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Transgenic Mice in Human Diseases: Insights from Molecular Research 4.0

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (31 December 2023) | Viewed by 14968

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Special Issue Editor

Dr. Timofey S. Rozhdestvensky

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Medical Faculty, Core Facility Transgenic Animal and Genetic Engineering Models (TRAM), University of Muenster, Von-Esmarch-Str. 56, D-48149 Muenster, Germany
Interests: genome editing; CRISPR-Cas9 technology; programmable DNA endonucleases; nervous system diseases; RNA biology; disease-associated RNAs; non-protein coding RNAs
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Transgenic mouse models are essential for understanding the molecular mechanisms and pathogenicity of most human diseases. Research based on live mouse models is important to discover and/or improve methods for the prevention, diagnosis, and treatment of diseases.

This Special Issue aims to cover all areas of molecular-based research to study various human diseases using genetically engineered mouse models. It welcomes original research, reviews, and short communication articles on cellular and molecular analyses of transgenic mouse models in areas including, but not limited to, functional genomics of disease, epigenomics, proteomics, RNA biology, systems biology, approaches and methods of mouse genome editing, software tools, etc.

Topics of interest for the Issue include:

Generation of transgenic mouse models and targeting constructs;
Mouse genome editing approaches;
Transgenic mouse models in cancer research;
Transgenic mouse models to study infectious diseases;
Transgenic mouse models for mitochondrial diseases;
Transgenic mouse models in:

Cardiovascular diseases;
Developmental disorders;
Digestive system diseases;
Endocrine system diseases;
Immune diseases;
Integumentary system diseases;
Lymphatic system diseases;
Metabolism, obesity, and metabolic diseases;
Nervous system diseases (including sensory organ disorders);
Reproductive system diseases;
Respiratory system diseases;
Skeletal and muscular system diseases;
Urinary system diseases.

Dr. Timofey S. Rozhdestvensky
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

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Published Papers (10 papers)

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Research

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19 pages, 15926 KiB

Open AccessArticle

The Abundant Distribution and Duplication of SARS-CoV-2 in the Cerebrum and Lungs Promote a High Mortality Rate in Transgenic hACE2-C57 Mice

by Heng Li, Xin Zhao, Shasha Peng, Yingyan Li, Jing Li, Huiwen Zheng, Yifan Zhang, Yurong Zhao, Yuan Tian, Jinling Yang, Yibin Wang, Xinglong Zhang and Longding Liu

Int. J. Mol. Sci. 2024, 25(2), 997; https://doi.org/10.3390/ijms25020997 - 13 Jan 2024

Cited by 1 | Viewed by 1052

Abstract

Patients with COVID-19 have been reported to experience neurological complications, although the main cause of death in these patients was determined to be lung damage. Notably, SARS-CoV-2-induced pathological injuries in brains with a viral presence were also found in all fatal animal cases. Thus, an appropriate animal model that mimics severe infections in the lungs and brain needs to be developed. In this paper, we compared SARS-CoV-2 infection dynamics and pathological injuries between C57BL/6Smoc-Ace2^{em3(hACE2-flag-Wpre-pA)Smoc} transgenic hACE2-C57 mice and Syrian hamsters. Importantly, the greatest viral distribution in mice occurred in the cerebral cortex neuron area, where pathological injuries and cell death were observed. In contrast, in hamsters, viral replication and distribution occurred mainly in the lungs but not in the cerebrum, although obvious ACE2 expression was validated in the cerebrum. Consistent with the spread of the virus, significant increases in IL-1β and IFN-γ were observed in the lungs of both animals. However, in hACE2-C57 mice, the cerebrum showed noticeable increases in IL-1β but only mild increases in IFN-γ. Notably, our findings revealed that both the cerebrum and the lungs were prominent infection sites in hACE2 mice infected with SARS-CoV-2 with obvious pathological damage. Furthermore, hamsters exhibited severe interstitial pneumonia from 3 dpi to 5 dpi, followed by gradual recovery. Conversely, all the hACE2-C57 mice experienced severe pathological injuries in the cerebrum and lungs, leading to mortality before 5 dpi. According to these results, transgenic hACE2-C57 mice may be valuable for studying SARS-CoV-2 pathogenesis and clearance in the cerebrum. Additionally, a hamster model could serve as a crucial resource for exploring the mechanisms of recovery from infection at different dosage levels. Full article

(This article belongs to the Special Issue Transgenic Mice in Human Diseases: Insights from Molecular Research 4.0)

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19 pages, 4387 KiB

Open AccessArticle

Conditional Deletion of Foxg1 Delayed Myelination during Early Postnatal Brain Development

by Guangliang Cao, Congli Sun, Hualin Shen, Dewei Qu, Chuanlu Shen and Haiqin Lu

Int. J. Mol. Sci. 2023, 24(18), 13921; https://doi.org/10.3390/ijms241813921 - 10 Sep 2023

Cited by 1 | Viewed by 1117

Abstract

FOXG1 (forkhead box G1) syndrome is a neurodevelopmental disorder caused by variants in the Foxg1 gene that affect brain structure and function. Individuals affected by FOXG1 syndrome frequently exhibit delayed myelination in neuroimaging studies, which may impair the rapid conduction of nerve impulses. To date, the specific effects of FOXG1 on oligodendrocyte lineage progression and myelination during early postnatal development remain unclear. Here, we investigated the effects of Foxg1 deficiency on myelin development in the mouse brain by conditional deletion of Foxg1 in neural progenitors using NestinCreER;Foxg1^fl/fl mice and tamoxifen induction at postnatal day 0 (P0). We found that Foxg1 deficiency resulted in a transient delay in myelination, evidenced by decreased myelin formation within the first two weeks after birth, but ultimately recovered to the control levels by P30. We also found that Foxg1 deletion prevented the timely attenuation of platelet-derived growth factor receptor alpha (PDGFRα) signaling and reduced the cell cycle exit of oligodendrocyte precursor cells (OPCs), leading to their excessive proliferation and delayed maturation. Additionally, Foxg1 deletion increased the expression of Hes5, a myelin formation inhibitor, as well as Olig2 and Sox10, two promoters of OPC differentiation. Our results reveal the important role of Foxg1 in myelin development and provide new clues for further exploring the pathological mechanisms of FOXG1 syndrome. Full article

(This article belongs to the Special Issue Transgenic Mice in Human Diseases: Insights from Molecular Research 4.0)

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13 pages, 3229 KiB

Open AccessArticle

PD-L1 Downregulation and DNA Methylation Inhibition for Molecular Therapy against Cancer Stem Cells in Hepatocellular Carcinoma

by Caecilia Sukowati, Loraine Kay D. Cabral, Beatrice Anfuso, Francesco Dituri, Roberto Negro, Gianluigi Giannelli and Claudio Tiribelli

Int. J. Mol. Sci. 2023, 24(17), 13357; https://doi.org/10.3390/ijms241713357 - 29 Aug 2023

Viewed by 1294

Abstract

Hepatocellular carcinoma (HCC) is a heterogeneous cancer characterized by various cellular subtypes. This study investigates the potential of a combination strategy using immunotherapy and epigenetic reprogramming against HCC. We used a transgenic HCC mouse C57BL/6J-TG(ALB1HBV)44BRI/J to assess the dynamics of the programmed death receptor and its ligand (PD-1/PD-L1) and DNA methylation markers. In parallel, PD-L1 RNA silencing was performed in various human HCC cell lines, while combination therapy was performed in a co-culture system using long-term exposure of 5-Azacytidine (5-AZA) and an anti-PD-L1. Data from the mouse model showed that the expressions of Pdcd1, Pdcd1l1, and DNA methyltransferase 1 (Dnmt1) were significantly higher in HCC as compared to the wild-type mice (p < 0.01), supported by the high presence of PD-L1 methylated DNA. In HCC cell lines, PD-L1 silencing was accompanied by DNMT1 reduction, mostly noted in aggressive HCC cell lines, followed by the dysregulation of the cancer stem cell marker EpCAM. In combination therapy, the growth of HCC cells and lymphocytes was limited by the PD-L1 antibody, further reduced in the presence of 5-AZA by up to 20% (p < 0.001). The data demonstrated that combination therapy might be an option as a potential treatment for heterogeneous HCC. Full article

(This article belongs to the Special Issue Transgenic Mice in Human Diseases: Insights from Molecular Research 4.0)

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14 pages, 7468 KiB

Open AccessArticle

A Novel Transgenic Mouse Model Implicates Sirt2 as a Promoter of Hepatocellular Carcinoma

by Alexandra V. Schmidt, Satdarshan P. Monga, Edward V. Prochownik and Eric S. Goetzman

Int. J. Mol. Sci. 2023, 24(16), 12618; https://doi.org/10.3390/ijms241612618 - 09 Aug 2023

Viewed by 983

Abstract

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer deaths globally. Incidence rates are steadily increasing, creating an unmet need for new therapeutic options. Recently, the inhibition of sirtuin-2 (Sirt2) was proposed as a potential treatment for HCC, despite contradictory findings of its role as both a tumor promoter and suppressor in vitro. Sirt2 functions as a lysine deacetylase enzyme. However, little is known about its biological influence, despite its implication in several age-related diseases. This study evaluated Sirt2’s role in HCC in vivo using an inducible c-MYC transgene in Sirt2⁺^/+ and Sirt2^−/− mice. Sirt2^−/− HCC mice had smaller, less proliferative, and more differentiated liver tumors, suggesting that Sirt2 functions as a tumor promoter in this context. Furthermore, Sirt2^−/− HCCs had significantly less c-MYC oncoprotein and reduction in c-MYC nuclear localization. The RNA-seq showed that only three genes were significantly dysregulated due to loss of Sirt2, suggesting the underlying mechanism is due to Sirt2-mediated changes in the acetylome, and that the therapeutic inhibition of Sirt2 would not perturb the oncogenic transcriptome. The findings of this study suggest that Sirt2 inhibition could be a promising molecular target for slowing HCC growth. Full article

(This article belongs to the Special Issue Transgenic Mice in Human Diseases: Insights from Molecular Research 4.0)

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16 pages, 1551 KiB

Open AccessArticle

Effects of Low-Intensity Pulsed Ultrasound-Induced Blood–Brain Barrier Opening in P301S Mice Modeling Alzheimer’s Disease Tauopathies

by Amandine Géraudie, Maximilien Riche, Thaïs Lestra, Alexandre Trotier, Léo Dupuis, Bertrand Mathon, Alexandre Carpentier and Benoît Delatour

Int. J. Mol. Sci. 2023, 24(15), 12411; https://doi.org/10.3390/ijms241512411 - 03 Aug 2023

Cited by 2 | Viewed by 1302

Abstract

Alzheimer’s disease (AD) is the leading cause of dementia. No treatments have led to clinically meaningful impacts. A major obstacle for peripherally administered therapeutics targeting the central nervous system is related to the blood–brain barrier (BBB). Ultrasounds associated with microbubbles have been shown to transiently and safely open the BBB. In AD mouse models, the sole BBB opening with no adjunct drugs may be sufficient to reduce lesions and mitigate cognitive decline. However, these therapeutic effects are for now mainly assessed in preclinical mouse models of amyloidosis and remain less documented in tau lesions. The aim of the present study was therefore to evaluate the effects of repeated BBB opening using low-intensity pulsed ultrasounds (LIPU) in tau transgenic P301S mice with two main readouts: tau-positive lesions and microglial cells. Our results show that LIPU-induced BBB opening does not decrease tau pathology and may even potentiate the accumulation of pathological tau in selected brain regions. In addition, LIPU-BBB opening in P301S mice strongly reduced microglia densities in brain parenchyma, suggesting an anti-inflammatory action. These results provide a baseline for future studies using LIPU-BBB opening, such as adjunct drug therapies, in animal models and in AD patients. Full article

(This article belongs to the Special Issue Transgenic Mice in Human Diseases: Insights from Molecular Research 4.0)

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25 pages, 3413 KiB

Open AccessArticle

Reversal of Tau-Dependent Cognitive Decay by Blocking Adenosine A1 Receptors: Comparison of Transgenic Mouse Models with Different Levels of Tauopathy

by Marta Anglada-Huguet, Heike Endepols, Astrid Sydow, Ronja Hilgers, Bernd Neumaier, Alexander Drzezga, Senthilvelrajan Kaniyappan, Eckhard Mandelkow and Eva-Maria Mandelkow

Int. J. Mol. Sci. 2023, 24(11), 9260; https://doi.org/10.3390/ijms24119260 - 25 May 2023

Cited by 2 | Viewed by 1449

Abstract

The accumulation of tau is a hallmark of several neurodegenerative diseases and is associated with neuronal hypoactivity and presynaptic dysfunction. Oral administration of the adenosine A₁ receptor antagonist rolofylline (KW-3902) has previously been shown to reverse spatial memory deficits and to normalize the basic synaptic transmission in a mouse line expressing full-length pro-aggregant tau (Tau^ΔK) at low levels, with late onset of disease. However, the efficacy of treatment remained to be explored for cases of more aggressive tauopathy. Using a combination of behavioral assays, imaging with several PET-tracers, and analysis of brain tissue, we compared the curative reversal of tau pathology by blocking adenosine A1 receptors in three mouse models expressing different types and levels of tau and tau mutants. We show through positron emission tomography using the tracer [¹⁸F]CPFPX (a selective A1 receptor ligand) that intravenous injection of rolofylline effectively blocks A₁ receptors in the brain. Moreover, when administered to Tau^ΔK mice, rolofylline can reverse tau pathology and synaptic decay. The beneficial effects are also observed in a line with more aggressive tau pathology, expressing the amyloidogenic repeat domain of tau (TauRD^ΔK) with higher aggregation propensity. Both models develop a progressive tau pathology with missorting, phosphorylation, accumulation of tau, loss of synapses, and cognitive decline. TauRD^ΔK causes pronounced neurofibrillary tangle assembly concomitant with neuronal death, whereas Tau^ΔK accumulates only to tau pretangles without overt neuronal loss. A third model tested, the rTg4510 line, has a high expression of mutant Tau^P301L and hence a very aggressive phenotype starting at ~3 months of age. This line failed to reverse pathology upon rolofylline treatment, consistent with a higher accumulation of tau-specific PET tracers and inflammation. In conclusion, blocking adenosine A1 receptors by rolofylline can reverse pathology if the pathological potential of tau remains below a threshold value that depends on concentration and aggregation propensity. Full article

(This article belongs to the Special Issue Transgenic Mice in Human Diseases: Insights from Molecular Research 4.0)

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18 pages, 1610 KiB

Open AccessArticle

Dysfunction of Foxp3⁺ Regulatory T Cells Induces Dysbiosis of Gut Microbiota via Aberrant Binding of Immunoglobulins to Microbes in the Intestinal Lumen

by Kouhei Koshida, Mitsuki Ito, Kyosuke Yakabe, Yoshimitsu Takahashi, Yuki Tai, Ryouhei Akasako, Tatsuki Kimizuka, Shunsuke Takano, Natsumi Sakamoto, Kei Haniuda, Shuhei Ogawa, Shunsuke Kimura, Yun-Gi Kim, Koji Hase and Yohsuke Harada

Int. J. Mol. Sci. 2023, 24(10), 8549; https://doi.org/10.3390/ijms24108549 - 10 May 2023

Cited by 1 | Viewed by 2061

Abstract

Foxp3⁺ regulatory T (Treg) cells prevent excessive immune responses against dietary antigens and commensal bacteria in the intestine. Moreover, Treg cells contribute to the establishment of a symbiotic relationship between the host and gut microbes, partly through immunoglobulin A. However, the mechanism by which Treg cell dysfunction disturbs the balanced intestinal microbiota remains unclear. In this study, we used Foxp3 conditional knockout mice to conditionally ablate the Foxp3 gene in adult mice and examine the relationship between Treg cells and intestinal bacterial communities. Deletion of Foxp3 reduced the relative abundance of Clostridia, suggesting that Treg cells have a role in maintaining Treg-inducing microbes. Additionally, the knockout increased the levels of fecal immunoglobulins and immunoglobulin-coated bacteria. This increase was due to immunoglobulin leakage into the gut lumen as a result of loss of mucosal integrity, which is dependent on the gut microbiota. Our findings suggest that Treg cell dysfunction leads to gut dysbiosis via aberrant antibody binding to the intestinal microbes. Full article

(This article belongs to the Special Issue Transgenic Mice in Human Diseases: Insights from Molecular Research 4.0)

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23 pages, 8231 KiB

Open AccessArticle

Growth-Restricted Fetuses and Offspring Reveal Adverse Sex-Specific Metabolic Responses in Preeclamptic Mice Expressing Human sFLT1

by Rebekka Vogtmann, Mian Bao, Monia Vanessa Dewan, Alina Riedel, Rainer Kimmig, Ursula Felderhoff-Müser, Ivo Bendix, Torsten Plösch and Alexandra Gellhaus

Int. J. Mol. Sci. 2023, 24(8), 6885; https://doi.org/10.3390/ijms24086885 - 07 Apr 2023

Cited by 2 | Viewed by 1505

Abstract

Fetal adaptations to harmful intrauterine environments due to pregnancy disorders such as preeclampsia (PE) can negatively program the offspring’s metabolism, resulting in long-term metabolic changes. PE is characterized by increased circulating levels of sFLT1, placental dysfunction and fetal growth restriction (FGR). Here we examine the consequences of systemic human sFLT1 overexpression in transgenic PE/FGR mice on the offspring’s metabolic phenotype. Histological and molecular analyses of fetal and offspring livers as well as examinations of offspring serum hormones were performed. At 18.5 dpc, sFLT1 overexpression resulted in growth-restricted fetuses with a reduced liver weight, combined with reduced hepatic glycogen storage and histological signs of hemorrhages and hepatocyte apoptosis. This was further associated with altered gene expression of the molecules involved in fatty acid and glucose/glycogen metabolism. In most analyzed features males were more affected than females. The postnatal follow-up revealed an increased weight gain of male PE offspring, and increased serum levels of Insulin and Leptin. This was associated with changes in hepatic gene expression regulating fatty acid and glucose metabolism in male PE offspring. To conclude, our results indicate that sFLT1-related PE/FGR in mice leads to altered fetal liver development, which might result in an adverse metabolic pre-programming of the offspring, specifically targeting males. This could be linked to the known sex differences seen in PE pregnancies in human. Full article

(This article belongs to the Special Issue Transgenic Mice in Human Diseases: Insights from Molecular Research 4.0)

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19 pages, 5812 KiB

Open AccessArticle

Deregulated Transcription and Proteostasis in Adult mapt Knockout Mouse

by Pol Andrés-Benito, África Flores, Sara Busquet-Areny, Margarita Carmona, Karina Ausín, Paz Cartas-Cejudo, Mercedes Lachén-Montes, José Antonio Del Rio, Joaquín Fernández-Irigoyen, Enrique Santamaría and Isidro Ferrer

Int. J. Mol. Sci. 2023, 24(7), 6559; https://doi.org/10.3390/ijms24076559 - 31 Mar 2023

Cited by 1 | Viewed by 2008

Abstract

Transcriptomics and phosphoproteomics were carried out in the cerebral cortex of B6.Cg-Mapttm1(EGFP)Klt (tau knockout: tau-KO) and wild-type (WT) 12 month-old mice to learn about the effects of tau ablation. Compared with WT mice, tau-KO mice displayed reduced anxiety-like behavior and lower fear expression induced by aversive conditioning, whereas recognition memory remained unaltered. Cortical transcriptomic analysis revealed 69 downregulated and 105 upregulated genes in tau-KO mice, corresponding to synaptic structures, neuron cytoskeleton and transport, and extracellular matrix components. RT-qPCR validated increased mRNA levels of col6a4, gabrq, gad1, grm5, grip2, map2, rab8a, tubb3, wnt16, and an absence of map1a in tau-KO mice compared with WT mice. A few proteins were assessed with Western blotting to compare mRNA expression with corresponding protein levels. Map1a mRNA and protein levels decreased. However, β-tubulin III and GAD1 protein levels were reduced in tau-KO mice. Cortical phosphoproteomics revealed 121 hypophosphorylated and 98 hyperphosphorylated proteins in tau-KO mice. Deregulated phosphoproteins were categorized into cytoskeletal (n = 45) and membrane proteins, including proteins of the synapses and vesicles, myelin proteins, and proteins linked to membrane transport and ion channels (n = 84), proteins related to DNA and RNA metabolism (n = 36), proteins connected to the ubiquitin-proteasome system (UPS) (n = 7), proteins with kinase or phosphatase activity (n = 21), and 22 other proteins related to variegated pathways such as metabolic pathways, growth factors, or mitochondrial function or structure. The present observations reveal a complex altered brain transcriptome and phosphoproteome in tau-KO mice with only mild behavioral alterations. Full article

(This article belongs to the Special Issue Transgenic Mice in Human Diseases: Insights from Molecular Research 4.0)

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Review

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23 pages, 2877 KiB

Open AccessReview

Mouse Models of Cardiomyopathies Caused by Mutations in Troponin C

by Svetlana B. Tikunova, Jenna Thuma and Jonathan P. Davis

Int. J. Mol. Sci. 2023, 24(15), 12349; https://doi.org/10.3390/ijms241512349 - 02 Aug 2023

Viewed by 1476

Abstract

Cardiac muscle contraction is regulated via Ca²⁺ exchange with the hetero-trimeric troponin complex located on the thin filament. Binding of Ca²⁺ to cardiac troponin C, a Ca²⁺ sensing subunit within the troponin complex, results in a series of conformational re-arrangements among the thin filament components, leading to an increase in the formation of actomyosin cross-bridges and muscle contraction. Ultimately, a decline in intracellular Ca²⁺ leads to the dissociation of Ca²⁺ from troponin C, inhibiting cross-bridge cycling and initiating muscle relaxation. Therefore, troponin C plays a crucial role in the regulation of cardiac muscle contraction and relaxation. Naturally occurring and engineered mutations in troponin C can lead to altered interactions among components of the thin filament and to aberrant Ca²⁺ binding and exchange with the thin filament. Mutations in troponin C have been associated with various forms of cardiac disease, including hypertrophic, restrictive, dilated, and left ventricular noncompaction cardiomyopathies. Despite progress made to date, more information from human studies, biophysical characterizations, and animal models is required for a clearer understanding of disease drivers that lead to cardiomyopathies. The unique use of engineered cardiac troponin C with the L48Q mutation that had been thoroughly characterized and genetically introduced into mouse myocardium clearly demonstrates that Ca²⁺ sensitization in and of itself should not necessarily be considered a disease driver. This opens the door for small molecule and protein engineering strategies to help boost impaired systolic function. On the other hand, the engineered troponin C mutants (I61Q and D73N), genetically introduced into mouse myocardium, demonstrate that Ca²⁺ desensitization under basal conditions may be a driving factor for dilated cardiomyopathy. In addition to enhancing our knowledge of molecular mechanisms that trigger hypertrophy, dilation, morbidity, and mortality, these cardiomyopathy mouse models could be used to test novel treatment strategies for cardiovascular diseases. In this review, we will discuss (1) the various ways mutations in cardiac troponin C might lead to disease; (2) relevant data on mutations in cardiac troponin C linked to human disease, and (3) all currently existing mouse models containing cardiac troponin C mutations (disease-associated and engineered). Full article

(This article belongs to the Special Issue Transgenic Mice in Human Diseases: Insights from Molecular Research 4.0)

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