vial, C.; Streichenberger, N.; Romero, N.; Bouchet-Seraphin, C.; Bruneel, A.; Dupre, T.; Seta, N.; Menassa, R.; et al. Dilated cardiomyopathy and limb-girdle muscular dystrophy-dystroglycanopathy due to novel pathogenic variants in the DPM3 gene. Neuromuscul. Disord. 2019, 29, 497–502. [Google Scholar] [CrossRef] [PubMed]
  124. Heuser, A.; Plovie, E.R.; Ellinor, P.T.; Grossmann, K.S.; Shin, J.T.; Wichter, T.; Basson, C.T.; Lerman, B.B.; Sasse-Klaassen, S.; Thierfelder, L.; et al. Mutant desmocollin-2 causes arrhythmogenic right ventricular cardiomyopathy. Am. J. Hum. Genet. 2006, 79, 1081–1088. [Google Scholar] [CrossRef] [PubMed]
  125. Posch, M.G.; Posch, M.J.; Geier, C.; Erdmann, B.; Mueller, W.; Richter, A.; Ruppert, V.; Pankuweit, S.; Maisch, B.; Perrot, A.; et al. A missense variant in desmoglein-2 predisposes to dilated cardiomyopathy. Mol. Genet. Metab. 2008, 95, 74–80. [Google Scholar] [CrossRef]
  126. Awad, M.M.; Dalal, D.; Cho, E.; Amat-Alarcon, N.; James, C.; Tichnell, C.; Tucker, A.; Russell, S.D.; Bluemke, D.A.; Dietz, H.C.; et al. DSG2 mutations contribute to arrhythmogenic right ventricular dysplasia/cardiomyopathy. Am. J. Hum. Genet. 2006, 79, 136–142. [Google Scholar] [CrossRef] [PubMed]
  127. Pilichou, K.; Nava, A.; Basso, C.; Beffagna, G.; Bauce, B.; Lorenzon, A.; Frigo, G.; Vettori, A.; Valente, M.; Towbin, J.; et al. Mutations in desmoglein-2 gene are associated with arrhythmogenic right ventricular cardiomyopathy. Circulation 2006, 113, 1171–1179. [Google Scholar] [CrossRef]
  128. Norgett, E.E.; Hatsell, S.J.; Carvajal-Huerta, L.; Cabezas, J.C.; Common, J.; Purkis, P.E.; Whittock, N.; Leigh, I.M.; Stevens, H.P.; Kelsell, D.P. Recessive mutation in desmoplakin disrupts desmoplakin-intermediate filament interactions and causes dilated cardiomyopathy, woolly hair and keratoderma. Hum. Mol. Genet. 2000, 9, 2761–2766. [Google Scholar] [CrossRef] [Green Version]
  129. Williams, T.; Machann, W.; Kuhler, L.; Hamm, H.; Muller-Hocker, J.; Zimmer, M.; Ertl, G.; Ritter, O.; Beer, M.; Schonberger, J. Novel desmoplakin mutation: Juvenile biventricular cardiomyopathy with left ventricular non-compaction and acantholytic palmoplantar keratoderma. Clin. Res. Cardiol. 2011, 100, 1087–1093. [Google Scholar] [CrossRef]
  130. Rampazzo, A.; Nava, A.; Malacrida, S.; Beffagna, G.; Bauce, B.; Rossi, V.; Zimbello, R.; Simionati, B.; Basso, C.; Thiene, G.; et al. Mutation in human desmoplakin domain binding to plakoglobin causes a dominant form of arrhythmogenic right ventricular cardiomyopathy. Am. J. Hum. Genet. 2002, 71, 1200–1206. [Google Scholar] [CrossRef]
  131. Cao, Q.; Shen, Y.; Liu, X.; Yu, X.; Yuan, P.; Wan, R.; Liu, X.; Peng, X.; He, W.; Pu, J.; et al. Phenotype and functional analyses in a transgenic mouse model of left ventricular noncompaction caused by a DTNA mutation. Int. Heart J. 2017, 58, 939–947. [Google Scholar] [CrossRef] [PubMed]
  132. Haack, T.B.; Kopajtich, R.; Freisinger, P.; Wieland, T.; Rorbach, J.; Nicholls, T.J.; Baruffini, E.; Walther, A.; Danhauser, K.; Zimmermann, F.A.; et al. ELAC2 mutations cause a mitochondrial RNA processing defect associated with hypertrophic cardiomyopathy. Am. J. Hum. Genet. 2013, 93, 211–223. [Google Scholar] [CrossRef] [PubMed]
  133. Zhang, M.; Chen, J.; Si, D.; Zheng, Y.; Jiao, H.; Feng, Z.; Hu, Z.; Duan, R. Whole exome sequencing identifies a novel EMD mutation in a Chinese family with dilated cardiomyopathy. BMC Med. Genet. 2014, 15, 77. [Google Scholar] [CrossRef] [PubMed]
  134. Tang, S.; Hoshida, H.; Kamisago, M.; Yagi, H.; Momma, K.; Matsuoka, R. Phenotype-genotype correlation in a patient with co-occurrence of Marfan and LEOPARD syndromes. Am. J. Med. Genet. Part A 2009, 149A, 2216–2219. [Google Scholar] [CrossRef] [PubMed]
  135. Jacobs, A.M.; Toudjarska, I.; Racine, A.; Tsipouras, P.; Kilpatrick, M.W.; Shanske, A. A recurring FBN1 gene mutation in neonatal Marfan syndrome. Arch. Pediatr. Adolesc. Med. 2002, 156, 1081–1085. [Google Scholar] [CrossRef] [PubMed]
  136. Parent, J.J.; Towbin, J.A.; Jefferies, J.L. Fibrillin-1 gene mutations in left ventricular non-compaction cardiomyopathy. Pediatr. Cardiol. 2016, 37, 1123–1126. [Google Scholar] [CrossRef]
  137. Al-Yacoub, N.; Shaheen, R.; Awad, S.M.; Kunhi, M.; Dzimiri, N.; Nguyen, H.C.; Xiong, Y.; Al-Buraiki, J.; Al-Habeeb, W.; Alkuraya, F.S.; et al. FBXO32, encoding a member of the SCF complex, is mutated in dilated cardiomyopathy. Genome Biol. 2016, 17, 2. [Google Scholar] [CrossRef]
  138. Al-Hassnan, Z.N.; Shinwari, Z.M.; Wakil, S.M.; Tulbah, S.; Mohammed, S.; Rahbeeni, Z.; Alghamdi, M.; Rababh, M.; Colak, D.; Kaya, N.; et al. A substitution mutation in cardiac ubiquitin ligase, FBXO32, is associated with an autosomal recessive form of dilated cardiomyopathy. BMC Med. Genet. 2016, 17, 3. [Google Scholar] [CrossRef] [PubMed]
  139. Arimura, T.; Hayashi, T.; Matsumoto, Y.; Shibata, H.; Hiroi, S.; Nakamura, T.; Inagaki, N.; Hinohara, K.; Takahashi, M.; Manatsu, S.I.; et al. Structural analysis of four and half LIM protein-2 in dilated cardiomyopathy. Biochem. Biophys. Res. Commun. 2007, 357, 162–167. [Google Scholar] [CrossRef]
  140. Ochoa, J.P.; Sabater-Molina, M.; Garcia-Pinilla, J.M.; Mogensen, J.; Restrepo-Cordoba, A.; Palomino-Doza, J.; Villacorta, E.; Martinez-Moreno, M.; Ramos-Maqueda, J.; Zorio, E.; et al. Formin Homology 2 Domain Containing 3 (FHOD3) Is a genetic basis for hypertrophic cardiomyopathy. J. Am. Coll. Cardiol. 2018, 72, 2457–2467. [Google Scholar] [CrossRef]
  141. Arimura, T.; Takeya, R.; Ishikawa, T.; Yamano, T.; Matsuo, A.; Tatsumi, T.; Nomura, T.; Sumimoto, H.; Kimura, A. Dilated cardiomyopathy-associated FHOD3 variant impairs the ability to induce activation of transcription factor serum response factor. Circ. J. 2013, 77, 2990–2996. [Google Scholar] [CrossRef] [PubMed]
  142. Muller, T.; Krasnianski, M.; Witthaut, R.; Deschauer, M.; Zierz, S. Dilated cardiomyopathy may be an early sign of the C826A Fukutin-related protein mutation. Neuromuscul. Disord. 2005, 15, 372–376. [Google Scholar] [CrossRef] [PubMed]
  143. Amiya, E.; Morita, H.; Hatano, M.; Nitta, D.; Hosoya, Y.; Maki, H.; Motozawa, Y.; Sato, N.; Ishiura, H.; Numakura, S.; et al. Fukutin gene mutations that cause left ventricular noncompaction. Int. J. Cardiol. 2016, 222, 727–729. [Google Scholar] [CrossRef] [PubMed]
  144. Begay, R.L.; Tharp, C.A.; Martin, A.; Graw, S.L.; Sinagra, G.; Miani, D.; Sweet, M.E.; Slavov, D.B.; Stafford, N.; Zeller, M.J.; et al. FLNC gene splice mutations cause dilated cardiomyopathy. JACC Basic Transl. Sci. 2016, 1, 344–359. [Google Scholar] [CrossRef] [PubMed]
  145. Ortiz-Genga, M.F.; Cuenca, S.; Dal Ferro, M.; Zorio, E.; Salgado-Aranda, R.; Climent, V.; Padron-Barthe, L.; Duro-Aguado, I.; Jimenez-Jaimez, J.; Hidalgo-Olivares, V.M.; et al. Truncating FLNC mutations are associated with high-risk dilated and arrhythmogenic cardiomyopathies. J. Am. Coll. Cardiol. 2016, 68, 2440–2451. [Google Scholar] [CrossRef] [PubMed]
  146. Minoretti, P.; Arra, M.; Emanuele, E.; Olivieri, V.; Aldeghi, A.; Politi, P.; Martinelli, V.; Pesenti, S.; Falcone, C. A W148R mutation in the human FOXD4 gene segregating with dilated cardiomyopathy, obsessive-compulsive disorder, and suicidality. Int. J. Mol. Med. 2007, 19, 369–372. [Google Scholar] [CrossRef]
  147. Payne, R.M.; Wagner, G.R. Cardiomyopathy in Friedreich ataxia: Clinical findings and research. J. Child Neurol. 2012, 27, 1179–1186. [Google Scholar] [CrossRef]
  148. Campuzano, V.; Montermini, L.; Molto, M.D.; Pianese, L.; Cossee, M.; Cavalcanti, F.; Monros, E.; Rodius, F.; Duclos, F.; Monticelli, A.; et al. Friedreich’s ataxia: Autosomal recessive disease caused by an intronic GAA triplet repeat expansion. Science 1996, 271, 1423–1427. [Google Scholar] [CrossRef]
  149. Li, R.G.; Li, L.; Qiu, X.B.; Yuan, F.; Xu, L.; Li, X.; Xu, Y.J.; Jiang, W.F.; Jiang, J.Q.; Liu, X.; et al. GATA4 loss-of-function mutation underlies familial dilated cardiomyopathy. Biochem. Biophys. Res. Commun. 2013, 439, 591–596. [Google Scholar] [CrossRef]
  150. Tang, V.T.; Arscott, P.; Helms, A.S.; Day, S.M. Whole-exome sequencing reveals GATA4 and PTEN mutations as a potential digenic cause of left ventricular noncompaction. Circ. Genom. Precis. Med. 2018, 11, e001966. [Google Scholar] [CrossRef]
  151. Zhang, X.L.; Dai, N.; Tang, K.; Chen, Y.Q.; Chen, W.; Wang, J.; Zhao, C.M.; Yuan, F.; Qiu, X.B.; Qu, X.K.; et al. GATA5 loss-of-function mutation in familial dilated cardiomyopathy. Int. J. Mol. Med. 2015, 35, 763–770. [Google Scholar] [CrossRef] [PubMed]
  152. Theis, J.L.; Sharpe, K.M.; Matsumoto, M.E.; Chai, H.S.; Nair, A.A.; Theis, J.D.; de Andrade, M.; Wieben, E.D.; Michels, V.V.; Olson, T.M. Homozygosity mapping and exome sequencing reveal GATAD1 mutation in autosomal recessive dilated cardiomyopathy. Circ. Cardiovasc. Genet. 2011, 4, 585–594. [Google Scholar] [CrossRef] [PubMed]
  153. Arad, M.; Penas-Lado, M.; Monserrat, L.; Maron, B.J.; Sherrid, M.; Ho, C.Y.; Barr, S.; Karim, A.; Olson, T.M.; Kamisago, M.; et al. Gene mutations in apical hypertrophic cardiomyopathy. Circulation 2005, 112, 2805–2811. [Google Scholar] [CrossRef] [PubMed]
  154. Kopajtich, R.; Nicholls, T.J.; Rorbach, J.; Metodiev, M.D.; Freisinger, P.; Mandel, H.; Vanlander, A.; Ghezzi, D.; Carrozzo, R.; Taylor, R.W.; et al. Mutations in GTPBP3 cause a mitochondrial translation defect associated with hypertrophic cardiomyopathy, lactic acidosis, and encephalopathy. Am. J. Hum. Genet. 2014, 95, 708–720. [Google Scholar] [CrossRef] [PubMed]
  155. Zhou, Y.M.; Dai, X.Y.; Qiu, X.B.; Yuan, F.; Li, R.G.; Xu, Y.J.; Qu, X.K.; Huang, R.T.; Xue, S.; Yang, Y.Q. HAND1 loss-of-function mutation associated with familial dilated cardiomyopathy. Clin. Chem. Lab. Med. 2016, 54, 1161–1167. [Google Scholar] [CrossRef] [PubMed]
  156. Liu, H.; Xu, Y.J.; Li, R.G.; Wang, Z.S.; Zhang, M.; Qu, X.K.; Qiao, Q.; Li, X.M.; Di, R.M.; Qiu, X.B.; et al. HAND2 loss-of-function mutation causes familial dilated cardiomyopathy. Eur. J. Med. Genet. 2018. [Google Scholar] [CrossRef] [PubMed]
  157. Milano, A.; Vermeer, A.M.; Lodder, E.M.; Barc, J.; Verkerk, A.O.; Postma, A.V.; van der Bilt, I.A.; Baars, M.J.; van Haelst, P.L.; Caliskan, K.; et al. HCN4 mutations in multiple families with bradycardia and left ventricular noncompaction cardiomyopathy. J. Am. Coll. Cardiol. 2014, 64, 745–756. [Google Scholar] [CrossRef] [PubMed]
  158. Hiippala, A.; Vasilescu, C.; Tallila, J.; Alastalo, T.P.; Paetau, A.; Tyni, T.; Suomalainen, A.; Euro, L.; Ojala, T. The rare Costello variant HRAS c.173C>T (p.T58I) with severe neonatal hypertrophic cardiomyopathy. Am. J. Med. Genet. Part A 2016, 170, 1433–1438. [Google Scholar] [CrossRef] [PubMed]
  159. Knoll, R.; Postel, R.; Wang, J.; Kratzner, R.; Hennecke, G.; Vacaru, A.M.; Vakeel, P.; Schubert, C.; Murthy, K.; Rana, B.K.; et al. Laminin-alpha4 and integrin-linked kinase mutations cause human cardiomyopathy via simultaneous defects in cardiomyocytes and endothelial cells. Circulation 2007, 116, 515–525. [Google Scholar] [CrossRef] [PubMed]
  160. Meder, B.; Haas, J.; Keller, A.; Heid, C.; Just, S.; Borries, A.; Boisguerin, V.; Scharfenberger-Schmeer, M.; Stahler, P.; Beier, M.; et al. Targeted next-generation sequencing for the molecular genetic diagnostics of cardiomyopathies. Circ. Cardiovasc. Genet. 2011, 4, 110–122. [Google Scholar] [CrossRef] [PubMed]
  161. Xu, Y.J.; Wang, Z.S.; Yang, C.X.; Di, R.M.; Qiao, Q.; Li, X.M.; Gu, J.N.; Guo, X.J.; Yang, Y.Q. Identification and functional characterization of an ISL1 mutation predisposing to dilated cardiomyopathy. J. Cardiovasc. Transl. Res. 2019, 12, 257–267. [Google Scholar] [CrossRef] [PubMed]
  162. Esposito, T.; Sampaolo, S.; Limongelli, G.; Varone, A.; Formicola, D.; Diodato, D.; Farina, O.; Napolitano, F.; Pacileo, G.; Gianfrancesco, F.; et al. Digenic mutational inheritance of the integrin alpha 7 and the myosin heavy chain 7B genes causes congenital myopathy with left ventricular non-compact cardiomyopathy. Orphanet J. Rare Dis. 2013, 8, 91. [Google Scholar] [CrossRef] [PubMed]
  163. Handley, M.T.; Reddy, K.; Wills, J.; Rosser, E.; Kamath, A.; Halachev, M.; Falkous, G.; Williams, D.; Cox, P.; Meynert, A.; et al. ITPase deficiency causes a Martsolf-like syndrome with a lethal infantile dilated cardiomyopathy. PLoS Genet. 2019, 15, e1007605. [Google Scholar] [CrossRef] [PubMed]
  164. Matsushita, Y.; Furukawa, T.; Kasanuki, H.; Nishibatake, M.; Kurihara, Y.; Ikeda, A.; Kamatani, N.; Takeshima, H.; Matsuoka, R. Mutation of junctophilin type 2 associated with hypertrophic cardiomyopathy. J. Hum. Genet. 2007, 52, 543–548. [Google Scholar] [CrossRef] [PubMed]
  165. Sabater-Molina, M.; Navarro, M.; Garcia-Molina Saez, E.; Garrido, I.; Pascual-Figal, D.; Gonzalez Carrillo, J.; Gimeno Blanes, J.R. Mutation in JPH2 cause dilated cardiomyopathy. Clin. Genet. 2016, 90, 468–469. [Google Scholar] [CrossRef] [PubMed]
  166. Xiong, Q.; Cao, Q.; Zhou, Q.; Xie, J.; Shen, Y.; Wan, R.; Yu, J.; Yan, S.; Marian, A.J.; Hong, K. Arrhythmogenic cardiomyopathy in a patient with a rare loss-of-function KCNQ1 mutation. J. Am. Heart Assoc. 2015, 4, e001526. [Google Scholar] [CrossRef] [PubMed]
  167. Hedberg-Oldfors, C.; Abramsson, A.; Osborn, D.P.S.; Danielsson, O.; Fazlinezhad, A.; Nilipour, Y.; Hubbert, L.; Nennesmo, I.; Visuttijai, K.; Bharj, J.; et al. Cardiomyopathy with lethal arrhythmias associated with inactivation of KLHL24. Hum. Mol. Genet. 2019, 28, 1919–1929. [Google Scholar] [CrossRef] [PubMed]
  168. Arad, M.; Maron, B.J.; Gorham, J.M.; Johnson, W.H., Jr.; Saul, J.P.; Perez-Atayde, A.R.; Spirito, P.; Wright, G.B.; Kanter, R.J.; Seidman, C.E.; et al. Glycogen storage diseases presenting as hypertrophic cardiomyopathy. N. Engl. J. Med. 2005, 352, 362–372. [Google Scholar] [CrossRef] [PubMed]
  169. Fratev, F.; Mihaylova, E.; Pajeva, I. Combination of genetic screening and molecular dynamics as a useful tool for identification of disease-related mutations: ZASP PDZ domain G54S mutation case. J. Chem. Inf. Model. 2014, 54, 1524–1536. [Google Scholar] [CrossRef]
  170. Vatta, M.; Mohapatra, B.; Jimenez, S.; Sanchez, X.; Faulkner, G.; Perles, Z.; Sinagra, G.; Lin, J.H.; Vu, T.M.; Zhou, Q.; et al. Mutations in Cypher/ZASP in patients with dilated cardiomyopathy and left ventricular non-compaction. J. Am. Coll. Cardiol. 2003, 42, 2014–2027. [Google Scholar] [CrossRef]
  171. Arimura, T.; Hayashi, T.; Terada, H.; Lee, S.Y.; Zhou, Q.; Takahashi, M.; Ueda, K.; Nouchi, T.; Hohda, S.; Shibutani, M.; et al. A Cypher/ZASP mutation associated with dilated cardiomyopathy alters the binding affinity to protein kinase C. J. Biol. Chem. 2004, 279, 6746–6752. [Google Scholar] [CrossRef] [PubMed]
  172. Shan, S.; He, X.; He, L.; Wang, M.; Liu, C. Coexistence of congenital left ventricular aneurysm and prominent left ventricular trabeculation in a patient with LDB3 mutation: A case report. J. Med. Case Rep. 2017, 11, 229. [Google Scholar] [CrossRef] [PubMed]
  173. Lopez-Ayala, J.M.; Ortiz-Genga, M.; Gomez-Milanes, I.; Lopez-Cuenca, D.; Ruiz-Espejo, F.; Sanchez-Munoz, J.J.; Oliva-Sandoval, M.J.; Monserrat, L.; Gimeno, J.R. A mutation in the Z-line Cypher/ZASP protein is associated with arrhythmogenic right ventricular cardiomyopathy. Clin. Genet. 2015, 88, 172–176. [Google Scholar] [CrossRef] [PubMed]
  174. Boone, P.M.; Yuan, B.; Gu, S.; Ma, Z.; Gambin, T.; Gonzaga-Jauregui, C.; Jain, M.; Murdock, T.J.; White, J.J.; Jhangiani, S.N.; et al. Hutterite-type cataract maps to chromosome 6p21.32-p21.31, cosegregates with a homozygous mutation in LEMD2, and is associated with sudden cardiac death. Mol. Genet. Genom. Med. 2016, 4, 77–94. [Google Scholar] [CrossRef] [PubMed]
  175. Liu, Z.; Shan, H.; Huang, J.; Li, N.; Hou, C.; Pu, J. A novel lamin A/C gene missense mutation (445 V > E) in immunoglobulin-like fold associated with left ventricular non-compaction. Europace 2016, 18, 617–622. [Google Scholar] [CrossRef] [PubMed]
  176. Qu, X.K.; Yuan, F.; Li, R.G.; Xu, L.; Jing, W.F.; Liu, H.; Xu, Y.J.; Zhang, M.; Liu, X.; Fang, W.Y.; et al. Prevalence and spectrum of LRRC10 mutations associated with idiopathic dilated cardiomyopathy. Mol. Med. Rep. 2015, 12, 3718–3724. [Google Scholar] [CrossRef]
  177. Luxan, G.; Casanova, J.C.; Martinez-Poveda, B.; Prados, B.; D’Amato, G.; MacGrogan, D.; Gonzalez-Rajal, A.; Dobarro, D.; Torroja, C.; Martinez, F.; et al. Mutations in the NOTCH pathway regulator MIB1 cause left ventricular noncompaction cardiomyopathy. Nat. Med. 2013, 19, 193–201. [Google Scholar] [CrossRef]
  178. Piccolo, P.; Attanasio, S.; Secco, I.; Sangermano, R.; Strisciuglio, C.; Limongelli, G.; Miele, E.; Mutarelli, M.; Banfi, S.; Nigro, V.; et al. MIB2 variants altering NOTCH signalling result in left ventricle hypertrabeculation/non-compaction and are associated with Menetrier-like gastropathy. Hum. Mol. Genet. 2017, 26, 33–43. [Google Scholar]
  179. Galmiche, L.; Serre, V.; Beinat, M.; Assouline, Z.; Lebre, A.S.; Chretien, D.; Nietschke, P.; Benes, V.; Boddaert, N.; Sidi, D.; et al. Exome sequencing identifies MRPL3 mutation in mitochondrial cardiomyopathy. Hum. Mutat. 2011, 32, 1225–1231. [Google Scholar] [CrossRef]
  180. Carroll, C.J.; Isohanni, P.; Poyhonen, R.; Euro, L.; Richter, U.; Brilhante, V.; Gotz, A.; Lahtinen, T.; Paetau, A.; Pihko, H.; et al. Whole-exome sequencing identifies a mutation in the mitochondrial ribosome protein MRPL44 to underlie mitochondrial infantile cardiomyopathy. J. Med. Genet. 2013, 50, 151–159. [Google Scholar] [CrossRef]
  181. Distelmaier, F.; Haack, T.B.; Catarino, C.B.; Gallenmuller, C.; Rodenburg, R.J.; Strom, T.M.; Baertling, F.; Meitinger, T.; Mayatepek, E.; Prokisch, H.; et al. MRPL44 mutations cause a slowly progressive multisystem disease with childhood-onset hypertrophic cardiomyopathy. NeuroGenet. 2015, 16, 319–323. [Google Scholar] [CrossRef] [PubMed]
  182. Watkins, H.; Conner, D.; Thierfelder, L.; Jarcho, J.A.; MacRae, C.; McKenna, W.J.; Maron, B.J.; Seidman, J.G.; Seidman, C.E. Mutations in the cardiac myosin binding protein-C gene on chromosome 11 cause familial hypertrophic cardiomyopathy. Nat. Genet. 1995, 11, 434–437. [Google Scholar] [CrossRef] [PubMed]
  183. Carrier, L.; Bonne, G.; Bahrend, E.; Yu, B.; Richard, P.; Niel, F.; Hainque, B.; Cruaud, C.; Gary, F.; Labeit, S.; et al. Organization and sequence of human cardiac myosin binding protein C gene (MYBPC3) and identification of mutations predicted to produce truncated proteins in familial hypertrophic cardiomyopathy. Circ. Res. 1997, 80, 427–434. [Google Scholar] [CrossRef] [PubMed]
  184. Ehlermann, P.; Weichenhan, D.; Zehelein, J.; Steen, H.; Pribe, R.; Zeller, R.; Lehrke, S.; Zugck, C.; Ivandic, B.T.; Katus, H.A. Adverse events in families with hypertrophic or dilated cardiomyopathy and mutations in the MYBPC3 gene. BMC Med. Genet. 2008, 9, 95. [Google Scholar] [CrossRef] [PubMed]
  185. Dellefave, L.M.; Pytel, P.; Mewborn, S.; Mora, B.; Guris, D.L.; Fedson, S.; Waggoner, D.; Moskowitz, I.; McNally, E.M. Sarcomere mutations in cardiomyopathy with left ventricular hypertrabeculation. Circ. Cardiovasc. Genet. 2009, 2, 442–449. [Google Scholar] [CrossRef] [PubMed]
  186. Wu, W.; Lu, C.X.; Wang, Y.N.; Liu, F.; Chen, W.; Liu, Y.T.; Han, Y.C.; Cao, J.; Zhang, S.Y.; Zhang, X. Novel phenotype-genotype correlations of restrictive cardiomyopathy with Myosin-Binding Protein C (MYBPC3) gene mutations tested by next-generation sequencing. J. Am. Heart Assoc. 2015, 4, e001879. [Google Scholar] [CrossRef]
  187. Barefield, D.Y.; Puckelwartz, M.J.; Kim, E.Y.; Wilsbacher, L.D.; Vo, A.H.; Waters, E.A.; Earley, J.U.; Hadhazy, M.; Dellefave-Castillo, L.; Pesce, L.L.; et al. Experimental modeling supports a role for MyBP-HL as a novel myofilament component in arrhythmia and dilated cardiomyopathy. Circulation 2017, 136, 1477–1491. [Google Scholar] [CrossRef] [PubMed]
  188. Carniel, E.; Taylor, M.R.; Sinagra, G.; Di Lenarda, A.; Ku, L.; Fain, P.R.; Boucek, M.M.; Cavanaugh, J.; Miocic, S.; Slavov, D.; et al. α-myosin heavy chain: A sarcomeric gene associated with dilated and hypertrophic phenotypes of cardiomyopathy. Circulation 2005, 112, 54–59. [Google Scholar] [CrossRef]
  189. Greenway, S.C.; Wilson, G.J.; Wilson, J.; George, K.; Kantor, P.F. Sudden death in an infant with angina, restrictive cardiomyopathy, and coronary artery bridging: An unusual phenotype for a beta-myosin heavy chain (MYH7) sarcomeric protein mutation. Circ. Heart Fail. 2012, 5, e92–e93. [Google Scholar] [CrossRef]
  190. Flavigny, J.; Richard, P.; Isnard, R.; Carrier, L.; Charron, P.; Bonne, G.; Forissier, J.F.; Desnos, M.; Dubourg, O.; Komajda, M.; et al. Identification of two novel mutations in the ventricular regulatory myosin light chain gene (MYL2) associated with familial and classical forms of hypertrophic cardiomyopathy. J. Mol. Med. 1998, 76, 208–214. [Google Scholar] [CrossRef]
  191. Caleshu, C.; Sakhuja, R.; Nussbaum, R.L.; Schiller, N.B.; Ursell, P.C.; Eng, C.; De Marco, T.; McGlothlin, D.; Burchard, E.G.; Rame, J.E. Furthering the link between the sarcomere and primary cardiomyopathies: Restrictive cardiomyopathy associated with multiple mutations in genes previously associated with hypertrophic or dilated cardiomyopathy. Am. J. Med. Genet. Part A 2011, 155A, 2229–2235. [Google Scholar] [CrossRef] [PubMed]
  192. Choi, J.O.; Yu, C.W.; Chun Nah, J.; Rang Park, J.; Lee, B.S.; Jeong Choi, Y.; Cho, B.R.; Lee, S.C.; Woo Park, S.; Kimura, A.; et al. Long-term outcome of 4 Korean families with hypertrophic cardiomyopathy caused by 4 different mutations. Clin. Cardiol. 2010, 33, 430–438. [Google Scholar] [CrossRef] [PubMed]
  193. Tobita, T.; Nomura, S.; Morita, H.; Ko, T.; Fujita, T.; Toko, H.; Uto, K.; Hagiwara, N.; Aburatani, H.; Komuro, I. Identification of MYLK3 mutations in familial dilated cardiomyopathy. Sci. Rep. 2017, 7, 17495. [Google Scholar] [CrossRef] [PubMed]
  194. Arola, A.M.; Sanchez, X.; Murphy, R.T.; Hasle, E.; Li, H.; Elliott, P.M.; McKenna, W.J.; Towbin, J.A.; Bowles, N.E. Mutations in PDLIM3 and MYOZ1 encoding myocyte Z line proteins are infrequently found in idiopathic dilated cardiomyopathy. Mol. Genet. Metab. 2007, 90, 435–440. [Google Scholar] [CrossRef] [PubMed]
  195. Osio, A.; Tan, L.; Chen, S.N.; Lombardi, R.; Nagueh, S.F.; Shete, S.; Roberts, R.; Willerson, J.T.; Marian, A.J. Myozenin 2 is a novel gene for human hypertrophic cardiomyopathy. Circ. Res. 2007, 100, 766–768. [Google Scholar] [CrossRef] [PubMed]
  196. Purevjav, E.; Arimura, T.; Augustin, S.; Huby, A.C.; Takagi, K.; Nunoda, S.; Kearney, D.L.; Taylor, M.D.; Terasaki, F.; Bos, J.M.; et al. Molecular basis for clinical heterogeneity in inherited cardiomyopathies due to myopalladin mutations. Hum. Mol. Genet. 2012, 21, 2039–2053. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  197. Meyer, T.; Ruppert, V.; Ackermann, S.; Richter, A.; Perrot, A.; Sperling, S.R.; Posch, M.G.; Maisch, B.; Pankuweit, S. Novel mutations in the sarcomeric protein myopalladin in patients with dilated cardiomyopathy. Eur. J. Hum. Genet. 2013, 21, 294–300. [Google Scholar] [CrossRef] [PubMed]
  198. Huby, A.C.; Mendsaikhan, U.; Takagi, K.; Martherus, R.; Wansapura, J.; Gong, N.; Osinska, H.; James, J.F.; Kramer, K.; Saito, K.; et al. Disturbance in Z-disk mechanosensitive proteins induced by a persistent mutant myopalladin causes familial restrictive cardiomyopathy. J. Am. Coll. Cardiol. 2014, 64, 2765–2776. [Google Scholar] [CrossRef]
  199. Roh, J.I.; Cheong, C.; Sung, Y.H.; Lee, J.; Oh, J.; Lee, B.S.; Lee, J.E.; Gho, Y.S.; Kim, D.K.; Park, C.B.; et al. Perturbation of NCOA6 leads to dilated cardiomyopathy. Cell Rep. 2014, 8, 991–998. [Google Scholar] [CrossRef]
  200. Fassone, E.; Taanman, J.W.; Hargreaves, I.P.; Sebire, N.J.; Cleary, M.A.; Burch, M.; Rahman, S. Mutations in the mitochondrial complex I assembly factor NDUFAF1 cause fatal infantile hypertrophic cardiomyopathy. J. Med. Genet. 2011, 48, 691–697. [Google Scholar] [CrossRef]
  201. Benit, P.; Beugnot, R.; Chretien, D.; Giurgea, I.; De Lonlay-Debeney, P.; Issartel, J.P.; Corral-Debrinski, M.; Kerscher, S.; Rustin, P.; Rotig, A.; et al. Mutant NDUFV2 subunit of mitochondrial complex I causes early onset hypertrophic cardiomyopathy and encephalopathy. Hum. Mutat. 2003, 21, 582–586. [Google Scholar] [CrossRef] [PubMed]
  202. Benit, P.; Slama, A.; Cartault, F.; Giurgea, I.; Chretien, D.; Lebon, S.; Marsac, C.; Munnich, A.; Rotig, A.; Rustin, P. Mutant NDUFS3 subunit of mitochondrial complex I causes Leigh syndrome. J. Med. Genet. 2004, 41, 14–17. [Google Scholar] [CrossRef] [PubMed]
  203. Perrot, A.; Tomasov, P.; Villard, E.; Faludi, R.; Melacini, P.; Lossie, J.; Lohmann, N.; Richard, P.; De Bortoli, M.; Angelini, A.; et al. Mutations in NEBL encoding the cardiac Z-disk protein nebulette are associated with various cardiomyopathies. Arch. Med. Sci. 2016, 12, 263–278. [Google Scholar] [CrossRef] [PubMed]
  204. Arimura, T.; Nakamura, T.; Hiroi, S.; Satoh, M.; Takahashi, M.; Ohbuchi, N.; Ueda, K.; Nouchi, T.; Yamaguchi, N.; Akai, J.; et al. Characterization of the human nebulette gene: A polymorphism in an actin-binding motif is associated with nonfamilial idiopathic dilated cardiomyopathy. Hum. Genet. 2000, 107, 440–451. [Google Scholar] [CrossRef] [PubMed]
  205. Wang, H.; Li, Z.; Wang, J.; Sun, K.; Cui, Q.; Song, L.; Zou, Y.; Wang, X.; Liu, X.; Hui, R.; et al. Mutations in NEXN, a Z-disc gene, are associated with hypertrophic cardiomyopathy. Am. J. Hum. Genet. 2010, 87, 687–693. [Google Scholar] [CrossRef] [PubMed]
  206. Hassel, D.; Dahme, T.; Erdmann, J.; Meder, B.; Huge, A.; Stoll, M.; Just, S.; Hess, A.; Ehlermann, P.; Weichenhan, D.; et al. Nexilin mutations destabilize cardiac Z-disks and lead to dilated cardiomyopathy. Nat. Med. 2009, 15, 1281–1288. [Google Scholar] [CrossRef] [PubMed]
  207. Yuen, T.; Borle, K.; Wenzel, K.; Eileen, P.; French, V.; Brodehl, A.; Lauzon, J.; Sharma, P.; Klaassen, S.; Gerull, B. Novel Variants in Nexilin are Associated with Left Ventricular Noncompaction Cardiomyopathy. Circulation 2014, 130, A17287. [Google Scholar]
  208. Xu, J.H.; Gu, J.Y.; Guo, Y.H.; Zhang, H.; Qiu, X.B.; Li, R.G.; Shi, H.Y.; Liu, H.; Yang, X.X.; Xu, Y.J.; et al. Prevalence and spectrum of NKX2-5 mutations associated with sporadic adult-onset dilated cardiomyopathy. Int. Heart J. 2017, 58, 521–529. [Google Scholar] [CrossRef]
  209. Marston, S.; Montgiraud, C.; Munster, A.B.; Copeland, O.; Choi, O.; Dos Remedios, C.; Messer, A.E.; Ehler, E.; Knoll, R. OBSCN mutations associated with dilated cardiomyopathy and haploinsufficiency. PLoS ONE 2015, 10, e0138568. [Google Scholar] [CrossRef] [PubMed]
  210. Biswas, A.; Raza, A.; Das, S.; Kapoor, M.; Jayarajan, R.; Verma, A.; Shamsudheen, K.V.; Murry, B.; Seth, S.; Bhargava, B.; et al. Loss of function mutation in the P2X7, a ligand-gated ion channel gene associated with hypertrophic cardiomyopathy. Purinergic Signall. 2019, 15, 205–210. [Google Scholar] [CrossRef]
  211. Ramond, F.; Janin, A.; Di Filippo, S.; Chanavat, V.; Chalabreysse, L.; Roux-Buisson, N.; Sanlaville, D.; Touraine, R.; Millat, G. Homozygous PKP2 deletion associated with neonatal left ventricle noncompaction. Clin. Genet. 2017, 91, 126–130. [Google Scholar] [CrossRef] [PubMed]
  212. Gerull, B.; Kirchner, F.; Chong, J.X.; Tagoe, J.; Chandrasekharan, K.; Strohm, O.; Waggoner, D.; Ober, C.; Duff, H.J. Homozygous founder mutation in desmocollin-2 (DSC2) causes arrhythmogenic cardiomyopathy in the Hutterite population. Circ. Cardiovasc. Genet. 2013, 6, 327–336. [Google Scholar] [CrossRef] [PubMed]
  213. Haghighi, K.; Kolokathis, F.; Pater, L.; Lynch, R.A.; Asahi, M.; Gramolini, A.O.; Fan, G.C.; Tsiapras, D.; Hahn, H.S.; Adamopoulos, S.; et al. Human phospholamban null results in lethal dilated cardiomyopathy revealing a critical difference between mouse and human. J. Clin. Investig. 2003, 111, 869–876. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  214. Schmitt, J.P.; Kamisago, M.; Asahi, M.; Li, G.H.; Ahmad, F.; Mende, U.; Kranias, E.G.; MacLennan, D.H.; Seidman, J.G.; Seidman, C.E. Dilated cardiomyopathy and heart failure caused by a mutation in phospholamban. Science 2003, 299, 1410–1413. [Google Scholar] [CrossRef] [PubMed]
  215. Iuso, A.; Wiersma, M.; Schuller, H.J.; Pode-Shakked, B.; Marek-Yagel, D.; Grigat, M.; Schwarzmayr, T.; Berutti, R.; Alhaddad, B.; Kanon, B.; et al. Mutations in PPCS, encoding phosphopantothenoylcysteine synthetase, cause autosomal-recessive dilated cardiomyopathy. Am. J. Hum. Genet. 2018, 102, 1018–1030. [Google Scholar] [CrossRef]
  216. Long, P.A.; Evans, J.M.; Olson, T.M. Diagnostic yield of whole exome sequencing in pediatric dilated cardiomyopathy. J. Cardiovasc. Dev. Dis. 2017, 4, 11. [Google Scholar] [CrossRef]
  217. Arndt, A.K.; Schafer, S.; Drenckhahn, J.D.; Sabeh, M.K.; Plovie, E.R.; Caliebe, A.; Klopocki, E.; Musso, G.; Werdich, A.A.; Kalwa, H.; et al. Fine mapping of the 1p36 deletion syndrome identifies mutation of PRDM16 as a cause of cardiomyopathy. Am. J. Hum. Genet. 2013, 93, 67–77. [Google Scholar] [CrossRef]
  218. Blair, E.; Redwood, C.; Ashrafian, H.; Oliveira, M.; Broxholme, J.; Kerr, B.; Salmon, A.; Ostman-Smith, I.; Watkins, H. Mutations in the γ(2) subunit of AMP-activated protein kinase cause familial hypertrophic cardiomyopathy: Evidence for the central role of energy compromise in disease pathogenesis. Hum. Mol. Genet. 2001, 10, 1215–1220. [Google Scholar] [CrossRef]
  219. Vaughan, C.J.; Hom, Y.; Okin, D.A.; McDermott, D.A.; Lerman, B.B.; Basson, C.T. Molecular genetic analysis of PRKAG2 in sporadic Wolff-Parkinson-White syndrome. J. Cardiovasc. Electrophysiol. 2003, 14, 263–268. [Google Scholar] [CrossRef]
  220. Li, D.; Parks, S.B.; Kushner, J.D.; Nauman, D.; Burgess, D.; Ludwigsen, S.; Partain, J.; Nixon, R.R.; Allen, C.N.; Irwin, R.P.; et al. Mutations of presenilin genes in dilated cardiomyopathy and heart failure. Am. J. Hum. Genet. 2006, 79, 1030–1039. [Google Scholar] [CrossRef]
  221. Gianni, D.; Li, A.; Tesco, G.; McKay, K.M.; Moore, J.; Raygor, K.; Rota, M.; Gwathmey, J.K.; Dec, G.W.; Aretz, T.; et al. Protein aggregates and novel presenilin gene variants in idiopathic dilated cardiomyopathy. Circulation 2010, 121, 1216–1226. [Google Scholar] [CrossRef] [PubMed]
  222. Tartaglia, M.; Mehler, E.L.; Goldberg, R.; Zampino, G.; Brunner, H.G.; Kremer, H.; van der Burgt, I.; Crosby, A.H.; Ion, A.; Jeffery, S.; et al. Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat. Genet. 2001, 29, 465–468. [Google Scholar] [CrossRef] [PubMed]
  223. Razzaque, M.A.; Nishizawa, T.; Komoike, Y.; Yagi, H.; Furutani, M.; Amo, R.; Kamisago, M.; Momma, K.; Katayama, H.; Nakagawa, M.; et al. Germline gain-of-function mutations in RAF1 cause Noonan syndrome. Nat. Genet. 2007, 39, 1013–1017. [Google Scholar] [CrossRef] [PubMed]
  224. Pandit, B.; Sarkozy, A.; Pennacchio, L.A.; Carta, C.; Oishi, K.; Martinelli, S.; Pogna, E.A.; Schackwitz, W.; Ustaszewska, A.; Landstrom, A.; et al. Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy. Nat. Genet. 2007, 39, 1007–1012. [Google Scholar] [CrossRef] [PubMed]
  225. Dhandapany, P.S.; Razzaque, M.A.; Muthusami, U.; Kunnoth, S.; Edwards, J.J.; Mulero-Navarro, S.; Riess, I.; Pardo, S.; Sheng, J.; Rani, D.S.; et al. RAF1 mutations in childhood-onset dilated cardiomyopathy. Nat. Genet. 2014, 46, 635–639. [Google Scholar] [CrossRef] [PubMed]
  226. Guo, W.; Schafer, S.; Greaser, M.L.; Radke, M.H.; Liss, M.; Govindarajan, T.; Maatz, H.; Schulz, H.; Li, S.; Parrish, A.M.; et al. RBM20, a gene for hereditary cardiomyopathy, regulates titin splicing. Nat. Med. 2012, 18, 766–773. [Google Scholar] [CrossRef] [PubMed]
  227. Sedaghat-Hamedani, F.; Haas, J.; Zhu, F.; Geier, C.; Kayvanpour, E.; Liss, M.; Lai, A.; Frese, K.; Pribe-Wolferts, R.; Amr, A.; et al. Clinical genetics and outcome of left ventricular non-compaction cardiomyopathy. Eur. Heart J. 2017, 38, 3449–3460. [Google Scholar] [CrossRef]
  228. Van den Hoogenhof, M.M.G.; Beqqali, A.; Amin, A.S.; van der Made, I.; Aufiero, S.; Khan, M.A.F.; Schumacher, C.A.; Jansweijer, J.A.; van Spaendonck-Zwarts, K.Y.; Remme, C.A.; et al. RBM20 mutations induce an arrhythmogenic dilated cardiomyopathy related to disturbed calcium handling. Circulation 2018, 138, 1330–1342. [Google Scholar] [CrossRef]
  229. Parikh, V.N.; Caleshu, C.; Reuter, C.; Lazzeroni, L.C.; Ingles, J.; Garcia, J.; McCaleb, K.; Adesiyun, T.; Sedaghat-Hamedani, F.; Kumar, S.; et al. Regional variation in RBM20 causes a highly penetrant arrhythmogenic cardiomyopathy. Circ. Heart Fail. 2019, 12, e005371. [Google Scholar] [CrossRef] [PubMed]
  230. Long, P.A.; Zimmermann, M.T.; Kim, M.; Evans, J.M.; Xu, X.; Olson, T.M. De novo RRAGC mutation activates mTORC1 signaling in syndromic fetal dilated cardiomyopathy. Hum. Genet. 2016, 135, 909–917. [Google Scholar] [CrossRef]
  231. Mann, S.A.; Castro, M.L.; Ohanian, M.; Guo, G.; Zodgekar, P.; Sheu, A.; Stockhammer, K.; Thompson, T.; Playford, D.; Subbiah, R.; et al. R222Q SCN5A mutation is associated with reversible ventricular ectopy and dilated cardiomyopathy. J. Am. Coll. Cardiol. 2012, 60, 1566–1573. [Google Scholar] [CrossRef] [PubMed]
  232. Erkapic, D.; Neumann, T.; Schmitt, J.; Sperzel, J.; Berkowitsch, A.; Kuniss, M.; Hamm, C.W.; Pitschner, H.F. Electrical storm in a patient with arrhythmogenic right ventricular cardiomyopathy and SCN5A mutation. Europace 2008, 10, 884–887. [Google Scholar] [CrossRef] [PubMed]
  233. Jaksch, M.; Ogilvie, I.; Yao, J.; Kortenhaus, G.; Bresser, H.G.; Gerbitz, K.D.; Shoubridge, E.A. Mutations in SCO2 are associated with a distinct form of hypertrophic cardiomyopathy and cytochrome c oxidase deficiency. Hum. Mol. Genet. 2000, 9, 795–801. [Google Scholar] [CrossRef] [PubMed]
  234. Levitas, A.; Muhammad, E.; Harel, G.; Saada, A.; Caspi, V.C.; Manor, E.; Beck, J.C.; Sheffield, V.; Parvari, R. Familial neonatal isolated cardiomyopathy caused by a mutation in the flavoprotein subunit of succinate dehydrogenase. Eur. J. Hum. Genet. 2010, 18, 1160–1165. [Google Scholar] [CrossRef] [PubMed]
  235. Van Spaendonck-Zwarts, K.Y.; van Rijsingen, I.A.; van den Berg, M.P.; Lekanne Deprez, R.H.; Post, J.G.; van Mil, A.M.; Asselbergs, F.W.; Christiaans, I.; van Langen, I.M.; Wilde, A.A.; et al. Genetic analysis in 418 index patients with idiopathic dilated cardiomyopathy: Overview of 10 years’ experience. Eur. J. Heart Fail. 2013, 15, 628–636. [Google Scholar] [CrossRef] [PubMed]
  236. Tsubata, S.; Bowles, K.R.; Vatta, M.; Zintz, C.; Titus, J.; Muhonen, L.; Bowles, N.E.; Towbin, J.A. Mutations in the human δ-sarcoglycan gene in familial and sporadic dilated cardiomyopathy. J. Clin. Investig. 2000, 106, 655–662. [Google Scholar] [CrossRef] [PubMed]
  237. Hoban, R.; Roberts, A.E.; Demmer, L.; Jethva, R.; Shephard, B. Noonan syndrome due to a SHOC2 mutation presenting with fetal distress and fatal hypertrophic cardiomyopathy in a premature infant. Am. J. Med. Genet. Part A 2012, 158A, 1411–1413. [Google Scholar] [CrossRef]
  238. Sandra, M.; Maria Pia, L.; Stefano, C.; Pietro, P.; Crociani, P.; Aldo, R.; Giuseppe, D.S.; Massimo, C. Emery-dreifuss muscular dystrophy type 4: A new SYNE1 mutation associated with hypertrophic cardiomyopathy masked by a perinatal distress-related spastic diplegia. Clin. Case Rep. 2019, 7, 1078–1082. [Google Scholar] [CrossRef]
  239. Puckelwartz, M.J.; Kessler, E.J.; Kim, G.; Dewitt, M.M.; Zhang, Y.; Earley, J.U.; Depreux, F.F.; Holaska, J.; Mewborn, S.K.; Pytel, P.; et al. Nesprin-1 mutations in human and murine cardiomyopathy. J. Mol. Cell. Cardiol. 2010, 48, 600–608. [Google Scholar] [CrossRef] [Green Version]
  240. Bione, S.; D’Adamo, P.; Maestrini, E.; Gedeon, A.K.; Bolhuis, P.A.; Toniolo, D. A novel X-linked gene, G4.5. is responsible for Barth syndrome. Nat. Genet. 1996, 12, 385–389. [Google Scholar] [CrossRef]
  241. Xing, Y.; Ichida, F.; Matsuoka, T.; Isobe, T.; Ikemoto, Y.; Higaki, T.; Tsuji, T.; Haneda, N.; Kuwabara, A.; Chen, R.; et al. Genetic analysis in patients with left ventricular noncompaction and evidence for genetic heterogeneity. Mol. Genet. Metab. 2006, 88, 71–77. [Google Scholar] [CrossRef] [PubMed]
  242. Wang, C.; Hata, Y.; Hirono, K.; Takasaki, A.; Ozawa, S.W.; Nakaoka, H.; Saito, K.; Miyao, N.; Okabe, M.; Ibuki, K.; et al. A wide and specific spectrum of genetic variants and genotype-phenotype correlations revealed by next-generation sequencing in patients with left ventricular noncompaction. J. Am. Heart Assoc. 2017, 6, e006210. [Google Scholar] [CrossRef] [PubMed]
  243. Kirk, E.P.; Sunde, M.; Costa, M.W.; Rankin, S.A.; Wolstein, O.; Castro, M.L.; Butler, T.L.; Hyun, C.; Guo, G.; Otway, R.; et al. Mutations in cardiac T-box factor gene TBX20 are associated with diverse cardiac pathologies, including defects of septation and valvulogenesis and cardiomyopathy. Am. J. Hum. Genet. 2007, 81, 280–291. [Google Scholar] [CrossRef] [PubMed]
  244. Zhao, C.M.; Bing, S.; Song, H.M.; Wang, J.; Xu, W.J.; Jiang, J.F.; Qiu, X.B.; Yuan, F.; Xu, J.H.; Yang, Y.Q. TBX20 loss-of-function mutation associated with familial dilated cardiomyopathy. Clin. Chem. Lab. Med. 2016, 54, 325–332. [Google Scholar] [CrossRef] [PubMed]
  245. Hayashi, T.; Arimura, T.; Itoh-Satoh, M.; Ueda, K.; Hohda, S.; Inagaki, N.; Takahashi, M.; Hori, H.; Yasunami, M.; Nishi, H.; et al. Tcap gene mutations in hypertrophic cardiomyopathy and dilated cardiomyopathy. J. Am. Coll. Cardiol. 2004, 44, 2192–2201. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  246. Beffagna, G.; Occhi, G.; Nava, A.; Vitiello, L.; Ditadi, A.; Basso, C.; Bauce, B.; Carraro, G.; Thiene, G.; Towbin, J.A.; et al. Regulatory mutations in transforming growth factor-beta3 gene cause arrhythmogenic right ventricular cardiomyopathy type 1. Cardiovasc. Res. 2005, 65, 366–373. [Google Scholar] [CrossRef] [PubMed]
  247. De Bortoli, M.; Postma, A.V.; Poloni, G.; Calore, M.; Minervini, G.; Mazzotti, E.; Rigato, I.; Ebert, M.; Lorenzon, A.; Vazza, G.; et al. Whole-exome sequencing identifies pathogenic variants in TJP1 gene associated with arrhythmogenic cardiomyopathy. Circ. Genom. Precis. Med. 2018, 11, e002123. [Google Scholar] [CrossRef]
  248. Yu, H.C.; Coughlin, C.R.; Geiger, E.A.; Salvador, B.J.; Elias, E.R.; Cavanaugh, J.L.; Chatfield, K.C.; Miyamoto, S.D.; Shaikh, T.H. Discovery of a potentially deleterious variant in TMEM87B in a patient with a hemizygous 2q13 microdeletion suggests a recessive condition characterized by congenital heart disease and restrictive cardiomyopathy. Cold Spring Harb. Mol. Case Stud. 2016, 2, a000844. [Google Scholar] [CrossRef]
  249. Mogensen, J.; Murphy, R.T.; Shaw, T.; Bahl, A.; Redwood, C.; Watkins, H.; Burke, M.; Elliott, P.M.; McKenna, W.J. Severe disease expression of cardiac troponin C and T mutations in patients with idiopathic dilated cardiomyopathy. J. Am. Coll. Cardiol. 2004, 44, 2033–2040. [Google Scholar] [CrossRef] [Green Version]
  250. Ploski, R.; Rydzanicz, M.; Ksiazczyk, T.M.; Franaszczyk, M.; Pollak, A.; Kosinska, J.; Michalak, E.; Stawinski, P.; Ziolkowska, L.; Bilinska, Z.T.; et al. Evidence for troponin C (TNNC1) as a gene for autosomal recessive restrictive cardiomyopathy with fatal outcome in infancy. Am. J. Med. Genet. Part A 2016, 170, 3241–3248. [Google Scholar] [CrossRef]
  251. Murphy, R.T.; Mogensen, J.; Shaw, A.; Kubo, T.; Hughes, S.; McKenna, W.J. Novel mutation in cardiac troponin I in recessive idiopathic dilated cardiomyopathy. Lancet 2004, 363, 371–372. [Google Scholar] [CrossRef]
  252. Fujino, M.; Tsuda, E.; Hirono, K.; Nakata, M.; Ichida, F.; Hata, Y.; Nishida, N.; Kurosaki, K. The TNNI3 Arg192His mutation in a 13-year-old girl with left ventricular noncompaction. J. Cardiol. Cases 2018, 18, 33–36. [Google Scholar] [CrossRef] [PubMed]
  253. Fan, L.L.; Huang, H.; Jin, J.Y.; Li, J.J.; Chen, Y.Q.; Zhao, S.P.; Xiang, R. Whole exome sequencing identifies a novel mutation (c.333 + 2T > C) of TNNI3K in a Chinese family with dilated cardiomyopathy and cardiac conduction disease. Gene 2018, 648, 63–67. [Google Scholar] [CrossRef] [PubMed]
  254. Hanson, E.L.; Jakobs, P.M.; Keegan, H.; Coates, K.; Bousman, S.; Dienel, N.H.; Litt, M.; Hershberger, R.E. Cardiac troponin T lysine 210 deletion in a family with dilated cardiomyopathy. J. Card. Fail. 2002, 8, 28–32. [Google Scholar] [CrossRef] [PubMed]
  255. Luedde, M.; Ehlermann, P.; Weichenhan, D.; Will, R.; Zeller, R.; Rupp, S.; Muller, A.; Steen, H.; Ivandic, B.T.; Ulmer, H.E.; et al. Severe familial left ventricular non-compaction cardiomyopathy due to a novel troponin T (TNNT2) mutation. Cardiovasc. Res. 2010, 86, 452–460. [Google Scholar] [CrossRef] [PubMed]
  256. Poloni, G.; Calore, M.; Rigato, I.; Marras, E.; Minervini, G.; Mazzotti, E.; Lorenzon, A.; Li Mura, I.E.A.; Telatin, A.; Zara, I.; et al. A targeted next-generation gene panel reveals a novel heterozygous nonsense variant in the TP63 gene in patients with arrhythmogenic cardiomyopathy. Heart Rhythm 2019, 16, 773–780. [Google Scholar] [CrossRef]
  257. Karibe, A.; Tobacman, L.S.; Strand, J.; Butters, C.; Back, N.; Bachinski, L.L.; Arai, A.E.; Ortiz, A.; Roberts, R.; Homsher, E.; et al. Hypertrophic cardiomyopathy caused by a novel α-tropomyosin mutation (V95A) is associated with mild cardiac phenotype, abnormal calcium binding to troponin, abnormal myosin cycling, and poor prognosis. Circulation 2001, 103, 65–71. [Google Scholar] [CrossRef]
  258. Lakdawala, N.K.; Dellefave, L.; Redwood, C.S.; Sparks, E.; Cirino, A.L.; Depalma, S.; Colan, S.D.; Funke, B.; Zimmerman, R.S.; Robinson, P.; et al. Familial dilated cardiomyopathy caused by an α-tropomyosin mutation: The distinctive natural history of sarcomeric dilated cardiomyopathy. J. Am. Coll. Cardiol. 2010, 55, 320–329. [Google Scholar] [CrossRef]
  259. Chang, B.; Nishizawa, T.; Furutani, M.; Fujiki, A.; Tani, M.; Kawaguchi, M.; Ibuki, K.; Hirono, K.; Taneichi, H.; Uese, K.; et al. Identification of a novel TPM1 mutation in a family with left ventricular noncompaction and sudden death. Mol. Genet. Metab. 2011, 102, 200–206. [Google Scholar] [CrossRef]
  260. Chen, S.N.; Czernuszewicz, G.; Tan, Y.; Lombardi, R.; Jin, J.; Willerson, J.T.; Marian, A.J. Human molecular genetic and functional studies identify TRIM63, encoding muscle RING finger protein 1, as a novel gene for human hypertrophic cardiomyopathy. Circ. Res. 2012, 111, 907–919. [Google Scholar] [CrossRef]
  261. Saito, Y.; Nakamura, K.; Nishi, N.; Igawa, O.; Yoshida, M.; Miyoshi, T.; Watanabe, A.; Morita, H.; Ito, H. TRPM4 mutation in patients with ventricular noncompaction and cardiac conduction disease. Circ. Genom. Precis. Med. 2018, 11, e002103. [Google Scholar] [CrossRef] [PubMed]
  262. Perli, E.; Pisano, A.; Glasgow, R.I.C.; Carbo, M.; Hardy, S.A.; Falkous, G.; He, L.; Cerbelli, B.; Pignataro, M.G.; Zacara, E.; et al. Novel compound mutations in the mitochondrial translation elongation factor (TSFM) gene cause severe cardiomyopathy with myocardial fibro-adipose replacement. Sci. Rep. 2019, 9, 5108. [Google Scholar] [CrossRef] [PubMed]
  263. Satoh, M.; Takahashi, M.; Sakamoto, T.; Hiroe, M.; Marumo, F.; Kimura, A. Structural analysis of the titin gene in hypertrophic cardiomyopathy: Identification of a novel disease gene. Biochem. Biophys. Res. Commun. 1999, 262, 411–417. [Google Scholar] [CrossRef] [PubMed]
  264. Itoh-Satoh, M.; Hayashi, T.; Nishi, H.; Koga, Y.; Arimura, T.; Koyanagi, T.; Takahashi, M.; Hohda, S.; Ueda, K.; Nouchi, T.; et al. Titin mutations as the molecular basis for dilated cardiomyopathy. Biochem. Biophys. Res. Commun. 2002, 291, 385–393. [Google Scholar] [CrossRef] [PubMed]
  265. Li, S.; Zhang, C.; Liu, N.; Bai, H.; Hou, C.; Song, L.; Pu, J. Titin-truncating variants are associated with heart failure events in patients with left ventricular noncompaction cardiomyopathy. Clin. Cardiol. 2019, 42, 530–535. [Google Scholar] [CrossRef] [PubMed]
  266. Saraiva, M.J.; Almeida Mdo, R.; Sherman, W.; Gawinowicz, M.; Costa, P.; Costa, P.P.; Goodman, D.S. A new transthyretin mutation associated with amyloid cardiomyopathy. Am. J. Hum. Genet. 1992, 50, 1027–1030. [Google Scholar]
  267. Holmgren, G.; Hellman, U.; Anan, I.; Lundgren, H.E.; Jonasson, J.; Stafberg, C.; Fahoum, S.; Suhr, O.B. Cardiomyopathy in Swedish patients with the Gly53Glu and His88Arg transthyretin variants. Amyloid 2005, 12, 184–188. [Google Scholar] [CrossRef]
  268. Sibbing, D.; Pfeufer, A.; Perisic, T.; Mannes, A.M.; Fritz-Wolf, K.; Unwin, S.; Sinner, M.F.; Gieger, C.; Gloeckner, C.J.; Wichmann, H.E.; et al. Mutations in the mitochondrial thioredoxin reductase gene TXNRD2 cause dilated cardiomyopathy. Eur. Heart J. 2011, 32, 1121–1133. [Google Scholar] [CrossRef]
  269. Vasile, V.C.; Will, M.L.; Ommen, S.R.; Edwards, W.D.; Olson, T.M.; Ackerman, M.J. Identification of a metavinculin missense mutation, R975W, associated with both hypertrophic and dilated cardiomyopathy. Mol. Genet. Metab. 2006, 87, 169–174. [Google Scholar] [CrossRef]
  270. Vasile, V.C.; Ommen, S.R.; Edwards, W.D.; Ackerman, M.J. A missense mutation in a ubiquitously expressed protein, vinculin, confers susceptibility to hypertrophic cardiomyopathy. Biochem. Biophys. Res. Commun. 2006, 345, 998–1003. [Google Scholar] [CrossRef]
  271. Olson, T.M.; Illenberger, S.; Kishimoto, N.Y.; Huttelmaier, S.; Keating, M.T.; Jockusch, B.M. Metavinculin mutations alter actin interaction in dilated cardiomyopathy. Circulation 2002, 105, 431–437. [Google Scholar] [CrossRef] [PubMed]
  272. Buyandelger, B.; Mansfield, C.; Kostin, S.; Choi, O.; Roberts, A.M.; Ware, J.S.; Mazzarotto, F.; Pesce, F.; Buchan, R.; Isaacson, R.L.; et al. ZBTB17 (MIZ1) is important for the cardiac stress response and a novel candidate gene for cardiomyopathy and heart failure. Circ. Cardiovasc. Genet. 2015, 8, 643–652. [Google Scholar] [CrossRef] [PubMed]
  273. Sun, Y.M.; Wang, J.; Xu, Y.J.; Wang, X.H.; Yuan, F.; Liu, H.; Li, R.G.; Zhang, M.; Li, Y.J.; Shi, H.Y.; et al. ZBTB17 loss-of-function mutation contributes to familial dilated cardiomyopathy. Heart Vessels 2018, 33, 722–732. [Google Scholar] [CrossRef] [PubMed]
  274. Gurdon, J.B.; Elsdale, T.R.; Fischberg, M. Sexually mature individuals of Xenopus laevis from the transplantation of single somatic nuclei. Nature 1958, 182, 64–65. [Google Scholar] [CrossRef] [PubMed]
  275. Elsdale, T.R.; Gurdon, J.B.; Fischberg, M. A description of the technique for nuclear transplantation in Xenopus laevis. J. Embryol. Exp. Morphol. 1960, 8, 437–444. [Google Scholar] [PubMed]
  276. Holmes, D. Stem cell scientists share 2012 Nobel Prize for medicine. Lancet 2012, 380, 1295. [Google Scholar] [CrossRef]
  277. Wilmut, I.; Schnieke, A.E.; McWhir, J.; Kind, A.J.; Campbell, K.H. Viable offspring derived from fetal and adult mammalian cells. Nature 1997, 385, 810–813. [Google Scholar] [CrossRef] [PubMed]
  278. Takahashi, K.; Yamanaka, S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 2006, 126, 663–676. [Google Scholar] [CrossRef]
  279. Okita, K.; Ichisaka, T.; Yamanaka, S. Generation of germline-competent induced pluripotent stem cells. Nature 2007, 448, 313–317. [Google Scholar] [CrossRef] [PubMed]
  280. Nakagawa, M.; Koyanagi, M.; Tanabe, K.; Takahashi, K.; Ichisaka, T.; Aoi, T.; Okita, K.; Mochiduki, Y.; Takizawa, N.; Yamanaka, S. Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts. Nat. Biotechnol. 2008, 26, 101–106. [Google Scholar] [CrossRef] [PubMed]
  281. Takahashi, K.; Tanabe, K.; Ohnuki, M.; Narita, M.; Ichisaka, T.; Tomoda, K.; Yamanaka, S. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 2007, 131, 861–872. [Google Scholar] [CrossRef] [PubMed]
  282. Blelloch, R.; Venere, M.; Yen, J.; Ramalho-Santos, M. Generation of induced pluripotent stem cells in the absence of drug selection. Cell Stem Cell 2007, 1, 245–247. [Google Scholar] [CrossRef] [PubMed]
  283. Yu, J.; Vodyanik, M.A.; Smuga-Otto, K.; Antosiewicz-Bourget, J.; Frane, J.L.; Tian, S.; Nie, J.; Jonsdottir, G.A.; Ruotti, V.; Stewart, R.; et al. Induced pluripotent stem cell lines derived from human somatic cells. Science 2007, 318, 1917–1920. [Google Scholar] [CrossRef] [PubMed]
  284. Brambrink, T.; Foreman, R.; Welstead, G.G.; Lengner, C.J.; Wernig, M.; Suh, H.; Jaenisch, R. Sequential expression of pluripotency markers during direct reprogramming of mouse somatic cells. Cell Stem Cell 2008, 2, 151–159. [Google Scholar] [CrossRef] [PubMed]
  285. Soldner, F.; Hockemeyer, D.; Beard, C.; Gao, Q.; Bell, G.W.; Cook, E.G.; Hargus, G.; Blak, A.; Cooper, O.; Mitalipova, M.; et al. Parkinson’s disease patient-derived induced pluripotent stem cells free of viral reprogramming factors. Cell 2009, 136, 964–977. [Google Scholar] [CrossRef] [PubMed]
  286. Hacein-Bey-Abina, S.; von Kalle, C.; Schmidt, M.; Le Deist, F.; Wulffraat, N.; McIntyre, E.; Radford, I.; Villeval, J.L.; Fraser, C.C.; Cavazzana-Calvo, M.; et al. A serious adverse event after successful gene therapy for X-linked severe combined immunodeficiency. N. Engl. J. Med. 2003, 348, 255–256. [Google Scholar] [CrossRef] [PubMed]
  287. Kaji, K.; Norrby, K.; Paca, A.; Mileikovsky, M.; Mohseni, P.; Woltjen, K. Virus-free induction of pluripotency and subsequent excision of reprogramming factors. Nature 2009, 458, 771–775. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  288. Zhou, W.; Freed, C.R. Adenoviral gene delivery can reprogram human fibroblasts to induced pluripotent stem cells. Stem Cells 2009, 27, 2667–2674. [Google Scholar] [CrossRef] [PubMed]
  289. Meraviglia, V.; Zanon, A.; Lavdas, A.A.; Schwienbacher, C.; Silipigni, R.; Di Segni, M.; Chen, H.S.; Pramstaller, P.P.; Hicks, A.A.; Rossini, A. Generation of induced pluripotent stem cells from frozen buffy coats using non-integrating episomal plasmids. J. Vis. Exp. 2015, 100, e52885. [Google Scholar] [CrossRef]
  290. Okita, K.; Nakagawa, M.; Hyenjong, H.; Ichisaka, T.; Yamanaka, S. Generation of mouse induced pluripotent stem cells without viral vectors. Science 2008, 322, 949–953. [Google Scholar] [CrossRef]
  291. Fusaki, N.; Ban, H.; Nishiyama, A.; Saeki, K.; Hasegawa, M. Efficient induction of transgene-free human pluripotent stem cells using a vector based on Sendai virus, an RNA virus that does not integrate into the host genome. Proc. Acad. Ser. B 2009, 85, 348–362. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  292. Judson, R.L.; Babiarz, J.E.; Venere, M.; Blelloch, R. Embryonic stem cell-specific microRNAs promote induced pluripotency. Nat. Biotechnol. 2009, 27, 459–461. [Google Scholar] [CrossRef] [PubMed]
  293. Card, D.A.; Hebbar, P.B.; Li, L.; Trotter, K.W.; Komatsu, Y.; Mishina, Y.; Archer, T.K. Oct4/Sox2-regulated miR-302 targets cyclin D1 in human embryonic stem cells. Mol. Cell. Biol. 2008, 28, 6426–6438. [Google Scholar] [CrossRef] [PubMed]
  294. Anokye-Danso, F.; Trivedi, C.M.; Juhr, D.; Gupta, M.; Cui, Z.; Tian, Y.; Zhang, Y.; Yang, W.; Gruber, P.J.; Epstein, J.A.; et al. Highly efficient miRNA-mediated reprogramming of mouse and human somatic cells to pluripotency. Cell Stem Cell 2011, 8, 376–388. [Google Scholar] [CrossRef] [PubMed]
  295. Schlaeger, T.M.; Daheron, L.; Brickler, T.R.; Entwisle, S.; Chan, K.; Cianci, A.; DeVine, A.; Ettenger, A.; Fitzgerald, K.; Godfrey, M.; et al. A comparison of non-integrating reprogramming methods. Nat. Biotechnol. 2015, 33, 58–63. [Google Scholar] [CrossRef] [PubMed]
  296. Freberg, C.T.; Dahl, J.A.; Timoskainen, S.; Collas, P. Epigenetic reprogramming of OCT4 and NANOG regulatory regions by embryonal carcinoma cell extract. Mol. Biol. Cell 2007, 18, 1543–1553. [Google Scholar] [CrossRef] [PubMed]
  297. Kim, D.; Kim, C.H.; Moon, J.I.; Chung, Y.G.; Chang, M.Y.; Han, B.S.; Ko, S.; Yang, E.; Cha, K.Y.; Lanza, R.; et al. Generation of human induced pluripotent stem cells by direct delivery of reprogramming proteins. Cell Stem Cell 2009, 4, 472–476. [Google Scholar] [CrossRef]
  298. Huangfu, D.; Maehr, R.; Guo, W.; Eijkelenboom, A.; Snitow, M.; Chen, A.E.; Melton, D.A. Induction of pluripotent stem cells by defined factors is greatly improved by small-molecule compounds. Nat. Biotechnol. 2008, 26, 795–797. [Google Scholar] [CrossRef]
  299. Li, W.; Ding, S. Small molecules that modulate embryonic stem cell fate and somatic cell reprogramming. Trends Pharmacol. Sci. 2010, 31, 36–45. [Google Scholar] [CrossRef]
  300. Bru, T.; Clarke, C.; McGrew, M.J.; Sang, H.M.; Wilmut, I.; Blow, J.J. Rapid induction of pluripotency genes after exposure of human somatic cells to mouse ES cell extracts. Exp. Cell Res. 2008, 314, 2634–2642. [Google Scholar] [CrossRef] [Green Version]
  301. Konermann, S.; Brigham, M.D.; Trevino, A.E.; Joung, J.; Abudayyeh, O.O.; Barcena, C.; Hsu, P.D.; Habib, N.; Gootenberg, J.S.; Nishimasu, H.; et al. Genome-scale transcriptional activation by an engineered CRISPR-Cas9 complex. Nature 2015, 517, 583–588. [Google Scholar] [CrossRef] [PubMed]
  302. Weltner, J.; Balboa, D.; Katayama, S.; Bespalov, M.; Krjutskov, K.; Jouhilahti, E.M.; Trokovic, R.; Kere, J.; Otonkoski, T. Human pluripotent reprogramming with CRISPR activators. Nat. Commun. 2018, 9, 2643. [Google Scholar] [CrossRef] [PubMed]
  303. Jinek, M.; Chylinski, K.; Fonfara, I.; Hauer, M.; Doudna, J.A.; Charpentier, E. A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science 2012, 337, 816–821. [Google Scholar] [CrossRef]
  304. Zetsche, B.; Gootenberg, J.S.; Abudayyeh, O.O.; Slaymaker, I.M.; Makarova, K.S.; Essletzbichler, P.; Volz, S.E.; Joung, J.; van der Oost, J.; Regev, A.; et al. Cpf1 is a single RNA-guided endonuclease of a class 2 CRISPR-Cas system. Cell 2015, 163, 759–771. [Google Scholar] [CrossRef] [PubMed]
  305. Joung, J.K.; Sander, J.D. TALENs: A widely applicable technology for targeted genome editing. Nat. Rev. Mol. Cell Biol. 2013, 14, 49–55. [Google Scholar] [CrossRef] [PubMed]
  306. Nemudryi, A.A.; Valetdinova, K.R.; Medvedev, S.P.; Zakian, S.M. TALEN and CRISPR/Cas genome editing systems: Tools of discovery. Acta Nat. 2014, 6, 19–40. [Google Scholar] [CrossRef]
  307. Debus, J.D.; Milting, H.; Brodehl, A.; Kassner, A.; Anselmetti, D.; Gummert, J.; Gaertner-Rommel, A. In vitro analysis of arrhythmogenic cardiomyopathy associated desmoglein-2 (DSG2) mutations reveals diverse glycosylation patterns. J. Mol. Cell. Cardiol. 2019, 129, 303–313. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  308. Sharma, A.; Toepfer, C.N.; Schmid, M.; Garfinkel, A.C.; Seidman, C.E. Differentiation and contractile analysis of GFP-sarcomere reporter hiPSC-cardiomyocytes. Curr. Protoc. Hum. Genet. 2018, 96, 21.12.1–21.12.12. [Google Scholar] [CrossRef] [PubMed]
  309. Matsa, E.; Dixon, J.E.; Medway, C.; Georgiou, O.; Patel, M.J.; Morgan, K.; Kemp, P.J.; Staniforth, A.; Mellor, I.; Denning, C. Allele-specific RNA interference rescues the long–QT syndrome phenotype in human-induced pluripotency stem cell cardiomyocytes. Eur. Heart J. 2014, 35, 1078–1087. [Google Scholar] [CrossRef] [PubMed]
  310. Dzilic, E.; Lahm, H.; Dressen, M.; Deutsch, M.A.; Lange, R.; Wu, S.M.; Krane, M.; Doppler, S.A. Genome editing redefines precision medicine in the cardiovascular field. Stem Cells Int. 2018, 2018, 4136473. [Google Scholar] [CrossRef]
  311. Gallagher, D.N.; Haber, J.E. Repair of a site-specific DNA cleavage: Old-school lessons for Cas9-mediated gene editing. ACS Chem. Biol. 2018, 13, 397–405. [Google Scholar] [CrossRef] [PubMed]
  312. Wei, H.; Zhang, X.H.; Clift, C.; Yamaguchi, N.; Morad, M. CRISPR/Cas9 Gene editing of RyR2 in human stem cell-derived cardiomyocytes provides a novel approach in investigating dysfunctional Ca(2+) signaling. Cell Calcium 2018, 73, 104–111. [Google Scholar] [CrossRef] [PubMed]
  313. Anderson, D.M.; Anderson, K.M.; Chang, C.L.; Makarewich, C.A.; Nelson, B.R.; McAnally, J.R.; Kasaragod, P.; Shelton, J.M.; Liou, J.; Bassel-Duby, R.; et al. A micropeptide encoded by a putative long noncoding RNA regulates muscle performance. Cell 2015, 160, 595–606. [Google Scholar] [CrossRef] [PubMed]
  314. Roberts, B.; Hendershott, M.C.; Arakaki, J.; Gerbin, K.A.; Malik, H.; Nelson, A.; Gehring, J.; Hookway, C.; Ludmann, S.A.; Yang, R.; et al. Fluorescent gene tagging of transcriptionally silent genes in hiPSCs. Stem Cell Rep. 2019, 12, 1145–1158. [Google Scholar] [CrossRef] [PubMed]
  315. Xiang, X.; Li, C.; Chen, X.; Dou, H.; Li, Y.; Zhang, X.; Luo, Y. CRISPR/Cas9-mediated gene tagging: A step-by-step protocol. Methods Mol. Biol. 2019, 1961, 255–269. [Google Scholar] [PubMed]
  316. Haupt, A.; Grancharova, T.; Arakaki, J.; Fuqua, M.A.; Roberts, B.; Gunawardane, R.N. Endogenous protein tagging in human induced pluripotent stem cells using CRISPR/Cas9. J. Vis. Exp. 2018, 138, e58130. [Google Scholar] [CrossRef]
  317. Liu, M.; Rehman, S.; Tang, X.; Gu, K.; Fan, Q.; Chen, D.; Ma, W. Methodologies for Improving HDR efficiency. Front. Genet. 2018, 9, 691. [Google Scholar] [CrossRef] [PubMed]
  318. Smirnikhina, S.A.; Anuchina, A.A.; Lavrov, A.V. Ways of improving precise knock-in by genome-editing technologies. Hum. Genet. 2019, 138, 1–19. [Google Scholar] [CrossRef]
  319. Pawelczak, K.S.; Gavande, N.S.; VanderVere-Carozza, P.S.; Turchi, J.J. Modulating DNA repair pathways to improve precision genome engineering. ACS Chem. Biol. 2018, 13, 389–396. [Google Scholar] [CrossRef]
  320. Gu, B.; Posfai, E.; Rossant, J. Efficient generation of targeted large insertions by microinjection into two-cell-stage mouse embryos. Nat. Biotechnol. 2018, 36, 632–637. [Google Scholar] [CrossRef]
  321. Savic, N.; Ringnalda, F.C.; Lindsay, H.; Berk, C.; Bargsten, K.; Li, Y.; Neri, D.; Robinson, M.D.; Ciaudo, C.; Hall, J.; et al. Covalent linkage of the DNA repair template to the CRISPR-Cas9 nuclease enhances homology-directed repair. eLife 2018, 7, e33761. [Google Scholar] [CrossRef] [PubMed]
  322. Savic, N.; Ringnalda, F.C.; Berk, C.; Bargsten, K.; Hall, J.; Jinek, M.; Schwank, G. In vitro generation of CRISPR-Cas9 complexes with covalently bound repair templates for genome editing in mammalian cells. Bio Protoc. 2019, 9, e3136. [Google Scholar] [CrossRef] [PubMed]
  323. Komor, A.C.; Kim, Y.B.; Packer, M.S.; Zuris, J.A.; Liu, D.R. Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage. Nature 2016, 533, 420–424. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  324. Zafra, M.P.; Schatoff, E.M.; Katti, A.; Foronda, M.; Breinig, M.; Schweitzer, A.Y.; Simon, A.; Han, T.; Goswami, S.; Montgomery, E.; et al. Optimized base editors enable efficient editing in cells, organoids and mice. Nat. Biotechnol. 2018, 36, 888–893. [Google Scholar] [CrossRef] [PubMed]
  325. Villiger, L.; Grisch-Chan, H.M.; Lindsay, H.; Ringnalda, F.; Pogliano, C.B.; Allegri, G.; Fingerhut, R.; Haberle, J.; Matos, J.; Robinson, M.D.; et al. Treatment of a metabolic liver disease by in vivo genome base editing in adult mice. Nat. Med. 2018, 24, 1519–1525. [Google Scholar] [CrossRef] [PubMed]
  326. Carvalho, A.B.; de Carvalho, A.C. Heart regeneration: Past, present and future. World J. Cardiol. 2010, 2, 107–111. [Google Scholar] [CrossRef] [PubMed]
  327. Claycomb, W.C.; Lanson, N.A., Jr.; Stallworth, B.S.; Egeland, D.B.; Delcarpio, J.B.; Bahinski, A.; Izzo, N.J., Jr. HL-1 cells: A cardiac muscle cell line that contracts and retains phenotypic characteristics of the adult cardiomyocyte. Proc. Natl. Acad. Sci. USA 1998, 95, 2979–2984. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  328. Mazzotta, S.; Lynch, A.T.; Hoppler, S. Cardiomyocyte differentiation from human embryonic stem cells. Methods Mol. Biol. 2018, 1816, 67–78. [Google Scholar] [PubMed]
  329. Hatani, T.; Miki, K.; Yoshida, Y. Induction of human induced pluripotent stem cells to cardiomyocytes using embryoid bodies. Methods Mol. Biol. 2018, 1816, 79–92. [Google Scholar]
  330. Zhang, J.; Wilson, G.F.; Soerens, A.G.; Koonce, C.H.; Yu, J.; Palecek, S.P.; Thomson, J.A.; Kamp, T.J. Functional cardiomyocytes derived from human induced pluripotent stem cells. Circ. Res. 2009, 104, e30–e41. [Google Scholar] [CrossRef]
  331. Pesl, M.; Acimovic, I.; Pribyl, J.; Hezova, R.; Vilotic, A.; Fauconnier, J.; Vrbsky, J.; Kruzliak, P.; Skladal, P.; Kara, T.; et al. Forced aggregation and defined factors allow highly uniform–sized embryoid bodies and functional cardiomyocytes from human embryonic and induced pluripotent stem cells. Heart Vessels 2014, 29, 834–846. [Google Scholar] [CrossRef] [PubMed]
  332. Yokoo, N.; Baba, S.; Kaichi, S.; Niwa, A.; Mima, T.; Doi, H.; Yamanaka, S.; Nakahata, T.; Heike, T. The effects of cardioactive drugs on cardiomyocytes derived from human induced pluripotent stem cells. Biochem. Biophys. Res. Commun. 2009, 387, 482–488. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  333. Zwi, L.; Caspi, O.; Arbel, G.; Huber, I.; Gepstein, A.; Park, I.H.; Gepstein, L. Cardiomyocyte differentiation of human induced pluripotent stem cells. Circulation 2009, 120, 1513–1523. [Google Scholar] [CrossRef] [PubMed]
  334. Burridge, P.W.; Thompson, S.; Millrod, M.A.; Weinberg, S.; Yuan, X.; Peters, A.; Mahairaki, V.; Koliatsos, V.E.; Tung, L.; Zambidis, E.T. A universal system for highly efficient cardiac differentiation of human induced pluripotent stem cells that eliminates interline variability. PLoS ONE 2011, 6, e18293. [Google Scholar] [CrossRef] [PubMed]
  335. Mummery, C.L.; Zhang, J.; Ng, E.S.; Elliott, D.A.; Elefanty, A.G.; Kamp, T.J. Differentiation of human embryonic stem cells and induced pluripotent stem cells to cardiomyocytes: A methods overview. Circ. Res. 2012, 111, 344–358. [Google Scholar] [CrossRef] [PubMed]
  336. Besser, R.R.; Ishahak, M.; Mayo, V.; Carbonero, D.; Claure, I.; Agarwal, A. Engineered microenvironments for maturation of stem cell derived cardiac myocytes. Theranostics 2018, 8, 124–140. [Google Scholar] [CrossRef] [PubMed]
  337. Tzahor, E. Wnt/beta-catenin signaling and cardiogenesis: Timing does matter. Dev. Cell 2007, 13, 10–13. [Google Scholar] [CrossRef] [PubMed]
  338. Nakajima, Y.; Yamagishi, T.; Hokari, S.; Nakamura, H. Mechanisms involved in valvuloseptal endocardial cushion formation in early cardiogenesis: Roles of transforming growth factor (TGF)-β and bone morphogenetic protein (BMP). Anat. Rec. 2000, 258, 119–127. [Google Scholar] [CrossRef]
  339. Mably, J.D.; Liew, C.C. Factors involved in cardiogenesis and the regulation of cardiac-specific gene expression. Circ. Res. 1996, 79, 4–13. [Google Scholar] [CrossRef]
  340. Govindsamy, A.; Naidoo, S.; Cerf, M.E. Cardiac development and transcription factors: Insulin signalling, insulin resistance, and intrauterine nutritional programming of cardiovascular disease. J. Nutr. Metab. 2018, 2018, 8547976. [Google Scholar] [CrossRef]
  341. Yan, S.; Jiao, K. Functions of miRNAs during mammalian heart development. Int. J. Mol. Sci. 2016, 17, 789. [Google Scholar] [CrossRef]
  342. Rajala, K.; Pekkanen-Mattila, M.; Aalto-Setala, K. Cardiac differentiation of pluripotent stem cells. Stem Cells Int. 2011, 2011, 383709. [Google Scholar] [CrossRef] [PubMed]
  343. Yassa, M.E.; Mansour, I.A.; Sewelam, N.I.; Hamza, H.; Gaafar, T. The impact of growth factors on human induced pluripotent stem cells differentiation into cardiomyocytes. Life Sci. 2018, 196, 38–47. [Google Scholar] [CrossRef] [PubMed]
  344. Kim, M.S.; Horst, A.; Blinka, S.; Stamm, K.; Mahnke, D.; Schuman, J.; Gundry, R.; Tomita-Mitchell, A.; Lough, J. Activin-A and Bmp4 levels modulate cell type specification during CHIR-induced cardiomyogenesis. PLoS ONE 2015, 10, e0118670. [Google Scholar] [CrossRef] [PubMed]
  345. Fonoudi, H.; Ansari, H.; Abbasalizadeh, S.; Larijani, M.R.; Kiani, S.; Hashemizadeh, S.; Zarchi, A.S.; Bosman, A.; Blue, G.M.; Pahlavan, S.; et al. A universal and robust integrated platform for the scalable production of human cardiomyocytes from pluripotent stem cells. Stem Cells Transl. Med. 2015, 4, 1482–1494. [Google Scholar] [CrossRef]
  346. Hemmi, N.; Tohyama, S.; Nakajima, K.; Kanazawa, H.; Suzuki, T.; Hattori, F.; Seki, T.; Kishino, Y.; Hirano, A.; Okada, M.; et al. A massive suspension culture system with metabolic purification for human pluripotent stem cell-derived cardiomyocytes. Life Sci. 2014, 3, 1473–1483. [Google Scholar] [CrossRef] [PubMed]
  347. Burridge, P.W.; Holmstrom, A.; Wu, J.C. Chemically defined culture and cardiomyocyte differentiation of human pluripotent stem cells. Curr. Protoc. Hum. Genet. 2015, 87, 21.3.1–21.3.15. [Google Scholar]
  348. Zhao, Y.; Rafatian, N.; Feric, N.T.; Cox, B.J.; Aschar-Sobbi, R.; Wang, E.Y.; Aggarwal, P.; Zhang, B.; Conant, G.; Ronaldson-Bouchard, K.; et al. A platform for generation of chamber-specific cardiac tissues and disease modeling. Cell 2019, 176, 913–927.e18. [Google Scholar] [CrossRef]
  349. Talkhabi, M.; Aghdami, N.; Baharvand, H. Human cardiomyocyte generation from pluripotent stem cells: A state-of-art. Life Sci. 2016, 145, 98–113. [Google Scholar] [CrossRef]
  350. Fatima, A.; Xu, G.; Shao, K.; Papadopoulos, S.; Lehmann, M.; Arnaiz-Cot, J.J.; Rosa, A.O.; Nguemo, F.; Matzkies, M.; Dittmann, S.; et al. In vitro modeling of ryanodine receptor 2 dysfunction using human induced pluripotent stem cells. Cell. Physiol. Biochem. 2011, 28, 579–592. [Google Scholar] [CrossRef]
  351. Pradhapan, P.; Kuusela, J.; Viik, J.; Aalto-Setala, K.; Hyttinen, J. Cardiomyocyte MEA data analysis (CardioMDA)—A novel field potential data analysis software for pluripotent stem cell derived cardiomyocytes. PLoS ONE 2013, 8, e73637. [Google Scholar] [CrossRef] [PubMed]
  352. Penttinen, K.; Siirtola, H.; Avalos-Salguero, J.; Vainio, T.; Juhola, M.; Aalto-Setala, K. Novel analysis software for detecting and classifying Ca2+ transient abnormalities in stem cell-derived cardiomyocytes. PLoS ONE 2015, 10, e0135806. [Google Scholar] [CrossRef] [PubMed]
  353. Tsurumi, F.; Baba, S.; Yoshinaga, D.; Umeda, K.; Hirata, T.; Takita, J.; Heike, T. The intracellular Ca2+ concentration is elevated in cardiomyocytes differentiated from hiPSCs derived from a Duchenne muscular dystrophy patient. PLoS ONE 2019, 14, e0213768. [Google Scholar] [CrossRef]
  354. Ahola, A.; Polonen, R.P.; Aalto-Setala, K.; Hyttinen, J. Simultaneous measurement of contraction and calcium transients in stem cell derived cardiomyocytes. Ann. Biomed. Eng. 2018, 46, 148–158. [Google Scholar] [CrossRef]
  355. Hortigon-Vinagre, M.P.; Zamora, V.; Burton, F.L.; Green, J.; Gintant, G.A.; Smith, G.L. The use of ratiometric fluorescence measurements of the voltage sensitive dye Di-4-ANEPPS to examine action potential characteristics and drug effects on human induced pluripotent stem cell-derived cardiomyocytes. Toxicol. Sci. 2016, 154, 320–331. [Google Scholar] [CrossRef] [PubMed]
  356. Wheelwright, M.; Win, Z.; Mikkila, J.L.; Amen, K.Y.; Alford, P.W.; Metzger, J.M. Investigation of human Ipsc-derived cardiac myocyte functional maturation by single cell traction force microscopy. PLoS ONE 2018, 13, e0194909. [Google Scholar] [CrossRef]
  357. Pesl, M.; Pribyl, J.; Acimovic, I.; Vilotic, A.; Jelinkova, S.; Salykin, A.; Lacampagne, A.; Dvorak, P.; Meli, A.C.; Skladal, P.; et al. Atomic force microscopy combined with human pluripotent stem cell derived cardiomyocytes for biomechanical sensing. Biosens. Bioelectron. 2016, 85, 751–757. [Google Scholar] [CrossRef]
  358. Liu, J.; Sun, N.; Bruce, M.A.; Wu, J.C.; Butte, M.J. Atomic force mechanobiology of pluripotent stem cell-derived cardiomyocytes. PLoS ONE 2012, 7, e37559. [Google Scholar] [CrossRef]
  359. Feaster, T.K.; Cadar, A.G.; Wang, L.; Williams, C.H.; Chun, Y.W.; Hempel, J.E.; Bloodworth, N.; Merryman, W.D.; Lim, C.C.; Wu, J.C.; et al. Matrigel mattress: A method for the generation of single contracting human-induced pluripotent stem cell-derived cardiomyocytes. Circ. Res. 2015, 117, 995–1000. [Google Scholar] [CrossRef]
  360. Carvajal-Vergara, X.; Sevilla, A.; D’Souza, S.L.; Ang, Y.S.; Schaniel, C.; Lee, D.F.; Yang, L.; Kaplan, A.D.; Adler, E.D.; Rozov, R.; et al. Patient-specific induced pluripotent stem-cell-derived models of LEOPARD syndrome. Nature 2010, 465, 808–812. [Google Scholar] [CrossRef] [Green Version]
  361. Digilio, M.C.; Conti, E.; Sarkozy, A.; Mingarelli, R.; Dottorini, T.; Marino, B.; Pizzuti, A.; Dallapiccola, B. Grouping of multiple-lentigines/LEOPARD and Noonan syndromes on the PTPN11 gene. Am. J. Hum. Genet. 2002, 71, 389–394. [Google Scholar] [CrossRef] [PubMed]
  362. Ganigara, M.; Prabhu, A.; Kumar, R.S. LEOPARD syndrome in an infant with severe hypertrophic cardiomyopathy and PTPN11 mutation. Ann. Pediatr. Cardiol. 2011, 4, 74–76. [Google Scholar] [CrossRef] [PubMed]
  363. Limongelli, G.; Pacileo, G.; Russo, M.G.; Sarkozy, A.; Felicetti, M.; Di Salvo, G.; Morelli, C.; Calabro, P.; Paladini, D.; Marino, B.; et al. Severe, early onset hypertrophic cardiomyopathy in a family with LEOPARD syndrome. J. Prenat. Med. 2008, 2, 24–26. [Google Scholar]
  364. Molkentin, J.D. Calcineurin-NFAT signaling regulates the cardiac hypertrophic response in coordination with the MAPKs. Cardiovasc. Res. 2004, 63, 467–475. [Google Scholar] [CrossRef] [PubMed]
  365. Adamcova, M.; Skarkova, V.; Seifertova, J.; Rudolf, E. Cardiac troponins are among targets of doxorubicin-induced cardiotoxicity in hiPCS-CMs. Int. J. Mol. Sci. 2019, 20, 2638. [Google Scholar] [CrossRef]
  366. Lu, Y.; Bu, M.; Yun, H. Sevoflurane prevents hypoxia/reoxygenation-induced cardiomyocyte apoptosis by inhibiting PI3KC3-mediated autophagy. Hum. Cell 2019, 32, 150–159. [Google Scholar] [CrossRef] [PubMed]
  367. Naftali-Shani, N.; Molotski, N.; Nevo-Caspi, Y.; Arad, M.; Kuperstein, R.; Amit, U.; Huber, I.; Zeltzer, L.A.; Levich, A.; Abbas, H.; et al. Modeling peripartum cardiomyopathy with human induced pluripotent stem cells reveals distinctive abnormal function of cardiomyocytes. Circulation 2018, 138, 2721–2723. [Google Scholar] [CrossRef]
  368. Graneli, C.; Hicks, R.; Brolen, G.; Synnergren, J.; Sartipy, P. Diabetic cardiomyopathy modelling using induced pluripotent stem cell derived cardiomyocytes: Recent advances and emerging models. Stem Cell Rev. 2019, 15, 13–22. [Google Scholar] [CrossRef]
  369. Drawnel, F.M.; Boccardo, S.; Prummer, M.; Delobel, F.; Graff, A.; Weber, M.; Gerard, R.; Badi, L.; Kam-Thong, T.; Bu, L.; et al. Disease modeling and phenotypic drug screening for diabetic cardiomyopathy using human induced pluripotent stem cells. Cell Rep. 2014, 9, 810–821. [Google Scholar] [CrossRef]
  370. Ng, K.M.; Lau, Y.M.; Dhandhania, V.; Cai, Z.J.; Lee, Y.K.; Lai, W.H.; Tse, H.F.; Siu, C.W. Empagliflozin ammeliorates high glucose induced-cardiac dysfuntion in human iPSC-derived cardiomyocytes. Sci. Rep. 2018, 8, 14872. [Google Scholar] [CrossRef]
  371. Pant, T.; Mishra, M.K.; Bai, X.; Ge, Z.D.; Bosnjak, Z.J.; Dhanasekaran, A. Microarray analysis of long non-coding RNA and mRNA expression profiles in diabetic cardiomyopathy using human induced pluripotent stem cell-derived cardiomyocytes. Diabetes Vasc. Dis. Res. 2019, 16, 57–68. [Google Scholar] [CrossRef]
  372. Bozzi, A.; Sayed, N.; Matsa, E.; Sass, G.; Neofytou, E.; Clemons, K.V.; Correa-Oliveira, R.; Stevens, D.A.; Wu, J.C. Using human induced pluripotent stem cell-derived cardiomyocytes as a model to study Trypanosoma cruzi infection. Stem Cell Rep. 2019, 12, 1232–1241. [Google Scholar] [CrossRef] [PubMed]
  373. Sharma, A.; Marceau, C.; Hamaguchi, R.; Burridge, P.W.; Rajarajan, K.; Churko, J.M.; Wu, H.; Sallam, K.I.; Matsa, E.; Sturzu, A.C.; et al. Human induced pluripotent stem cell-derived cardiomyocytes as an in vitro model for coxsackievirus B3-induced myocarditis and antiviral drug screening platform. Circ. Res. 2014, 115, 556–566. [Google Scholar] [CrossRef] [PubMed]
  374. Judge, L.M.; Perez-Bermejo, J.A.; Truong, A.; Ribeiro, A.J.; Yoo, J.C.; Jensen, C.L.; Mandegar, M.A.; Huebsch, N.; Kaake, R.M.; So, P.L.; et al. A BAG3 chaperone complex maintains cardiomyocyte function during proteotoxic stress. JCI Insight 2017, 2, e94623. [Google Scholar] [CrossRef] [PubMed]
  375. Ma, N.; Zhang, J.; Itzhaki, I.; Zhang, S.L.; Chen, H.; Haddad, F.; Kitani, T.; Wilson, K.D.; Tian, L.; Shrestha, R.; et al. Determining the pathogenicity of a genomic variant of uncertain significance using CRISPR/Cas9 and human-induced pluripotent stem cells. Circulation 2018, 138, 2666–2681. [Google Scholar] [CrossRef]
  376. Bezzerides, V.J.; Caballero, A.; Wang, S.; Ai, Y.; Hylind, R.J.; Lu, F.; Heims-Waldron, D.A.; Chambers, K.D.; Zhang, D.; Abrams, D.J.; et al. Gene therapy for catecholaminergic polymorphic ventricular tachycardia by inhibition of Ca(2+)/calmodulin-dependent kinase II. Circulation 2019, 140, 405–419. [Google Scholar] [CrossRef] [PubMed]
  377. Gramlich, M.; Pane, L.S.; Zhou, Q.; Chen, Z.; Murgia, M.; Schotterl, S.; Goedel, A.; Metzger, K.; Brade, T.; Parrotta, E.; et al. Antisense-mediated exon skipping: A therapeutic strategy for titin-based dilated cardiomyopathy. EMBO Mol. Med. 2015, 7, 562–576. [Google Scholar] [CrossRef]
  378. Van Heesch, S.; Witte, F.; Schneider-Lunitz, V.; Schulz, J.F.; Adami, E.; Faber, A.B.; Kirchner, M.; Maatz, H.; Blachut, S.; Sandmann, C.L.; et al. The translational landscape of the human heart. Cell 2019, 178, 242–260.e29. [Google Scholar] [CrossRef]
  379. Kyrychenko, V.; Kyrychenko, S.; Tiburcy, M.; Shelton, J.M.; Long, C.; Schneider, J.W.; Zimmermann, W.H.; Bassel-Duby, R.; Olson, E.N. Functional correction of dystrophin actin binding domain mutations by genome editing. JCI Insight 2017, 2, e95918. [Google Scholar] [CrossRef]
  380. Smith, J.G.W.; Owen, T.; Bhagwan, J.R.; Mosqueira, D.; Scott, E.; Mannhardt, I.; Patel, A.; Barriales-Villa, R.; Monserrat, L.; Hansen, A.; et al. Isogenic pairs of hiPSC-CMs with hypertrophic cardiomyopathy/LVNC-associated ACTC1 E99K mutation unveil differential functional deficits. Stem Cell Rep. 2018, 11, 1226–1243. [Google Scholar] [CrossRef]
  381. Phelan, D.G.; Anderson, D.J.; Howden, S.E.; Wong, R.C.; Hickey, P.F.; Pope, K.; Wilson, G.R.; Pebay, A.; Davis, A.M.; Petrou, S.; et al. ALPK3-deficient cardiomyocytes generated from patient-derived induced pluripotent stem cells and mutant human embryonic stem cells display abnormal calcium handling and establish that ALPK3 deficiency underlies familial cardiomyopathy. Eur. Heart J. 2016, 37, 2586–2590. [Google Scholar] [CrossRef] [PubMed]
  382. Josowitz, R.; Mulero-Navarro, S.; Rodriguez, N.A.; Falce, C.; Cohen, N.; Ullian, E.M.; Weiss, L.A.; Rauen, K.A.; Sobie, E.A.; Gelb, B.D. Autonomous and Non-autonomous defects underlie hypertrophic cardiomyopathy in BRAF-mutant hiPSC-derived cardiomyocytes. Stem Cell Rep. 2016, 7, 355–369. [Google Scholar] [CrossRef] [PubMed]
  383. Meraviglia, V.; Benzoni, P.; Landi, S.; Murano, C.; Langione, M.; Motta, B.M.; Baratto, S.; Silipigni, R.; Di Segni, M.; Pramstaller, P.P.; et al. Generation of human induced pluripotent stem cells (EURACi001-A, EURACi002-A, EURACi003-A) from peripheral blood mononuclear cells of three patients carrying mutations in the CAV3 gene. Stem Cell Res. 2018, 27, 25–29. [Google Scholar] [CrossRef] [PubMed]
  384. Mitzelfelt, K.A.; Limphong, P.; Choi, M.J.; Kondrat, F.D.; Lai, S.; Kolander, K.D.; Kwok, W.M.; Dai, Q.; Grzybowski, M.N.; Zhang, H.; et al. The human 343delT HSPB5 chaperone associated with early-onset skeletal myopathy causes defects in protein solubility. J. Biol. Chem. 2016, 291, 14939–14953. [Google Scholar] [CrossRef] [PubMed]
  385. Fatima, A.; Dittmann, S.; Kaifeng, S.; Linke, M.; Zechner, U.; Hennies, H.C.; Stork, I.; Rosenkranz, S.; Farr, M.; Milting, H.; et al. Derivation of induced pluripotent stem (iPS) cells from a patient with an arrhythmogenic right ventricular cardiomyopathy (ARVC). J. Stem Cells Regen. Med. 2010, 6, 97. [Google Scholar] [PubMed]
  386. Khudiakov, A.; Kostina, D.; Zlotina, A.; Nikulina, T.; Sergushichev, A.; Gudkova, A.; Tomilin, A.; Malashicheva, A.; Kostareva, A. Generation of iPSC line from desmin-related cardiomyopathy patient carrying splice site mutation of DES gene. Stem Cell Res. 2017, 24, 77–80. [Google Scholar] [CrossRef]
  387. Tse, H.F.; Ho, J.C.; Choi, S.W.; Lee, Y.K.; Butler, A.W.; Ng, K.M.; Siu, C.W.; Simpson, M.A.; Lai, W.H.; Chan, Y.C.; et al. Patient-specific induced-pluripotent stem cells-derived cardiomyocytes recapitulate the pathogenic phenotypes of dilated cardiomyopathy due to a novel DES mutation identified by whole exome sequencing. Hum. Mol. Genet. 2013, 22, 1395–1403. [Google Scholar] [CrossRef]
  388. Eisen, B.; Ben Jehuda, R.; Cuttitta, A.J.; Mekies, L.N.; Shemer, Y.; Baskin, P.; Reiter, I.; Willi, L.; Freimark, D.; Gherghiceanu, M.; et al. Electrophysiological abnormalities in induced pluripotent stem cell-derived cardiomyocytes generated from Duchenne muscular dystrophy patients. J. Cell. Mol. Med. 2019, 23, 2125–2135. [Google Scholar] [CrossRef] [Green Version]
  389. Pioner, J.M.; Guan, X.; Klaiman, J.M.; Racca, A.W.; Pabon, L.; Muskheli, V.; Macadangdang, J.; Ferrantini, C.; Hoopmann, M.R.; Moritz, R.L.; et al. Absence of full-length dystrophin impairs normal maturation and contraction of cardiomyocytes derived from human induced pluripotent stem cells. Cardiovasc. Res. 2019. [Google Scholar] [CrossRef]
  390. Guan, X.; Mack, D.L.; Moreno, C.M.; Strande, J.L.; Mathieu, J.; Shi, Y.; Markert, C.D.; Wang, Z.; Liu, G.; Lawlor, M.W.; et al. Dystrophin-deficient cardiomyocytes derived from human urine: New biologic reagents for drug discovery. Stem Cell Res. 2014, 12, 467–480. [Google Scholar] [CrossRef] [PubMed]
  391. El-Battrawy, I.; Zhao, Z.; Lan, H.; Cyganek, L.; Tombers, C.; Li, X.; Buljubasic, F.; Lang, S.; Tiburcy, M.; Zimmermann, W.H.; et al. Electrical dysfunctions in human-induced pluripotent stem cell-derived cardiomyocytes from a patient with an arrhythmogenic right ventricular cardiomyopathy. Europace 2018, 20, f46–f56. [Google Scholar] [CrossRef] [PubMed]
  392. Ng, R.; Manring, H.R.; Papoutsidakis, N.; Albertelli, T.; Tsai, N.; See, C.; Li, X.; Park, J.; Stevens, T.L.; Bobbili, P.J.; et al. Patient mutations linked to arrhythmogenic cardiomyopathy enhance calpain-mediated desmoplakin degradation. JCI Insight 2019, 4, e128643. [Google Scholar] [CrossRef] [PubMed]
  393. Klein, S.; Dvornik, J.L.; Yarrabothula, A.R.; Schaniel, C. A Marfan syndrome human induced pluripotent stem cell line with a heterozygous FBN1 c.4082G > A mutation, ISMMSi002-B, for disease modeling. Stem Cell Res. 2017, 23, 73–76. [Google Scholar] [CrossRef] [PubMed]
  394. El-Battrawy, I.; Zhao, Z.; Lan, H.; Li, X.; Yucel, G.; Lang, S.; Sattler, K.; Schunemann, J.D.; Zimmermann, W.H.; Cyganek, L.; et al. Ion channel dysfunctions in dilated cardiomyopathy in limb-girdle muscular dystrophy. Circ. Genom. Precis. Med. 2018, 11, e001893. [Google Scholar] [CrossRef] [PubMed]
  395. Lee, Y.K.; Ho, P.W.; Schick, R.; Lau, Y.M.; Lai, W.H.; Zhou, T.; Li, Y.; Ng, K.M.; Ho, S.L.; Esteban, M.A.; et al. Modeling of Friedreich ataxia-related iron overloading cardiomyopathy using patient-specific-induced pluripotent stem cells. Pflugers Arch. Eur. J. Physiol. 2014, 466, 1831–1844. [Google Scholar] [CrossRef] [PubMed]
  396. Hick, A.; Wattenhofer-Donze, M.; Chintawar, S.; Tropel, P.; Simard, J.P.; Vaucamps, N.; Gall, D.; Lambot, L.; Andre, C.; Reutenauer, L.; et al. Neurons and cardiomyocytes derived from induced pluripotent stem cells as a model for mitochondrial defects in Friedreich’s ataxia. Dis. Models Mech. 2013, 6, 608–621. [Google Scholar] [CrossRef] [PubMed]
  397. Chien, Y.; Chou, S.J.; Chang, Y.L.; Leu, H.B.; Yang, Y.P.; Tsai, P.H.; Lai, Y.H.; Chen, K.H.; Chang, W.C.; Sung, S.H.; et al. Inhibition of arachidonate 12/15-lipoxygenase improves α-galactosidase efficacy in iPSC-derived cardiomyocytes from fabry patients. Int. J. Mol. Sci. 2018, 19, 1480. [Google Scholar] [CrossRef] [PubMed]
  398. Chou, S.J.; Yu, W.C.; Chang, Y.L.; Chen, W.Y.; Chang, W.C.; Chien, Y.; Yen, J.C.; Liu, Y.Y.; Chen, S.J.; Wang, C.Y.; et al. Energy utilization of induced pluripotent stem cell–derived cardiomyocyte in Fabry disease. Int. J. Cardiol. 2017, 232, 255–263. [Google Scholar] [CrossRef]
  399. Yoshida, S.; Nakanishi, C.; Okada, H.; Mori, M.; Yokawa, J.; Yoshimuta, T.; Ohta, K.; Konno, T.; Fujino, N.; Kawashiri, M.A.; et al. Characteristics of induced pluripotent stem cells from clinically divergent female monozygotic twins with Danon disease. J. Mol. Cell. Cardiol. 2018, 114, 234–242. [Google Scholar] [CrossRef]
  400. Hashem, S.I.; Murphy, A.N.; Divakaruni, A.S.; Klos, M.L.; Nelson, B.C.; Gault, E.C.; Rowland, T.J.; Perry, C.N.; Gu, Y.; Dalton, N.D.; et al. Impaired mitophagy facilitates mitochondrial damage in Danon disease. J. Mol. Cell. Cardiol. 2017, 108, 86–94. [Google Scholar] [CrossRef]
  401. Chi, C.; Leonard, A.; Knight, W.E.; Beussman, K.M.; Zhao, Y.; Cao, Y.; Londono, P.; Aune, E.; Trembley, M.A.; Small, E.M.; et al. LAMP-2B regulates human cardiomyocyte function by mediating autophagosome-lysosome fusion. Proc. Natl. Acad. Sci. USA 2019, 116, 556–565. [Google Scholar] [CrossRef] [PubMed]
  402. Shah, D.; Virtanen, L.; Prajapati, C.; Kiamehr, M.; Gullmets, J.; West, G.; Kreutzer, J.; Pekkanen-Mattila, M.; Helio, T.; Kallio, P.; et al. Modeling of LMNA-related dilated cardiomyopathy using human induced pluripotent stem cells. Cells 2019, 8, 594. [Google Scholar] [CrossRef] [PubMed]
  403. Ho, J.C.; Zhou, T.; Lai, W.H.; Huang, Y.; Chan, Y.C.; Li, X.; Wong, N.L.; Li, Y.; Au, K.W.; Guo, D.; et al. Generation of induced pluripotent stem cell lines from 3 distinct laminopathies bearing heterogeneous mutations in lamin A/C. Aging 2011, 3, 380–390. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  404. Siu, C.W.; Lee, Y.K.; Ho, J.C.; Lai, W.H.; Chan, Y.C.; Ng, K.M.; Wong, L.Y.; Au, K.W.; Lau, Y.M.; Zhang, J.; et al. Modeling of lamin A/C mutation premature cardiac aging using patient-specific induced pluripotent stem cells. Aging 2012, 4, 803–822. [Google Scholar] [CrossRef] [Green Version]
  405. Lee, Y.K.; Lau, Y.M.; Cai, Z.J.; Lai, W.H.; Wong, L.Y.; Tse, H.F.; Ng, K.M.; Siu, C.W. Modeling treatment response for lamin A/C related dilated cardiomyopathy in human induced pluripotent stem cells. J. Am. Heart Assoc. 2017, 6, e005677. [Google Scholar] [CrossRef]
  406. Salvarani, N.; Crasto, S.; Miragoli, M.; Bertero, A.; Paulis, M.; Kunderfranco, P.; Serio, S.; Forni, A.; Lucarelli, C.; Dal Ferro, M.; et al. The K219T-Lamin mutation induces conduction defects through epigenetic inhibition of SCN5A in human cardiac laminopathy. Nat. Commun. 2019, 10, 2267. [Google Scholar] [CrossRef]
  407. Li, S.; Pan, H.; Tan, C.; Sun, Y.; Song, Y.; Zhang, X.; Yang, W.; Wang, X.; Li, D.; Dai, Y.; et al. Mitochondrial dysfunctions contribute to hypertrophic cardiomyopathy in patient iPSC-derived cardiomyocytes with MT-RNR2 mutation. Stem Cell Rep. 2018, 10, 808–821. [Google Scholar] [CrossRef] [PubMed]
  408. Wu, H.; Yang, H.; Rhee, J.W.; Zhang, J.Z.; Lam, C.K.; Sallam, K.; Chang, A.C.Y.; Ma, N.; Lee, J.; Zhang, H.; et al. Modelling diastolic dysfunction in induced pluripotent stem cell-derived cardiomyocytes from hypertrophic cardiomyopathy patients. Eur. Heart J. 2019. [Google Scholar] [CrossRef] [PubMed]
  409. Dementyeva, E.V.; Medvedev, S.P.; Kovalenko, V.R.; Vyatkin, Y.V.; Kretov, E.I.; Slotvitsky, M.M.; Shtokalo, D.N.; Pokushalov, E.A.; Zakian, S.M. Applying patient-specific induced pluripotent stem cells to create a model of hypertrophic cardiomyopathy. Biochemistry (Mosc) 2019, 84, 291–298. [Google Scholar] [CrossRef] [PubMed]
  410. Dambrot, C.; Braam, S.R.; Tertoolen, L.G.; Birket, M.; Atsma, D.E.; Mummery, C.L. Serum supplemented culture medium masks hypertrophic phenotypes in human pluripotent stem cell derived cardiomyocytes. J. Cell. Mol. Med. 2014, 18, 1509–1518. [Google Scholar] [CrossRef]
  411. Birket, M.J.; Ribeiro, M.C.; Kosmidis, G.; Ward, D.; Leitoguinho, A.R.; van de Pol, V.; Dambrot, C.; Devalla, H.D.; Davis, R.P.; Mastroberardino, P.G.; et al. Contractile defect caused by mutation in MYBPC3 revealed under conditions optimized for human PSC-cardiomyocyte function. Cell Rep. 2015, 13, 733–745. [Google Scholar] [CrossRef] [PubMed]
  412. Holliday, M.; Ross, S.B.; Lim, S.; Semsarian, C. Generation of an induced pluripotent stem cell line from a hypertrophic cardiomyopathy patient with a pathogenic myosin binding protein C (MYBPC3) p.Arg502Trp mutation. Stem Cell Res. 2018, 33, 56–59. [Google Scholar] [CrossRef] [PubMed]
  413. Cohn, R.; Thakar, K.; Lowe, A.; Ladha, F.A.; Pettinato, A.M.; Romano, R.; Meredith, E.; Chen, Y.S.; Atamanuk, K.; Huey, B.D.; et al. A contraction stress model of hypertrophic cardiomyopathy due to sarcomere mutations. Stem Cell Rep. 2019, 12, 71–83. [Google Scholar] [CrossRef] [PubMed]
  414. Davis, J.; Davis, L.C.; Correll, R.N.; Makarewich, C.A.; Schwanekamp, J.A.; Moussavi-Harami, F.; Wang, D.; York, A.J.; Wu, H.; Houser, S.R.; et al. A tension-based model distinguishes hypertrophic versus dilated cardiomyopathy. Cell 2016, 165, 1147–1159. [Google Scholar] [CrossRef] [PubMed]
  415. Seeger, T.; Shrestha, R.; Lam, C.K.; Chen, C.; McKeithan, W.L.; Lau, E.; Wnorowski, A.; McMullen, G.; Greenhaw, M.; Lee, J.; et al. A premature termination codon mutation in MYBPC3 causes hypertrophic cardiomyopathy via chronic activation of nonsense-mediated decay. Circulation 2019, 139, 799–811. [Google Scholar] [CrossRef] [PubMed]
  416. Tanaka, A.; Yuasa, S.; Mearini, G.; Egashira, T.; Seki, T.; Kodaira, M.; Kusumoto, D.; Kuroda, Y.; Okata, S.; Suzuki, T.; et al. Endothelin-1 induces myofibrillar disarray and contractile vector variability in hypertrophic cardiomyopathy-induced pluripotent stem cell-derived cardiomyocytes. J. Am. Heart Assoc. 2014, 3, e001263. [Google Scholar] [CrossRef] [PubMed]
  417. Ojala, M.; Prajapati, C.; Polonen, R.P.; Rajala, K.; Pekkanen-Mattila, M.; Rasku, J.; Larsson, K.; Aalto-Setala, K. Mutation-specific phenotypes in hiPSC-derived cardiomyocytes carrying either myosin-binding protein C or α-tropomyosin mutation for hypertrophic cardiomyopathy. Stem Cells Int. 2016, 2016, 1684792. [Google Scholar] [CrossRef] [PubMed]
  418. Prajapati, C.; Ojala, M.; Aalto-Setala, K. Divergent effects of adrenaline in human induced pluripotent stem cell-derived cardiomyocytes obtained from hypertrophic cardiomyopathy. Dis. Models Mech. 2018, 11, dmm032896. [Google Scholar] [CrossRef]
  419. Prondzynski, M.; Kramer, E.; Laufer, S.D.; Shibamiya, A.; Pless, O.; Flenner, F.; Muller, O.J.; Munch, J.; Redwood, C.; Hansen, A.; et al. Evaluation of MYBPC3 trans-splicing and gene replacement as therapeutic options in human iPSC-derived cardiomyocytes. Mol. Ther. Nucleic Acids 2017, 7, 475–486. [Google Scholar] [CrossRef]
  420. Viswanathan, S.K.; Puckelwartz, M.J.; Mehta, A.; Ramachandra, C.J.A.; Jagadeesan, A.; Fritsche-Danielson, R.; Bhat, R.V.; Wong, P.; Kandoi, S.; Schwanekamp, J.A.; et al. Association of cardiomyopathy with MYBPC3 D389V and MYBPC3Delta25bpIntronic deletion in South Asian descendants. JAMA Cardiol. 2018, 3, 481–488. [Google Scholar] [CrossRef]
  421. Mosqueira, D.; Mannhardt, I.; Bhagwan, J.R.; Lis-Slimak, K.; Katili, P.; Scott, E.; Hassan, M.; Prondzynski, M.; Harmer, S.C.; Tinker, A.; et al. CRISPR/Cas9 editing in human pluripotent stem cell-cardiomyocytes highlights arrhythmias, hypocontractility, and energy depletion as potential therapeutic targets for hypertrophic cardiomyopathy. Eur. Heart J. 2018, 39, 3879–3892. [Google Scholar] [CrossRef]
  422. Ross, S.B.; Fraser, S.T.; Nowak, N.; Semsarian, C. Generation of induced pluripotent stem cells (iPSCs) from a hypertrophic cardiomyopathy patient with the pathogenic variant p.Val698Ala in β-myosin heavy chain (MYH7) gene. Stem Cell Res. 2017, 20, 88–90. [Google Scholar] [CrossRef] [PubMed]
  423. Yang, K.C.; Breitbart, A.; De Lange, W.J.; Hofsteen, P.; Futakuchi-Tsuchida, A.; Xu, J.; Schopf, C.; Razumova, M.V.; Jiao, A.; Boucek, R.; et al. Novel adult-onset systolic cardiomyopathy due to MYH7 E848G mutation in patient-derived induced pluripotent stem cells. JACC Basic Transl. Sci. 2018, 3, 728–740. [Google Scholar] [CrossRef] [PubMed]
  424. Pioner, J.M.; Racca, A.W.; Klaiman, J.M.; Yang, K.C.; Guan, X.; Pabon, L.; Muskheli, V.; Zaunbrecher, R.; Macadangdang, J.; Jeong, M.Y.; et al. Isolation and mechanical measurements of myofibrils from human induced pluripotent stem cell-derived cardiomyocytes. Stem Cell Rep. 2016, 6, 885–896. [Google Scholar] [CrossRef] [PubMed]
  425. Holliday, M.; Ross, S.B.; Lim, S.; Mangala, M.; Hill, A.; Szappanos, H.C.; Hool, L.; Semsarian, C. Development of induced pluripotent stem cells from a patient with hypertrophic cardiomyopathy who carries the pathogenic myosin heavy chain 7 mutation p.Arg403Gln. Stem Cell Res. 2018, 33, 269–273. [Google Scholar] [CrossRef]
  426. Lan, F.; Lee, A.S.; Liang, P.; Sanchez-Freire, V.; Nguyen, P.K.; Wang, L.; Han, L.; Yen, M.; Wang, Y.; Sun, N.; et al. Abnormal calcium handling properties underlie familial hypertrophic cardiomyopathy pathology in patient-specific induced pluripotent stem cells. Cell Stem Cell 2013, 12, 101–113. [Google Scholar] [CrossRef] [PubMed]
  427. Han, L.; Li, Y.; Tchao, J.; Kaplan, A.D.; Lin, B.; Li, Y.; Mich-Basso, J.; Lis, A.; Hassan, N.; London, B.; et al. Study familial hypertrophic cardiomyopathy using patient-specific induced pluripotent stem cells. Cardiovasc. Res. 2014, 104, 258–269. [Google Scholar] [CrossRef]
  428. Zhou, W.; Bos, J.M.; Ye, D.; Tester, D.J.; Hrstka, S.; Maleszewski, J.J.; Ommen, S.R.; Nishimura, R.A.; Schaff, H.V.; Kim, C.S.; et al. Induced pluripotent stem cell-derived cardiomyocytes from a patient with MYL2-R58Q-mediated apical hypertrophic cardiomyopathy show hypertrophy, myofibrillar disarray, and calcium perturbations. J. Cardiovasc. Transl. Res. 2019, 1–10. [Google Scholar] [CrossRef]
  429. Ma, D.; Wei, H.; Lu, J.; Ho, S.; Zhang, G.; Sun, X.; Oh, Y.; Tan, S.H.; Ng, M.L.; Shim, W.; et al. Generation of patient-specific induced pluripotent stem cell-derived cardiomyocytes as a cellular model of arrhythmogenic right ventricular cardiomyopathy. Eur. Heart J. 2013, 34(15), 1122–1133. [Google Scholar] [CrossRef]
  430. Kim, C.; Wong, J.; Wen, J.; Wang, S.; Wang, C.; Spiering, S.; Kan, N.G.; Forcales, S.; Puri, P.L.; Leone, T.C.; et al. Studying arrhythmogenic right ventricular dysplasia with patient-specific iPSCs. Nature 2013, 494, 105–110. [Google Scholar] [CrossRef] [Green Version]
  431. Martewicz, S.; Luni, C.; Serena, E.; Pavan, P.; Chen, H.V.; Rampazzo, A.; Elvassore, N. Transcriptomic characterization of a human in vitro model of arrhythmogenic cardiomyopathy under topological and mechanical stimuli. Ann. Biomed. Eng. 2019, 47, 852–865. [Google Scholar] [CrossRef] [PubMed]
  432. Akdis, D.; Saguner, A.M.; Shah, K.; Wei, C.; Medeiros-Domingo, A.; von Eckardstein, A.; Luscher, T.F.; Brunckhorst, C.; Chen, H.S.V.; Duru, F. Sex hormones affect outcome in arrhythmogenic right ventricular cardiomyopathy/dysplasia: From a stem cell derived cardiomyocyte-based model to clinical biomarkers of disease outcome. Eur. Heart J. 2017, 38, 1498–1508. [Google Scholar] [CrossRef]
  433. Caspi, O.; Huber, I.; Gepstein, A.; Arbel, G.; Maizels, L.; Boulos, M.; Gepstein, L. Modeling of arrhythmogenic right ventricular cardiomyopathy with human induced pluripotent stem cells. Circ. Cardiovasc. Genet. 2013, 6, 557–568. [Google Scholar] [CrossRef] [PubMed]
  434. Khudiakov, A.; Kostina, D.; Zlotina, A.; Yany, N.; Sergushichev, A.; Pervunina, T.; Tomilin, A.; Kostareva, A.; Malashicheva, A. Generation of iPSC line from patient with arrhythmogenic right ventricular cardiomyopathy carrying mutations in PKP2 gene. Stem Cell Res. 2017, 24, 85–88. [Google Scholar] [CrossRef] [PubMed]
  435. Ermon, B.; Volpato, C.B.; Cattelan, G.; Silipigni, R.; Di Segni, M.; Cantaloni, C.; Casella, M.; Pramstaller, P.P.; Pompilio, G.; Sommariva, E.; et al. Derivation of human induced pluripotent stem cell line EURACi004-A from skin fibroblasts of a patient with arrhythmogenic cardiomyopathy carrying the heterozygous PKP2 mutation c.2569_3018del50. Stem Cell Res. 2018, 32, 78–82. [Google Scholar] [CrossRef] [PubMed]
  436. Ceholski, D.K.; Turnbull, I.C.; Kong, C.W.; Koplev, S.; Mayourian, J.; Gorski, P.A.; Stillitano, F.; Skodras, A.A.; Nonnenmacher, M.; Cohen, N.; et al. Functional and transcriptomic insights into pathogenesis of R9C phospholamban mutation using human induced pluripotent stem cell-derived cardiomyocytes. J. Mol. Cell. Cardiol. 2018, 119, 147–154. [Google Scholar] [CrossRef]
  437. Karakikes, I.; Stillitano, F.; Nonnenmacher, M.; Tzimas, C.; Sanoudou, D.; Termglinchan, V.; Kong, C.W.; Rushing, S.; Hansen, J.; Ceholski, D.; et al. Correction of human phospholamban R14del mutation associated with cardiomyopathy using targeted nucleases and combination therapy. Nat. Commun. 2015, 6, 6955. [Google Scholar] [CrossRef]
  438. Stillitano, F.; Turnbull, I.C.; Karakikes, I.; Nonnenmacher, M.; Backeris, P.; Hulot, J.S.; Kranias, E.G.; Hajjar, R.J.; Costa, K.D. Genomic correction of familial cardiomyopathy in human engineered cardiac tissues. Eur. Heart J. 2016, 37, 3282–3284. [Google Scholar] [CrossRef] [Green Version]
  439. Ben Jehuda, R.; Eisen, B.; Shemer, Y.; Mekies, L.N.; Szantai, A.; Reiter, I.; Cui, H.; Guan, K.; Haron-Khun, S.; Freimark, D.; et al. CRISPR correction of the PRKAG2 gene mutation in the patient’s induced pluripotent stem cell-derived cardiomyocytes eliminates electrophysiological and structural abnormalities. Heart Rhythm 2018, 15, 267–276. [Google Scholar] [CrossRef]
  440. Hinson, J.T.; Chopra, A.; Lowe, A.; Sheng, C.C.; Gupta, R.M.; Kuppusamy, R.; O’Sullivan, J.; Rowe, G.; Wakimoto, H.; Gorham, J.; et al. Integrative analysis of PRKAG2 cardiomyopathy iPS and microtissue models identifies AMPK as a regulator of metabolism, survival, and fibrosis. Cell Rep. 2017, 19, 2410. [Google Scholar] [CrossRef]
  441. Li, R.; Baskfield, A.; Lin, Y.; Beers, J.; Zou, J.; Liu, C.; Jaffre, F.; Roberts, A.E.; Ottinger, E.A.; Kontaridis, M.I.; et al. Generation of an induced pluripotent stem cell line (TRNDi003-A) from a Noonan syndrome with multiple lentigines (NSML) patient carrying a p.Q510P mutation in the PTPN11 gene. Stem Cell Res. 2019, 34, 101374. [Google Scholar] [CrossRef] [PubMed]
  442. Jaffre, F.; Miller, C.L.; Schanzer, A.; Evans, T.; Roberts, A.E.; Hahn, A.; Kontaridis, M.I. iPSC-derived cardiomyocytes reveal aberrant ERK5 and MEK1/2 signaling concomitantly promote hypertrophic cardiomyopathy in RAF1-associated noonan syndrome. Circulation 2019, 140, 207–224. [Google Scholar] [CrossRef] [PubMed]
  443. Streckfuss-Bomeke, K.; Tiburcy, M.; Fomin, A.; Luo, X.; Li, W.; Fischer, C.; Ozcelik, C.; Perrot, A.; Sossalla, S.; Haas, J.; et al. Severe DCM phenotype of patient harboring RBM20 mutation S635A can be modeled by patient-specific induced pluripotent stem cell-derived cardiomyocytes. J. Mol. Cell. Cardiol. 2017, 113, 9–21. [Google Scholar] [CrossRef] [PubMed]
  444. Wyles, S.P.; Li, X.; Hrstka, S.C.; Reyes, S.; Oommen, S.; Beraldi, R.; Edwards, J.; Terzic, A.; Olson, T.M.; Nelson, T.J. Modeling structural and functional deficiencies of RBM20 familial dilated cardiomyopathy using human induced pluripotent stem cells. Hum. Mol. Genet. 2016, 25, 254–265. [Google Scholar] [CrossRef]
  445. Wyles, S.P.; Hrstka, S.C.; Reyes, S.; Terzic, A.; Olson, T.M.; Nelson, T.J. Pharmacological modulation of calcium homeostasis in familial dilated cardiomyopathy: An in vitro analysis from an RBM20 patient-derived iPSC model. Clin. Transl. Sci. 2016, 9, 158–167. [Google Scholar] [CrossRef] [PubMed]
  446. Te Riele, A.S.; Agullo-Pascual, E.; James, C.A.; Leo–Macias, A.; Cerrone, M.; Zhang, M.; Lin, X.; Lin, B.; Sobreira, N.L.; Amat-Alarcon, N.; et al. Multilevel analyses of SCN5A mutations in arrhythmogenic right ventricular dysplasia/cardiomyopathy suggest non-canonical mechanisms for disease pathogenesis. Cardiovasc. Res. 2017, 113, 102–111. [Google Scholar] [CrossRef]
  447. Moreau, A.; Gosselin-Badaroudine, P.; Mercier, A.; Burger, B.; Keller, D.I.; Chahine, M. A leaky voltage sensor domain of cardiac sodium channels causes arrhythmias associated with dilated cardiomyopathy. Sci. Rep. 2018, 8, 13804. [Google Scholar] [CrossRef]
  448. Hallas, T.; Eisen, B.; Shemer, Y.; Ben Jehuda, R.; Mekies, L.N.; Naor, S.; Schick, R.; Eliyahu, S.; Reiter, I.; Vlodavsky, E.; et al. Investigating the cardiac pathology of SCO2-mediated hypertrophic cardiomyopathy using patients induced pluripotent stem cell-derived cardiomyocytes. J. Cell. Mol. Med. 2018, 22, 913–925. [Google Scholar] [CrossRef]
  449. Wang, G.; McCain, M.L.; Yang, L.; He, A.; Pasqualini, F.S.; Agarwal, A.; Yuan, H.; Jiang, D.; Zhang, D.; Zangi, L.; et al. Modeling the mitochondrial cardiomyopathy of Barth syndrome with induced pluripotent stem cell and heart-on-chip technologies. Nat. Med. 2014, 20, 616–623. [Google Scholar] [CrossRef]
  450. Kodo, K.; Ong, S.G.; Jahanbani, F.; Termglinchan, V.; Hirono, K.; InanlooRahatloo, K.; Ebert, A.D.; Shukla, P.; Abilez, O.J.; Churko, J.M.; et al. iPSC-derived cardiomyocytes reveal abnormal TGF-β signalling in left ventricular non-compaction cardiomyopathy. Nat. Cell Biol. 2016, 18, 1031–1042. [Google Scholar] [CrossRef]
  451. Sun, N.; Yazawa, M.; Liu, J.; Han, L.; Sanchez-Freire, V.; Abilez, O.J.; Navarrete, E.G.; Hu, S.; Wang, L.; Lee, A.; et al. Patient-specific induced pluripotent stem cells as a model for familial dilated cardiomyopathy. Sci. Transl. Med. 2012, 4, 130ra47. [Google Scholar] [CrossRef] [PubMed]
  452. Wu, H.; Lee, J.; Vincent, L.G.; Wang, Q.; Gu, M.; Lan, F.; Churko, J.M.; Sallam, K.I.; Matsa, E.; Sharma, A.; et al. Epigenetic regulation of phosphodiesterases 2A and 3A underlies compromised β-adrenergic signaling in an iPSC model of dilated cardiomyopathy. Cell Stem Cell 2015, 17, 89–100. [Google Scholar] [CrossRef] [PubMed]
  453. Karakikes, I.; Termglinchan, V.; Cepeda, D.A.; Lee, J.; Diecke, S.; Hendel, A.; Itzhaki, I.; Ameen, M.; Shrestha, R.; Wu, H.; et al. A comprehensive TALEN-based knockout library for generating human-induced pluripotent stem cell-based models for cardiovascular diseases. Circ. Res. 2017, 120, 1561–1571. [Google Scholar] [CrossRef] [PubMed]
  454. Broughton, K.M.; Li, J.; Sarmah, E.; Warren, C.M.; Lin, Y.H.; Henze, M.P.; Sanchez-Freire, V.; Solaro, R.J.; Russell, B. A myosin activator improves actin assembly and sarcomere function of human-induced pluripotent stem cell-derived cardiomyocytes with a troponin T point mutation. Am. J. Physiol. Heart Circ. Physiol. 2016, 311, H107–H117. [Google Scholar] [CrossRef] [PubMed]
  455. Wang, L.; Kryshtal, D.O.; Kim, K.; Parikh, S.; Cadar, A.G.; Bersell, K.R.; He, H.; Pinto, J.R.; Knollmann, B.C. Myofilament calcium-buffering dependent action potential triangulation in human-induced pluripotent stem cell model of hypertrophic cardiomyopathy. J. Am. Coll. Cardiol. 2017, 70, 2600–2602. [Google Scholar] [CrossRef] [PubMed]
  456. Wang, L.; Kim, K.; Parikh, S.; Cadar, A.G.; Bersell, K.R.; He, H.; Pinto, J.R.; Kryshtal, D.O.; Knollmann, B.C. Hypertrophic cardiomyopathy-linked mutation in troponin T causes myofibrillar disarray and pro-arrhythmic action potential changes in human iPSC cardiomyocytes. J. Mol. Cell. Cardiol. 2018, 114, 320–327. [Google Scholar] [CrossRef] [PubMed]
  457. Hinson, J.T.; Chopra, A.; Nafissi, N.; Polacheck, W.J.; Benson, C.C.; Swist, S.; Gorham, J.; Yang, L.; Schafer, S.; Sheng, C.C.; et al. Titin mutations in iPS cells define sarcomere insufficiency as a cause of dilated cardiomyopathy. Science 2015, 349, 982–986. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  458. Schick, R.; Mekies, L.N.; Shemer, Y.; Eisen, B.; Hallas, T.; Ben Jehuda, R.; Ben-Ari, M.; Szantai, A.; Willi, L.; Shulman, R.; et al. Functional abnormalities in induced pluripotent stem cell-derived cardiomyocytes generated from titin-mutated patients with dilated cardiomyopathy. PLoS ONE 2018, 13, e0205719. [Google Scholar] [CrossRef] [PubMed]
  459. Leung, A.; Nah, S.K.; Reid, W.; Ebata, A.; Koch, C.M.; Monti, S.; Genereux, J.C.; Wiseman, R.L.; Wolozin, B.; Connors, L.H.; et al. Induced pluripotent stem cell modeling of multisystemic, hereditary transthyretin amyloidosis. Stem Cell Rep. 2013, 1, 451–463. [Google Scholar] [CrossRef]
  460. Pinto, A.R.; Ilinykh, A.; Ivey, M.J.; Kuwabara, J.T.; D’Antoni, M.L.; Debuque, R.; Chandran, A.; Wang, L.; Arora, K.; Rosenthal, N.A.; et al. Revisiting cardiac cellular composition. Circ. Res. 2016, 118, 400–409. [Google Scholar] [CrossRef]
  461. Castro, L.; Geertz, B.; Reinsch, M.; Aksehirlioglu, B.; Hansen, A.; Eschenhagen, T.; Reichenspurner, H.; Weinberger, F.; Pecha, S. Implantation of hiPSC-derived cardiac-muscle patches after myocardial injury in a Guinea pig model. J. Vis. Exp. 2019, 145, e58810. [Google Scholar] [CrossRef] [PubMed]
  462. Lemoine, M.D.; Mannhardt, I.; Breckwoldt, K.; Prondzynski, M.; Flenner, F.; Ulmer, B.; Hirt, M.N.; Neuber, C.; Horvath, A.; Kloth, B.; et al. Human iPSC-derived cardiomyocytes cultured in 3D engineered heart tissue show physiological upstroke velocity and sodium current density. Sci. Rep. 2017, 7, 5464. [Google Scholar] [CrossRef] [PubMed]
  463. Breckwoldt, K.; Letuffe-Breniere, D.; Mannhardt, I.; Schulze, T.; Ulmer, B.; Werner, T.; Benzin, A.; Klampe, B.; Reinsch, M.C.; Laufer, S.; et al. Differentiation of cardiomyocytes and generation of human engineered heart tissue. Nat. Protoc. 2017, 12, 1177–1197. [Google Scholar] [CrossRef] [PubMed]
  464. Weinberger, F.; Mannhardt, I.; Eschenhagen, T. Engineering cardiac muscle tissue: A maturating field of research. Circ. Res. 2017, 120, 1487–1500. [Google Scholar] [CrossRef] [PubMed]
  465. Meyer, T.; Tiburcy, M.; Zimmermann, W.H. Cardiac macrotissues-on-a-plate models for phenotypic drug screens. Adv. Drug Deliv. Rev. 2019, 140, 93–100. [Google Scholar] [CrossRef] [PubMed]
  466. Garber, K. RIKEN suspends first clinical trial involving induced pluripotent stem cells. Nat. Biotechnol. 2015, 33, 890–891. [Google Scholar] [CrossRef] [PubMed]
  467. Mayshar, Y.; Ben-David, U.; Lavon, N.; Biancotti, J.C.; Yakir, B.; Clark, A.T.; Plath, K.; Lowry, W.E.; Benvenisty, N. Identification and classification of chromosomal aberrations in human induced pluripotent stem cells. Cell Stem Cell 2010, 7, 521–531. [Google Scholar] [CrossRef] [PubMed]
  468. Yoshihara, M.; Hayashizaki, Y.; Murakawa, Y. Genomic instability of iPSCs: Challenges towards their clinical applications. Stem Cell Rev. 2017, 13, 7–16. [Google Scholar] [CrossRef]
  469. Liu, P.; Kaplan, A.; Yuan, B.; Hanna, J.H.; Lupski, J.R.; Reiner, O. Passage number is a major contributor to genomic structural variations in mouse iPSCs. Stem Cells 2014, 32, 2657–2667. [Google Scholar] [CrossRef]
  470. Kempf, H.; Zweigerdt, R. Scalable cardiac differentiation of pluripotent stem cells using specific growth factors and small molecules. In Engineering and Application of Pluripotent Stem Cells; Springer: Cham, Switzerland, 2017; Volume 163, pp. 39–69. [Google Scholar]
  471. Goktepe, S.; Abilez, O.J.; Parker, K.K.; Kuhl, E. A multiscale model for eccentric and concentric cardiac growth through sarcomerogenesis. J. Theor. Biol. 2010, 265, 433–442. [Google Scholar] [CrossRef]
  472. Gherghiceanu, M.; Barad, L.; Novak, A.; Reiter, I.; Itskovitz-Eldor, J.; Binah, O.; Popescu, L.M. Cardiomyocytes derived from human embryonic and induced pluripotent stem cells: Comparative ultrastructure. J. Cell. Mol. Med. 2011, 15, 2539–2551. [Google Scholar] [CrossRef] [PubMed]
  473. Jiang, Y.; Park, P.; Hong, S.M.; Ban, K. Maturation of cardiomyocytes derived from human pluripotent stem cells: Current strategies and limitations. Mol. Cells 2018, 41, 613–621. [Google Scholar] [PubMed]
  474. Koivumaki, J.T.; Naumenko, N.; Tuomainen, T.; Takalo, J.; Oksanen, M.; Puttonen, K.A.; Lehtonen, S.; Kuusisto, J.; Laakso, M.; Koistinaho, J.; et al. Structural immaturity of human iPSC-derived cardiomyocytes: In silico investigation of effects on function and disease modeling. Front. Physiol. 2018, 9, 80. [Google Scholar] [CrossRef]
  475. Bedada, F.B.; Wheelwright, M.; Metzger, J.M. Maturation status of sarcomere structure and function in human iPSC-derived cardiac myocytes. Biochim. Biophys. Acta 2016, 1863, 1829–1838. [Google Scholar] [CrossRef] [PubMed]
  476. Vermij, S.H.; Abriel, H.; van Veen, T.A. Refining the molecular organization of the cardiac intercalated disc. Cardiovasc. Res. 2017, 113, 259–275. [Google Scholar] [CrossRef] [PubMed]
  477. Fujiwara, M.; Yan, P.; Otsuji, T.G.; Narazaki, G.; Uosaki, H.; Fukushima, H.; Kuwahara, K.; Harada, M.; Matsuda, H.; Matsuoka, S.; et al. Induction and enhancement of cardiac cell differentiation from mouse and human induced pluripotent stem cells with cyclosporin-A. PLoS ONE 2011, 6, e16734. [Google Scholar] [CrossRef]
  478. Zuppinger, C.; Gibbons, G.; Dutta-Passecker, P.; Segiser, A.; Most, H.; Suter, T.M. Characterization of cytoskeleton features and maturation status of cultured human iPSC-derived cardiomyocytes. Eur. J. Histochem. 2017, 61, 2763. [Google Scholar] [CrossRef] [Green Version]
  479. Scuderi, G.J.; Butcher, J. Naturally engineered maturation of cardiomyocytes. Front. Cell Dev. Biol. 2017, 5, 50. [Google Scholar] [CrossRef]
  480. Brodsky, V.; Chernyaev, A.L.; Vasilyeva, I.A. Variability of the cardiomyocyte ploidy in normal human hearts. Virchows Archiv. B 1991, 61, 289–294. [Google Scholar] [CrossRef]
  481. Feric, N.T.; Radisic, M. Maturing human pluripotent stem cell-derived cardiomyocytes in human engineered cardiac tissues. Adv. Drug Deliv. Rev. 2016, 96, 110–134. [Google Scholar] [CrossRef]
  482. Veerman, C.C.; Kosmidis, G.; Mummery, C.L.; Casini, S.; Verkerk, A.O.; Bellin, M. Immaturity of human stem-cell-derived cardiomyocytes in culture: Fatal flaw or soluble problem? Stem Cells Dev. 2015, 24, 1035–1052. [Google Scholar] [CrossRef] [PubMed]
  483. Nguyen, M.D.; Tinney, J.P.; Ye, F.; Elnakib, A.A.; Yuan, F.; El-Baz, A.; Sethu, P.; Keller, B.B.; Giridharan, G.A. Effects of physiologic mechanical stimulation on embryonic chick cardiomyocytes using a microfluidic cardiac cell culture model. Anal. Chem. 2015, 87, 2107–2113. [Google Scholar] [CrossRef] [PubMed]
  484. Sarig, U.; Sarig, H.; de-Berardinis, E.; Chaw, S.Y.; Nguyen, E.B.; Ramanujam, V.S.; Thang, V.D.; Al-Haddawi, M.; Liao, S.; Seliktar, D.; et al. Natural myocardial ECM patch drives cardiac progenitor based restoration even after scarring. Acta Biomater. 2016, 44, 209–220. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  485. Chen, W.C.; Wang, Z.; Missinato, M.A.; Park, D.W.; Long, D.W.; Liu, H.J.; Zeng, X.; Yates, N.A.; Kim, K.; Wang, Y. Decellularized zebrafish cardiac extracellular matrix induces mammalian heart regeneration. Sci. Adv. 2016, 2, e1600844. [Google Scholar] [CrossRef] [PubMed]
  486. Kim, C.; Majdi, M.; Xia, P.; Wei, K.A.; Talantova, M.; Spiering, S.; Nelson, B.; Mercola, M.; Chen, H.S. Non-cardiomyocytes influence the electrophysiological maturation of human embryonic stem cell–derived cardiomyocytes during differentiation. Stem Cells Dev. 2010, 19, 783–795. [Google Scholar] [CrossRef] [PubMed]
  487. Kolanowski, T.J.; Antos, C.L.; Guan, K. Making human cardiomyocytes up to date: Derivation, maturation state and perspectives. Int. J. Cardiol. 2017, 241, 379–386. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  488. Glazier, A.A.; Thompson, A.; Day, S.M. Allelic imbalance and haploinsufficiency in MYBPC3-linked hypertrophic cardiomyopathy. Pflugers Archiv Eur. J. Physiol. 2019, 471, 781–793. [Google Scholar] [CrossRef] [PubMed]
  489. Clemen, C.S.; Stockigt, F.; Strucksberg, K.H.; Chevessier, F.; Winter, L.; Schutz, J.; Bauer, R.; Thorweihe, J.M.; Wenzel, D.; Schlotzer-Schrehardt, U.; et al. The toxic effect of R350P mutant desmin in striated muscle of man and mouse. Acta Neuropathol. 2015, 129, 297–315. [Google Scholar] [CrossRef]
  490. Sugawara, M.; Kato, K.; Komatsu, M.; Wada, C.; Kawamura, K.; Shindo, P.S.; Yoshioka, P.N.; Tanaka, K.; Watanabe, S.; Toyoshima, I. A novel de novo mutation in the desmin gene causes desmin myopathy with toxic aggregates. Neurology 2000, 55, 986–990. [Google Scholar] [CrossRef] [PubMed]
  491. Ma, H.; Marti-Gutierrez, N.; Park, S.W.; Wu, J.; Lee, Y.; Suzuki, K.; Koski, A.; Ji, D.; Hayama, T.; Ahmed, R.; et al. Correction of a pathogenic gene mutation in human embryos. Nature 2017, 548, 413–419. [Google Scholar] [CrossRef]
  492. Echigoya, Y.; Lim, K.R.Q.; Nakamura, A.; Yokota, T. Multiple Exon skipping in the duchenne muscular dystrophy hot spots: Prospects and challenges. J. Personal. Med. 2018, 8, 41. [Google Scholar] [CrossRef] [PubMed]
  493. Aartsma-Rus, A.; van Ommen, G.J. Antisense-mediated exon skipping: A versatile tool with therapeutic and research applications. Rna 2007, 13, 1609–1624. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  494. Dick, E.; Kalra, S.; Anderson, D.; George, V.; Ritso, M.; Laval, S.H.; Barresi, R.; Aartsma-Rus, A.; Lochmuller, H.; Denning, C. Exon skipping and gene transfer restore dystrophin expression in human induced pluripotent stem cells-cardiomyocytes harboring DMD mutations. Stem Cells Dev. 2013, 22, 2714–2724. [Google Scholar] [CrossRef] [PubMed]
  495. Van Deutekom, J.C.; Janson, A.A.; Ginjaar, I.B.; Frankhuizen, W.S.; Aartsma-Rus, A.; Bremmer-Bout, M.; den Dunnen, J.T.; Koop, K.; van der Kooi, A.J.; Goemans, N.M.; et al. Local dystrophin restoration with antisense oligonucleotide PRO051. N. Engl. J. Med. 2007, 357, 2677–2686. [Google Scholar] [CrossRef] [PubMed]
  496. Zhang, Y.; Long, C.; Li, H.; McAnally, J.R.; Baskin, K.K.; Shelton, J.M.; Bassel-Duby, R.; Olson, E.N. CRISPR-Cpf1 correction of muscular dystrophy mutations in human cardiomyocytes and mice. Sci. Adv. 2017, 3, e1602814. [Google Scholar] [CrossRef] [PubMed]
  497. Min, Y.L.; Li, H.; Rodriguez-Caycedo, C.; Mireault, A.A.; Huang, J.; Shelton, J.M.; McAnally, J.R.; Amoasii, L.; Mammen, P.P.A.; Bassel-Duby, R.; et al. CRISPR-Cas9 corrects Duchenne muscular dystrophy exon 44 deletion mutations in mice and human cells. Sci. Adv. 2019, 5, eaav4324. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  498. White, J.A.; McAlpine, P.J.; Antonarakis, S.; Cann, H.; Eppig, J.T.; Frazer, K.; Frezal, J.; Lancet, D.; Nahmias, J.; Pearson, P.; et al. Guidelines for human gene nomenclature (1997). HUGO nomenclature committee. Genomics 1997, 45, 468–471. [Google Scholar] [CrossRef] [PubMed]
Ijms 20 04381 g001 550
Figure 1. Schematic overview on cardiomyopathy associated genes and related clinical phenotypes. DCM—Dilated cardiomyopathy. HCM—Hypertrophic cardiomyopathy, ACM—Arrhythmogenic cardiomyopathy, NCCM—Non-compaction cardiomyopathy, RCM—Restrictive cardiomyopathy (Images of the DCM or HCM heart were licensed from shutterstock.com).
Figure 1. Schematic overview on cardiomyopathy associated genes and related clinical phenotypes. DCM—Dilated cardiomyopathy. HCM—Hypertrophic cardiomyopathy, ACM—Arrhythmogenic cardiomyopathy, NCCM—Non-compaction cardiomyopathy, RCM—Restrictive cardiomyopathy (Images of the DCM or HCM heart were licensed from shutterstock.com).
Ijms 20 04381 g001
Ijms 20 04381 g002 550
Figure 2. Schematic overview about different delivery methods of the Yamanaka factors into somatic primary cells for reprogramming (sub-figures for the cell types and viruses were licensed from shutterstock.com).
Figure 2. Schematic overview about different delivery methods of the Yamanaka factors into somatic primary cells for reprogramming (sub-figures for the cell types and viruses were licensed from shutterstock.com).
Ijms 20 04381 g002
Table
Table 1. Overview of cardiomyopathy associated genes carrying mutations.
Table 1. Overview of cardiomyopathy associated genes carrying mutations.
GeneProteinFunctionHCMDCMNCCMACMRCM
ABCC9ATP Binding Cassette Subfamily C Member 9ABC transporter [77]
ACAD9Acyl-CoA Dehydrogenase Member 9Dehydrogenase[78]
ACADVLAcyl-CoA Dehydrogenase Very Long ChainDehydrogenase [79]
ACTC1Cardiac ActinSarcomere protein[43,80][81][82] [83]
ACTN2α-Actinin 2Z-band protein[84][85][86] [69]
ADRB2Adrenoreceptor β2G-protein coupled receptor [87]
AKAP9A Kinase Anchoring Protein 9Scaffolding protein[88]
ALMS1Alstrom Syndrome Protein 1Microtubule organization [89] 1
ALPK3α-Kinase 3Kinase[90][90]
ANK2Ankyrin 2Cytoskeleton linker protein[91] [92]
ANKRD1Ankyrin Repeat Domain Containing Protein 1Transcription factor[93][94,95]
BAG3Bcl-2 Associated Athanogene 3Co-chaperone [96] [69,97]
BRAFB-Raf Proto-Oncogene, Serine/Threonine KinaseKinase[98] 2
C2ORF40Chromosome 2 Open Reading Frame 40Hormone [99]
CACNA1CCalcium Voltage-Gated Channel Subunit α1CCalcium channel[100]
CALM3Calmodulin 3Calcium binding[101] 3
CALR3Calreticulin 3Calcium binding chaperone[46]
CASQ2Calsequestrin 2Calcium binding[46]
CASZ1Castor Zinc Finger 1Transcription factor [102][103]
CAV3Caveolin 3Scaffolding protein[104]
CAVIN4Muscle Restricted Coiled Coil ProteinMyofibrillar organization [105]
CDH2N-CadherinCell–cell adhesion [106,107]
CHRM2Cholinergic Receptor Muscarinic 2G-protein coupled receptor [108]
COL3A1Collagen Type III Alpha 1 ChainExtra cellular matrix protein [109] 4
COX15Cytochrome C Oxidase Assembly Homolog COX15Mitochondrial respiratory chain[110]
CRYABαB-CrystallinChaperone-like activity [111] [112]
CSRP3Muscle LIM ProteinScaffolding protein[113,114,115][116]
CTF1Cardiotrophin 1Cytokine [117]
CTNNA3αT-CateninCell–cell adhesion [118]
DESDesminIntermediate filament protein[25][24,119][30][26][28]
DLG1Discs Large MAGUK Scaffold Protein 1Scaffolding protein [88]
DMDDystrophinDystrophin–glycoprotein complex [120]
DNAJC19DNAJ Heat Shock Protein Family C19Co-chaperone [121] [121]
DOLKDolichol KinasePhosphorylation of dolichol [122] 5
DPM3Dolichyl-Phosphate Mannosyltransferase Subunit 3Mannosyltransferase [123]
DSC2Desmocollin 2Cell–cell adhesion [35] [124]
DSG2Desmoglein 2Cell–cell adhesion [125] [126,127]
DSPDesmoplakinCell–cell adhesion [128][129][130]
DTNAα-DystrobrevinDystrophin-glycoprotein complex [131]
ELAC2ElaC Ribonuclease Z23′-tRNA endoribonuclease[132]
EMDEmerinNuclear lamina associated protein [133]
EYA4Eyes Absent Homolog 4Transcription factor [51]
FBN1Fibrillin 1Extra cellular matrix protein[134] 6[135] 7[136] 7
FBXO32F-Box Only Protein 32Ubiquitin–protein ligase complex [137,138]
FHL1Four and a Half LIM Domain Protein 1Scaffolding protein[41]
FHL2Four and a Half LIM Domain Protein 2Scaffolding protein [139]
FHOD3Formin Homology 2 Domain Containing Protein 3Organization of actin-polymerization[140][141]
FKRPFukutin Related ProteinPosttranslational modification of dystroglycan [142] 8
FKTNFukutinGlycosyltransferase of dystroglycan [143]
FLNCFilamin CCell junction organization[45][144,145] [145][72]
FOXD4Forkhead Box Protein D4Transcription factor [146]
FXNFrataxinRegulation of mitochondrial iron transport[147] 9
GAAα-GlucosidaseGlycogen metabolism[148] 9
GATA4GATA Binding Protein 4Transcription factor [149][150] 10
GATA5GATA Binding Protein 5Transcription factor [151]
GATAD1GATA Zink Finger Domain Containing Protein 1Gene expression regulation [152]
GLAGalactosidase αGalactose metabolism[153] 11
GTPBP3GTP Binding Protein 3, MitochondrialMitochondrial tRNA modification[154] 12
HAND1Heart and Neural Crest Derivatives Expressed 1Transcription factor [155]
HAND2Heart and Neural Crest Derivatives Expressed 2Transcription factor [156]
HCN4Hyperpolarization Activated Cyclic Nucleotide Gated Potassium Channel 4Potassium channel [157]
HRASHRas Proto-Oncogene GTPaseSignaling protein[158]13
ILKIntegrin Linked KinaseScaffolding protein [159,160] [68]
ISL1ISL LIM Homeobox 1Transcription factor [161]
ITGA7Integrin Subunit A7Cell–cell and cell–matrix junction protein [162] 14
ITPAInosine Triphosphate PyrophosphataseNucleotide metabolism [163] 15
JPH2Junctophilin 2Junctional complex[164][165]
JUPPlakoglobinCell–cell adhesion [58]
KCNQ1Potassium Channel Voltage Gated KQT-Like Subfamily Member 1Potassium channel [166]
KLHL24Kelch Like 24Ubiquitin ligase substrate receptor[167]
LAMA4Laminin α4Extra cellular matrix protein [159]
LAMP2Lysosomal Associated Membrane Protein 2Chaperone-mediated autophagy[168] 16
LDB3LIM Domain Binding Protein 3Z-band protein[169][170,171][170,172][173]
LEMD2LEM Domain Containing Protein 2Nuclear lamina associated protein [64,174] 17
LMNALamin A/CNuclear lamina associated protein [49][175][63]
LRRC10Leucine Rich Repeat Containing Protein 10Actin and α-actinin binding protein [176]
MIB1Mindbomb Drosophila Homolog 1Ubiquitin ligase [177]
MIB2Mindbomb Drosophila Homolog 2Ubiquitin ligase [178] 18
MRPL3Mitochondrial Ribosomal Protein L3Mitochondrial ribosomal protein[179] 19
MRPL44Mitochondrial Ribosomal Protein L44Mitochondrial ribosomal protein[180,181]
MYBPC3Myosin Binding Protein C3Sarcomere protein[182,183][184][185] [186]
MYBPHLMyosin Binding Protein H-LikeSarcomere protein [187]
MYH6Myosin Heavy Chain 6Sarcomere protein[188][188]
MYH7Myosin Heavy Chain 7Sarcomere protein[22][48][7] [189]
MYH7BMyosin Heavy Chain 7BSarcomere protein [162] 20
MYL2Myosin Light Chain 2Sarcomere protein[190] [191]
MYL3Myosin Light Chain 3Sarcomere protein[192] [192]
MYLK3Myosin Light Chain Kinase 3Kinase [193]
MYOZ1Myozenin 1Calcineurin interacting protein [194]
MYOZ2Myozenin 2Calcineurin interacting protein[195]
MYPNMyopalladinZ-band protein[196][94,197] [196,198]
NCOA6Nuclear Receptor Coactivator 6Gene expression regulation [199]
NDUFAF1NADH: Ubiquinone Oxidoreductase Complex Assembly Factor 1Mitochondrial respiratory chain[200]
NDUFV2NADH: Ubiquinone Oxidoreductase Core Subunit V2Mitochondrial respiratory chain[201,202] 21
NEBLNebuletteZ-band protein[203][204][203]
NEXNNexilinSarcomere protein[205][206][207]
NKX2.5NK2 Homeobox 5Transcription factor [208]
OBSCNObscurinScaffolding protein [209]
P2RX7Purinergic receptor P2X7ATP gated ion channel[210]
PDLIM3PDZ And LIM Domain 3Z-band protein [194]
PKP2Plakophilin 2Cell-cell adhesion [35][211][212]
PLNPhospholambanRegulator of SERCA[46][213,214] [67]
PPCSPhosphopantothenoylcystein SynthetaseCo-enzyme A synthesis [215]
PRDM16PR Domain Containing Protein 16Transcription factor [216][217]
PRKAG2Protein Kinase AMP Activated Non-catalytic G2Energy sensor kinase[218,219] 22
PSEN1Presenilin 1γ-Secretase [220,221]
PSEN2Presenilin 2γ-Secretase [220]
PTENPhosphatase and Tensin HomologPhosphatase [150] 23
PTPN11Protein Tyrosine Phosphatase Non-Receptor Type 1Phosphatase[222] 24
RAF1Raf-1 Proto-Oncogene, Serine/Threonine KinaseKinase[223,224] 25[225]
RBM20RNA Binding Protein 20Splicing factor [52,226][227][228,229]
RRAGCRas Related GTP Binding CGTR/RAG GTP-binding protein [230]
RTKN2Rhotekin 2Scaffolding protein [99]
RYR2Ryanodine Receptor 2Calcium channel [66]
SCN5ASodium Channel Voltage Gated Type V Subunit ASodium channel [50,231] [232]
SCO2SCO2 Cytochrome C Oxidase Assembly ProteinMetallo-chaperone[233]
SDHASuccinate Dehydrogenase Complex Subunit AMitochondrial respiratory chain [234]
SGCBSarcoglycan βDystrophin-glycoprotein complex [235]
SGCDSarcoglycan δDystrophin-glycoprotein complex [236]
SHOC2Suppressor Of Clear, C. Elegans, HomologScaffolding protein[237]
SYNE1Nesprin 1Component of the LINC complex[238][239]
TAZTafazzinCardiolipin metabolism [240] 26[241,242]
TBX20T-Box Factor 20Transcription factor [243,244]
TCAPThelethoninTitin binding[245][244,245]
TGFB3Transforming Growth Factor β3Growth factor [246]
TJP1Zonula Occludens 1Tight junction adapter protein [247]
TMEM43Transmembrane Protein 43Nuclear lamina associated protein [9,10]
TMEM87BTransmembrane Protein 87BEndosome-to-trans-Golgi retrograde transport [248]
TNNC1Cardiac Troponin CSarcomere protein[39][249] [250]
TNNI3Cardiac Troponin ISarcomere protein[40][251][252] [71]
TNNI3KTNNI3 Interacting KinaseKinase [253]
TNNT2Cardiac Troponin TSarcomere protein[38][254][255] [83]
TP63Tumor Protein 63Transcription factor [256]
TPM1Tropomyosin 1Sarcomere protein[38,257][258][259] [191]
TRIM63Tripartite Motif Containing Protein 63Ubiquitin ligase[260]
TRPM4Transient Receptor Potential Cation Channel Subfamily MCation channel [261]
TSFMMitochondrial Translation Elongation Factor TsTranslation elongation factor [262]
TTNTitinSarcomere protein[263][32,264][87,265][33][34]
TTRTransthyretinCarrier protein[266,267] 27
TXNRD2Thioredoxin Reductase 2Reduces thioredoxins [268]
VCLVinculinCell–cell and cell–matrix junction protein[269,270][271]
ZBTB17Zinc Finger and BTB Domain Containing Protein 17Transcription factor [272,273]
1 Alström syndrome (MIM #203800); 2 Cardiofaciocutaneous syndrome (MIM #115150); 3 Modifier gene; 4 Ehlers–Danlos syndrome (MIM #130090); 5 Multi-organ involvement; 6 Digenetic with PTPN11 mutations, combined with Marfan and Leopard syndrome; 7 Marfan Syndrome (MIM #154700); 8 Limb-girdle muscular dystrophy; 9 Friedreich ataxia (MIM #229300); 10 Digenetic with PTEN; 11 Fabry disease; 12 In combination with lactic acidosis and encephalopathy; 13 Costello syndrome (MIM #218040); 14 Digenetic with MYH7B;15 Martsolf-like syndrome (MIM #212720) in combination with DCM; 16 Danon disease (MIM #300257); 17 In combination with cataract; 18 In combination with giant hypertrophic gastritis (MIM #137280, Ménétrier disease); 18 In combination with psychomotor retardation; 19 Digenetic with ITGA7; 20 In combination with encephalopathy; 21 Wolff–Parkinson–White syndrome (MIM #194200); 22 Digenetic with GATA4 mutation; 23 Noonan syndrome; 24 Noonan syndrome or Leopard syndrome; 25 Barth syndrome (MIM #302060); 26 Amyloid cardiomyopathy (MIM #105210); 27 Fabry disease.
Table
Table 2. Overview about important iPSC lines carrying mutations in genes associated with genetic cardiomyopathies or related diseases.
Table 2. Overview about important iPSC lines carrying mutations in genes associated with genetic cardiomyopathies or related diseases.
GeneProteinMutation(s)Method of GenerationMain Phenotypic FindingsAssociated DiseaseReferences
ACTC1Cardiac Actinp.E99K
▪
Sendai virus transduction
▪
Isogenic controls using CRISPR-Cas9 (PiggyBac)
ArrhythmiasHCM/LVNC[380]
ALPK3α-Kinase 3p.W1264XhomElectroporation with episomal plasmids
▪
Sarcomeric disarray
▪
Ca2+ handling defects
HCM[381]
BAG3Bcl-2 Associated Athanogene 3
▪
p.R90X
▪
p.R90Xhom
▪
p.R123X
▪
Electroporation with episomal plasmids
▪
& genome editing using
▪
CRISPR-Cas9
▪
TALENs
▪
Decreased BAG3 expression
▪
Sarcomeric disarray after prolonged culture
▪
Decreased contraction
DCM[374]
BRAFB-Raf Proto-Oncogene, Serine/Threonine Kinase
▪
p.Q257R
▪
p.T599R
▪
Retroviral transduction
▪
Electroporation with episomal plasmids
▪
Cellular hypertrophy
▪
Pro-hypertrophic gene expression
▪
Ca2+ handling defects
▪
Abnormal TGFβ signaling
CFCS/HCM[382]
CAVCaveolin
▪
c.303G > C
▪
c.233C > A
▪
c.∆184-192
Electroporation with episomal plasmidsNAMP[383]
CRYABαB-Crystallin
▪
c.343delThet
▪
c.343delThom
Retroviral transduction and genome editing (zinc finger nucleases)
▪
No detectable expression of mutant αB-Crystallin
▪
Loss of function mechanism
MFM[384]
DESDesminp.N116SLentiviral transductionNAACM[385]
DESDesminc.735+1G > ASendai virus transductionNADRC[386]
DESDesminp.A285VRetroviral transduction
▪
Desmin aggregation
▪
Z-disk streaming
▪
Decreased spontaneous beating rate
DCM[387]
DMDDystrophin
▪
∆Ex8-12
▪
c.5899C > T
Sendai virus transduction
▪
Electrophysiological alterations
▪
Arrhythmias
▪
Prolonged action potential
DMD[388]
DMDDystrophin
▪
∆Ex8-9
▪
∆Ex6-9
▪
∆Ex7-11
▪
∆Ex3-9
Sendai virus transduction in combination with CRISPR-Cas9
▪
Out of frame deletion ∆Ex8-9 reduce contraction force
▪
Second deletions to correct the reading fame of DMD restores the contractility
DMD[379]
DMDDystrophin
▪
c.263delG
▪
∆Ex50
Lentiviral transduction
CRISPR-Cas9
▪
Reduced contractility
▪
Ca2+ handling defects
DMD[389,390]
DSG2Desmoglein-2p.G638RSendai virus transduction
▪
Electrophysiological alterations
▪
Ion channel dysfunction
ACM[391]
DSPDesmoplakinp.R451GSendai virus transduction & genome editing for correction (CRISPR-Cas9)Reduced desmoplakin expressionACM[392]
FBN1Fibrillin 1c.4028G > ASendai virus transductionNAMarfan Syndrome (HCM)[393]
FKRPFukutin Related Proteinc.826C > AhomLentiviral transduction
▪
Abnormal action potential
▪
Electrophysiological alterations
▪
Decreased expression of SCN5A and CACNA1C
Limb-Girdle Muscular Dystrophy (DCM)[394]
FXNFrataxinExpanded GAA repeatsRetroviral transduction
▪
Iron homeostasis defects
▪
Disorganized mitochondria
▪
Cellular hypertrophy
▪
Increased BNP expression
▪
Ca2+ handling defects
Friedreich Ataxia (HCM)[395]
FXNFrataxinExpanded GAA repeats
▪
800/600
▪
900/400
Lentiviral transduction
▪
Impaired mitochondrial function
▪
Decreased mitochondrial membrane potential
▪
Degeneration of mitochondria
Friedreich Ataxia (HCM)[396]
GLAGalactosidase αIVS4+919G > ARetroviral transduction
▪
Decreased α-galactosidase activity
▪
Cellular hypertrophy
▪
Upregulation of fibrotic genes
Fabry Disease (HCM)[397,398]
LAMP2Lysosomal Associated Membrane Protein 2IVS6+1_4delGTGASendai virus transductionAutophagy dysfunctionDanon Disease (CM)[399]
LAMP2Lysosomal Associated Membrane Protein 2
▪
c.129-130insAT
▪
IVS-1.c64+1G > A
Unknown
▪
Mitochondrial-oxidative stress
▪
Apoptosis
▪
Disrupted mitophagic flux
▪
Mitochondrial respiratory deficiency
Danon Disease (CM)[400]
LAMP2Lysosomal Associated Membrane Protein 2
▪
c.1082delA
▪
c.247C > T
▪
c.64+1G > A
▪
Retroviral transduction
▪
Sendai virus transduction
▪
CRISPR-Cas9 for correction
▪
Defects in autophagic fusion
▪
Mitochondrial abnormalities
▪
Contractile abnormalities
Danon Disease (CM)[401]
LMNALamin A/Cp.S143PSendai virus transduction
▪
Sarcomere damage after hypoxia
▪
Arrhythmias after β-adrenergic stimulation
▪
Ca2+ handling defects
DCM[402]
LMNALamin A/Cp.S18fsXCombined lentiviral and retroviral transductionNormal nuclear membrane morphologyDCM[403]
LMNALamin A/Cp.R225XLentiviral transduction
▪
Reduced expression of lamin A/C
▪
Increased cellular apoptosis under electrical stimulation
DCM[404]
LMNALamin A/C
▪
p.R225X
▪
p.Q354X
▪
p.T518fsX29
Lentiviral transduction
▪
Increased nuclear blebbing under electrical stimulation
▪
Increased apoptosis under electrical stimulation
▪
Haploinsufficiency
▪
Treatment with PTC124 reverse the phenotypic findings
DCM & conduction disorders[405]
LMNALamin A/Cp.K219TLentiviral transduction
▪
Electrophysiological alterations
▪
Downregulation of SCN5A expression by epigenetic modulation of the promoter
DCM & conduction disorders[406]
MT-RNR2Mitochondrially Encoded 16S rRNAm.2336T > CRetroviral transduction
▪
Decreased stability of 16S rRNA
▪
Mitochondrial dysfunction
▪
Reduced ATP/ADP ratio
▪
Reduced mitochondrial potential
▪
Electrophysiological alterations
HCM[407]
MYBPC3Myosin Binding Protein C3
▪
p.V321M
▪
p.V219L
▪
c.2905+1G > A
Sendai virus transductionAbnormal Ca2+ handlingHCM[408]
MYBPC3Myosin Binding Protein C3p.R326QElectroporation with episomal plasmidsCa2+ handling deficitsHCM[409]
MYBPC3Myosin Binding Protein C3c.2373Lentiviral transduction
▪
Cellular hypertrophy
▪
Contractile defect
HCM[410,411]
MYBPC3Myosin Binding Protein C3p.R502WElectroporation with episomal plasmidsNAHCM[412]
MYBPC3Myosin Binding Protein C3
▪
p.R502W
▪
p.W792VfsX41
CRISPR-Cas9
▪
Hypercontractility
▪
P53 activation
▪
Oxidative stress
▪
Metabolic stress
HCM[413]
MYBPC3Myosin Binding Protein C3
▪
p.R943X
▪
p.R1073fsX4
Sendai virus transduction & genome editing for correction (CRISPR-Cas9)
▪
Reduced expression of MYBPC3 at the mRNA level but not at the protein level
▪
Ca2+ handling defects
▪
Activation of nonsense-mediated mRNA decay
HCM[414,415]
MYBPC3Myosin Binding Protein C3p.G999-Q1004delSendai virus transduction
▪
Cellular hypertrophy
▪
Myofibrillar disarray
▪
Reduced MYBPC3 expression
▪
Increased ANP expression
HCM[416]
MYBPC3Myosin Binding Protein C3p.Q1061X
▪
Sendai virus transduction
▪
Retroviral transduction
ArrhythmiasHCM[417,418]
MYBPC3Myosin Binding Protein C3p.V454CfsX21Retroviral transduction
▪
Haploinsufficiency (at the mRNA and protein level)
▪
Cellular hypertrophy
▪
Altered gene expression
▪
Efficient gene replacement using AAV9 reduce phenotypic findings
HCM[419]
MYBPC3Myosin Binding Protein C3∆25 bp in intron 32 including the splicing branch point & p.D389V (same allele)Sendai virus transduction
▪
Cellular hypertrophy
▪
Ca2+ handling deficits
HCM[420]
MYBPHLMyosin Binding Protein H-Likep.R255XElectroporation with episomal plasmidsHaploinsufficiency by nonsense mediated mRNA decayDCM & conduction disorders[187]
MYH7Myosin Heavy Chain 7p.R663HSendai virus transductionAbnormal Ca2+ handlingHCM[408]
MYH7Myosin Heavy Chain 7
▪
p.R453Chet
▪
p.R453Chom
CRISPR-Cas9
▪
Cellular hypertrophy
▪
Sarcomeric disarray
▪
Increased expression of hypertrophy markers
▪
Ca2+ handling deficits
HCM[421]
MYH7Myosin Heavy Chain 7
▪
p.R403Q
▪
p.V606M
CRISPR-Cas9
▪
Hypercontractility
▪
P53 activation
▪
Oxidative stress
▪
Metabolic stress
HCM[413]
MYH7Myosin Heavy Chain 7p.V698AElectroporation with episomal plasmidsNAHCM[422]
MYH7Myosin Heavy Chain 7p.E848GElectroporation with episomal plasmidsReduced contractile functionHCM[423,424]
MYH7Myosin Heavy Chain 7p.R403QElectroporation with episomal plasmidsNAHCM[425]
MYH7Myosin Heavy Chain 7p.R633HLentiviral transduction
▪
Ca2+ handling deficits
▪
Arrhythmias
▪
Cellular hypertrophy
HCM[414,426]
MYH7Myosin Heavy Chain 7p.R442GRetroviral transduction
▪
Disorganized sarcomeres
▪
Increased expression of genes involved in cell proliferation
▪
Electrophysiological alterations
HCM[427]
MYL2Myosin Light Chain 2p.R58QNon-integrating mRNA/miRNA technology
▪
Cellular hypertrophy
▪
Myofibrillar disarray
▪
Irregular contraction
▪
Decreased Ca2+ transients
HCM[428]
MYL3Myosin Light Chain 3
▪
p.A57Dhet
▪
p.A57Dhom
▪
p.A57Ghet
CRISPR-Cas9
▪
Asymptomatic
▪
Classification of benign GSVs
HCM[375]
PKP2Plakophilin-2p.L614PRetroviral transduction
▪
Reduced expression of plakophilin-2
▪
Adipogenic phenotype
ACM[429]
PKP2Plakophilin-2
▪
c.2484C > Thom
▪
c.2013delC
Retroviral transduction
▪
Lipogenesis
▪
Apoptosis
▪
Ca2+ handling deficits
▪
Pro-fibrotic gene expression
▪
Dysregulation of genes, encoding cell-cell connections.
ACM[430,431,432]
PKP2Plakophilin-2c.972insTRetroviral transduction
▪
Reduced expression of plakophilin-2
▪
Changes of the desmosomal structure
▪
Lipid droplet accumulation
ACM[433]
PKP2Plakophilin-2
▪
c.354delT
▪
p.K859R
Sendai virus transductionNAACM[434]
PKP2Plakophilin-2c.2569_3018del50Electroporation with episomal plasmidsNAACM[435]
PLNPhospholambanp.R9CCRISPR-Cas9
▪
Cellular hypertrophy
▪
Ca2+ handling deficits
▪
Increased expression of hypertrophic markers
▪
Altered metabolic state
▪
Changes of miRNA expression
▪
Increased expression of profibrotic genes
DCM[414,436]
PLNPhospholambanp.R14delTransfection with mRNAs& genome editing (TALENs) for mutation correction
▪
Ca2+ handling deficits
▪
Abnormal cytoplasmic localization of phospholamban
▪
Increased expression of hypertrophic markers
▪
Gene correction reverses the phenotypic findings
DCM[437,438]
PRGAG2Protein Kinase AMP-Activated Non-Catalytic Subunit Gamma 2p.R302QSendai virus transduction & genome editing for correction (CRISPR-Cas9)
▪
Arrhythmias
▪
Electrophysiological alterations
▪
Cellular hypertrophy
▪
Gene correction using CRISPR-Cas9 reverses the phenotypic findings
Wolff–Parkinson–White Syndrome (HCM)[439]
PRKAG2Protein Kinase AMP-Activated Non-Catalytic Subunit Gamma 2p.N488ILentiviral transduction & genome editing for correction (TALEN)
▪
Activated AMPK remodeled metabolism
▪
Cellular hypertrophy
HCM[440]
PTPN11Protein Tyrosine Phosphatase Non-Receptor Type 11p.T468MRetroviral transduction
▪
Cellular hypertrophy
▪
Impaired sarcomere structure
LEOPARD Syndrome (HCM)[360]
PTPN11Protein Tyrosine Phosphatase Non-Receptor Type 11p.Q510PSendai virus transductionNALEOPARD Syndrome (HCM)[441]
RAF1Raf-1 Proto-Oncogene, Serine/Threonine Kinasep.S257LElectroporation of episomal plasmids & genome editing for correction (CRISPR-Cas9)
▪
Cellular hypertrophy
▪
Myofibrillar disarray
▪
Hyperactivation of MEK1/2 pathway
▪
Increased ERK5 signaling
Noonan Syndrome (HCM)[442]
RBM20RNA Binding Motif Protein 20p.S635ALentiviral transduction
▪
Altered Ca2+ handling
▪
Impaired sarcomere structure
▪
Reduced titin N2B isoform expression
DCM[443]
RBM20RNA Binding Motif Protein 20p.R636SSendai virus transduction
▪
Impaired sarcomere structure
▪
Altered transcriptome
▪
Altered Ca2+ handling
▪
Apoptotic changes
▪
Therapeutic treatment using β-blockers or Ca2+ channel blockers reverse phenotypic findings
DCM[444,445]
RYR2Ryanodine Receptor 2p.F2483IRetroviral transduction
▪
Arrhythmias
▪
Altered Ca2+ handling
CPVT[350]
RYR2Ryanodine Receptor 2
▪
p.S404R & p.N685S
▪
p.G3946S & p.G1885E
Sendai virus transduction
▪
Altered Ca2+ handling
▪
Calmodulin-dependent protein kinase II inhibition reverse the arrhythmias
CPVT[376]
SCN5ASodium Voltage-Gated Channel Alpha Subunit 5
▪
p.S1898R
Sendai virus transduction & CRISPR-Cas9 for correction
▪
Reduction in peak sodium channel
ACM[446]
SCN5ASodium Voltage-Gated Channel Alpha Subunit 5p.R219HSendai virus transduction
▪
Proton leakage
▪
Disrupted ion homeostasis
▪
Structural abnormalities
▪
Electrophysiological alterations
▪
Reduced contraction
ACM/DCM[447]
SCO2SCO2 Cytochrome C Oxidase Assembly Protein
▪
p.E140K
▪
p.G193Shom
Sendai virus transduction
▪
Structural abnormalities
▪
Altered Ca2+ handling
HCM[448]
TAZTafazzin
▪
c.517delG
▪
c.328T > C
Transfection with synthetic mRNAs & CRISPR-Cas9 for correction
▪
Impaired sarcomere structure
▪
Decreased contraction
▪
Increased reactive oxygen species
Barth Syndrome[449]
TBX20T-Box Factor 20
▪
p.T262M
▪
p.Y317X
Sendai virus transduction
▪
Perturbed TGFβ signaling
▪
Reduced expression of cardiac transcription factors
LVNC[450]
TNNT2Cardiac Troponin Tp.R92WSendai virus transduction & CRISPR-Cas9 for correctionAbnormal Ca2+ handlingHCM[408]
TNNT2Cardiac Troponin Tp.R173WLentiviral transduction
▪
Decreased contractility
▪
Altered Ca2+ handling
▪
Impaired sarcomere structure
DCM[414,451,452,453,454]
TNNT2Cardiac Troponin T
▪
Compound heterozygous: ∆5bp and ∆2bp deletions in exon 2 leading to frameshifts
▪
Heterozygous ∆27bp deletion in exon 2 leading to a frameshift
TALEN
▪
Sarcomere disassembly
▪
Altered Ca2+ handling
DCM/HCM[453]
TNNT2Cardiac Troponin Tp.I79NCRISPR-Cas9
▪
Impaired sarcomere structure
▪
Increased systolic function
▪
Impaired relaxation
▪
Altered Ca2+ handling
HCM[455,456]
TPM1Tropomyosin-1p.D175N
▪
Sendai virus transduction
▪
Retroviral transduction
ArrhythmiasHCM[417,418]
TTNTitin
▪
p.W976R+/-
▪
p.V6382fs+/-
▪
p.V6382fs-/-
▪
p.A22352fs+/-
▪
p.P22582fs+/-
▪
p.N22577fs+/-
▪
p.N22577fs-/-
▪
p.T33520fs-/-
▪
Lentiviral transduction (for patient specific iPSC)
▪
CRISPR-Cas9 (for generation of isogenic iPSC)
▪
Impaired sarcomere structure
▪
Decreased contractility
▪
Diminished activation of growth factors, hypoxia regulating factors and MAP kinases
DCM[457]
TTNTitinp.S14450fsX4Sendai virus transductionAntisense-mediated exon skipping restores titin expressionDCM[377]
TTNTitin
▪
c.86076dupA
▪
c.70690dupAT
Lentiviral transduction
▪
Sarcomere defects
▪
Diminished inotropic and lusitropic responses
DCM[458]
TTRTransthyretinp.L55PLentiviral transductionIncreased oxidative stressHereditary Transthyretin Amyloidosis[459]
ACM—Arrhythmogenic cardiomyopathy; CFCS—Cardio facio cutaneous syndrome; CM—Cardiomyopathy; CPVT—Catecholaminergic polymorphic ventricular tachycardia; DCM—Dilated cardiomyopathy; DMD—Duchenne muscular dystrophy; DRC—Desmin-related cardiomyopathy; HCM—Hypertrophic cardiomyopathy; LVNC—Left-ventricular non-compaction cardiomyopathy; MFM—Myofibrillar myopathy; MP—Myopathy; NA—Not assessed; RCM—Restrictive cardiomyopathy.

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MDPI and ACS Style

Brodehl, A.; Ebbinghaus, H.; Deutsch, M.-A.; Gummert, J.; Gärtner, A.; Ratnavadivel, S.; Milting, H. Human Induced Pluripotent Stem-Cell-Derived Cardiomyocytes as Models for Genetic Cardiomyopathies. Int. J. Mol. Sci. 2019, 20, 4381. https://doi.org/10.3390/ijms20184381

AMA Style

Brodehl A, Ebbinghaus H, Deutsch M-A, Gummert J, Gärtner A, Ratnavadivel S, Milting H. Human Induced Pluripotent Stem-Cell-Derived Cardiomyocytes as Models for Genetic Cardiomyopathies. International Journal of Molecular Sciences. 2019; 20(18):4381. https://doi.org/10.3390/ijms20184381

Chicago/Turabian Style

Brodehl, Andreas, Hans Ebbinghaus, Marcus-André Deutsch, Jan Gummert, Anna Gärtner, Sandra Ratnavadivel, and Hendrik Milting. 2019. "Human Induced Pluripotent Stem-Cell-Derived Cardiomyocytes as Models for Genetic Cardiomyopathies" International Journal of Molecular Sciences 20, no. 18: 4381. https://doi.org/10.3390/ijms20184381

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