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Topical Collection "Feature Papers in Molecular Genetics and Genomics"

Editors

Dr. Cristoforo Comi
E-Mail Website
Guest Editor
Department of Translational Medicine, Section of Neurology, University of Piemonte Orientale, 28100 Novara, Italy
Interests: neurodegenerative diseases including Parkinson's disease, Huntington disease, other movement disorders, Alzheimer's disease; neuroimmune diseases including: multiple sclerosis, inflammatory neuropathies, myasthenia gravis
Special Issues and Collections in MDPI journals
Dr. Benoit Gauthier
E-Mail Website
Guest Editor
Andalusian Center for Molecular Biology and Regenerative Medicine CABIMER, Sevilla, Spain
Interests: Islet physiology; Genetics of Diabetes; Cell Regeneration; Drug development
Special Issues and Collections in MDPI journals
Prof. Dr. Dimitrios H. Roukos
E-Mail Website
Guest Editor
Centre for Biosystems and Genome Network Medicine, Ioannina University, Ioannina, Greece
Department of Surgery, Ioannina University Hospital, Ioannina, Greece
Department of Systems Biology, Biomedical Research Foundation of the Academy of Athens (BRFAA), Athens, Greece
Tel. +30 26510 07423; +302651005572; Fax: +30 26510 07094
Interests: cancer; precision medicine; intra-tumor heterogeneity with multi-regional next generation sequencing (NGS); circulating cell free DNA-NGS; genomebased biomarkers development; transcriptome-based drug development; cell-cell interactions
Prof. Dr. Alfredo Fusco
E-Mail Website
Guest Editor
Departement of Molecular Medicine and Medical Biotechnology, University of Naples "Federico II", Naples, Italy
Interests: Molecular oncology; genetics and molecular biology; thyroid cancer2; Pituitary tumors; hmga proteins

Topical Collection Information

Dear Colleagues,

This Topical Collection “Feature Papers in Molecular Genetics and Genomics” will collect high-quality research articles, short communications, and review articles in all the fields of molecular genetics and genomics. Since the aim of this Topical Collection is to illustrate, through selected works, frontier research in this field, we encourage Editorial Board Members of the Molecular Genetics and Genomics Section of the International Journal of Molecular Sciences to contribute papers reflecting the latest progress in their research field or to invite relevant experts and colleagues to do so. Topics include, but are not limited to, the following:

  • Gene regulation, chromatin, and epigenetics
  • Genome integrity, repair, and replication
  • Genes or genomes related to phenotypes and human physiopathology
  • Gene flow and transfer
  • Plant genetic studies
  • Animal genetic studies
  • Evolutionary genomics

Prof. Dr. Cristoforo Comi
Dr. Benoit Gauthier
Prof. Dr. Dimitrios Roukos
Prof. Dr. Alfredo Fusco
Guest Editors

Manuscript Submission Information

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Published Papers (11 papers)

2020

Jump to: 2019

Open AccessArticle
Rapid Cellular Perception of Gravitational Forces in Human Jurkat T Cells and Transduction into Gene Expression Regulation
Int. J. Mol. Sci. 2020, 21(2), 514; https://doi.org/10.3390/ijms21020514 - 14 Jan 2020
Abstract
Cellular processes are influenced in many ways by changes in gravitational force. In previous studies, we were able to demonstrate, in various cellular systems and research platforms that reactions and adaptation processes occur very rapidly after the onset of altered gravity. In this [...] Read more.
Cellular processes are influenced in many ways by changes in gravitational force. In previous studies, we were able to demonstrate, in various cellular systems and research platforms that reactions and adaptation processes occur very rapidly after the onset of altered gravity. In this study we systematically compared differentially expressed gene transcript clusters (TCs) in human Jurkat T cells in microgravity provided by a suborbital ballistic rocket with vector-averaged gravity (vag) provided by a 2D clinostat. Additionally, we included 9× g centrifuge experiments and rigorous controls for excluding other factors of influence than gravity. We found that 11 TCs were significantly altered in 5 min of flight-induced and vector-averaged gravity. Among the annotated clusters were G3BP1, KPNB1, NUDT3, SFT2D2, and POMK. Our results revealed that less than 1% of all examined TCs show the same response in vag and flight-induced microgravity, while 38% of differentially regulated TCs identified during the hypergravity phase of the suborbital ballistic rocket flight could be verified with a 9× g ground centrifuge. In the 2D clinostat system, doing one full rotation per second, vector effects of the gravitational force are only nullified if the sensing mechanism requires 1 s or longer. Due to the fact that vag with an integration period of 1 s was not able to reproduce the results obtained in flight-induced microgravity, we conclude that the initial trigger of gene expression response to microgravity requires less than 1 s reaction time. Additionally, we discovered extensive gene expression differences caused by simple handling of the cell suspension in control experiments, which underlines the need for rigorous standardization regarding mechanical forces during cell culture experiments in general. Full article
Open AccessArticle
Novel Loss-of-Function Variants in CDC14A are Associated with Recessive Sensorineural Hearing Loss in Iranian and Pakistani Patients
Int. J. Mol. Sci. 2020, 21(1), 311; https://doi.org/10.3390/ijms21010311 - 02 Jan 2020
Abstract
CDC14A encodes the Cell Division Cycle 14A protein and has been associated with autosomal recessive non-syndromic hearing loss (DFNB32), as well as hearing impairment and infertile male syndrome (HIIMS) since 2016. To date, only nine variants have been associated in patients whose initial [...] Read more.
CDC14A encodes the Cell Division Cycle 14A protein and has been associated with autosomal recessive non-syndromic hearing loss (DFNB32), as well as hearing impairment and infertile male syndrome (HIIMS) since 2016. To date, only nine variants have been associated in patients whose initial symptoms included moderate-to-profound hearing impairment. Exome analysis of Iranian and Pakistani probands who both showed bilateral, sensorineural hearing loss revealed a novel splice site variant (c.1421+2T>C, p.?) that disrupts the splice donor site and a novel frameshift variant (c.1041dup, p.Ser348Glnfs*2) in the gene CDC14A, respectively. To evaluate the pathogenicity of both loss-of-function variants, we analyzed the effects of both variants on the RNA-level. The splice variant was characterized using a minigene assay. Altered expression levels due to the c.1041dup variant were assessed using RT-qPCR. In summary, cDNA analysis confirmed that the c.1421+2T>C variant activates a cryptic splice site, resulting in a truncated transcript (c.1414_1421del, p.Val472Leufs*20) and the c.1041dup variant results in a defective transcript that is likely degraded by nonsense-mediated mRNA decay. The present study functionally characterizes two variants and provides further confirmatory evidence that CDC14A is associated with a rare form of hereditary hearing loss. Full article
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2019

Jump to: 2020

Open AccessArticle
Association of Complement Factor D and H Polymorphisms with Recurrent Pregnancy Loss
Int. J. Mol. Sci. 2020, 21(1), 17; https://doi.org/10.3390/ijms21010017 - 18 Dec 2019
Abstract
Recurrent pregnancy loss (RPL) is defined as two or more consecutive pregnancy losses prior to 20 weeks of gestation, and the incidence of RPL is estimated at 1% of all pregnancies. While the etiologies of RPL are diverse, immune function is considered to [...] Read more.
Recurrent pregnancy loss (RPL) is defined as two or more consecutive pregnancy losses prior to 20 weeks of gestation, and the incidence of RPL is estimated at 1% of all pregnancies. While the etiologies of RPL are diverse, immune function is considered to be an important cause of RPL. In particular, the complement system is essential for stable development of the placenta and fetus. Moreover, complement factor D (CFD) and complement factor H (CFH) are important regulators of the complement system and are associated with diseases, such as age-related macular degeneration. Therefore, we investigated whether polymorphisms of CFD and CFH are associated with RPL in 412 women with RPL and 384 control women. Genotyping of three polymorphisms (CFD rs2230216, CFH rs1065489, and CFH rs1061170) was performed by TaqMan probe real-time PCR and PCR-restriction fragment length polymorphism. Association of three polymorphisms with RPL was evaluated by statistical analysis. The GT/TC genotype combination of CFH rs1065489 G>T/CFH rs1061170 T>C was associated with a decreased risk of RPL occurrence compared with reference genotypes (adjusted odds ratio [AOR] = 0.439; 95% confidence interval [CI] = 0.238–0.810; p = 0.008), and this association remained significant after adjustment for multiple comparisons using false discovery rate (FDR) correction (p = 0.040). In addition, the CFH rs1065489G>T polymorphism is associated with homocysteine and prolactin level and CFH rs1061170 TC genotype is related to uric acid and triglycerides level in RPL patients. Therefore, those factors could be possible clinical risk factors in RPL patients. Full article
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Open AccessArticle
Genetic and Physiological Dissection of Photosynthesis in Barley Exposed to Drought Stress
Int. J. Mol. Sci. 2019, 20(24), 6341; https://doi.org/10.3390/ijms20246341 - 16 Dec 2019
Abstract
Balanced photosynthesis under drought is essential for better survival and for agricultural benefits in terms of biomass and yield. Given the current attempts to improve the photosynthetic efficiency for greater crop yield, the explanation of the genetic basis of that process, together with [...] Read more.
Balanced photosynthesis under drought is essential for better survival and for agricultural benefits in terms of biomass and yield. Given the current attempts to improve the photosynthetic efficiency for greater crop yield, the explanation of the genetic basis of that process, together with the phenotypic analysis, is significant in terms of both basic studies and potential agricultural application. Therefore, the main objective of this study was to uncover the molecular basis of the photosynthesis process under drought stress in barley. To address that goal, we conducted transcriptomic examination together with detailed photosynthesis analysis using the JIP-test. Using this approach, we indicated that photosynthesis is a process that is very early affected in barley seedlings treated with severe drought stress. Rather than focusing on individual genes, our strategy was pointed to the identification of groups of genes with similar expression patterns. As such, we identified and annotated almost 150 barley genes as crucial core-components of photosystems, electron transport components, and Calvin cycle enzymes. Moreover, we designated 17 possible regulatory interactions between photosynthesis-related genes and transcription factors in barley. Summarizing, our results provide a list of candidate genes for future genetic research and improvement of barley drought tolerance by targeting photosynthesis. Full article
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Open AccessCase Report
Novel JAG1 Deletion Variant in Patient with Atypical Alagille Syndrome
Int. J. Mol. Sci. 2019, 20(24), 6247; https://doi.org/10.3390/ijms20246247 - 11 Dec 2019
Abstract
Alagille syndrome (AGS) is an autosomal-dominant disorder characterized by various degrees of abnormalities in the liver, heart, eyes, vertebrae, kidneys, face, vasculature, skeleton, and pancreas. This case report describes a newborn child exhibiting a congenital neural tube defect and peculiar craniofacial appearance characterized [...] Read more.
Alagille syndrome (AGS) is an autosomal-dominant disorder characterized by various degrees of abnormalities in the liver, heart, eyes, vertebrae, kidneys, face, vasculature, skeleton, and pancreas. This case report describes a newborn child exhibiting a congenital neural tube defect and peculiar craniofacial appearance characterized by a prominent forehead, deep-set eyes, bulbous nasal tip, and subtle upper lip. Just a few hours after birth, congenital heart disease was suspected for cyanosis and confirmed by heart evaluation. In particular, echocardiography indicated pulmonary atresia with ventricular septal defect with severe hypoplasia of the pulmonary branches (1.5 mm), large patent ductus arteriosus and several major aortopulmonary collateral arteries. Due to the association of peculiar craniofacial appearance and congenital heart disease, a form of Alagille syndrome was suspected. In addition, on the fifth day after birth, the patient developed jaundice, had acholic stools, and high levels of conjugated bilirubin and gamma-glutamyltransferase (GGT) were detected in the blood. Genetic testing revealed the novel variant c.802del in a single copy of the JAG1 gene. No variants in the NOTCH2 gene were detected. To the best of our knowledge, this is the first clinical description of a congenital neural tube defect in a molecularly confirmed Alagille patient. This work demonstrates a novel pathogenic heterozygous JAG1 mutation is associated with an atypical form of Alagille syndrome, suggesting an increased risk for neural tube defects compared to other Alagille patients. Full article
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Open AccessArticle
The 1,10-Phenanthroline Ligand Enhances the Antiproliferative Activity of DNA-Intercalating Thiourea-Pd(II) and -Pt(II) Complexes Against Cisplatin-Sensitive and -Resistant Human Ovarian Cancer Cell Lines
Int. J. Mol. Sci. 2019, 20(24), 6122; https://doi.org/10.3390/ijms20246122 - 04 Dec 2019
Abstract
Ovarian cancer is the most lethal gynecological malignancy, often because of the frequent insurgence of chemoresistance to the drugs currently used. Thus, new therapeutical agents are needed. We tested the toxicity of 16 new DNA-intercalating agents to cisplatin (cDDP)-sensitive human ovarian carcinoma cell [...] Read more.
Ovarian cancer is the most lethal gynecological malignancy, often because of the frequent insurgence of chemoresistance to the drugs currently used. Thus, new therapeutical agents are needed. We tested the toxicity of 16 new DNA-intercalating agents to cisplatin (cDDP)-sensitive human ovarian carcinoma cell lines and their resistant counterparts. The compounds were the complexes of Pt(II) or Pd(II) with bipyridyl (bipy) and phenanthrolyl (phen) and with four different thiourea ancillary ligands. Within each of the four series of complexes characterized by the same thiourea ligand, the Pd(phen) drugs invariably showed the highest anti-proliferative efficacy. This paralleled both a higher intracellular drug accumulation and a more efficient DNA intercalation than all the other metal-bidentate ligand combinations. The consequent inhibition of topoisomerase II activity led to the greatest inhibition of DNA metabolism, evidenced by the inhibition of the expression of the folate cycle enzymes and a marked perturbation of cell-cycle distribution in both cell lines. These findings indicate that the particular interaction of Pd(II) with phenanthroline confers the best pharmacokinetic and pharmacodynamic properties that make this class of DNA intercalators remarkable inhibitors, even of the resistant cell growth. Full article
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Open AccessCase Report
Genotype–Phenotype Correlation in a Family with Brugada Syndrome Harboring the Novel p.Gln371* Nonsense Variant in the SCN5A Gene
Int. J. Mol. Sci. 2019, 20(22), 5522; https://doi.org/10.3390/ijms20225522 - 06 Nov 2019
Abstract
Brugada syndrome (BrS) is marked by coved ST-segment elevation and increased risk of sudden cardiac death. The genetics of this syndrome are elusive in over half of the cases. Variants in the SCN5A gene are the single most common known genetic unifier, accounting [...] Read more.
Brugada syndrome (BrS) is marked by coved ST-segment elevation and increased risk of sudden cardiac death. The genetics of this syndrome are elusive in over half of the cases. Variants in the SCN5A gene are the single most common known genetic unifier, accounting for about a third of cases. Research models, such as animal models and cell lines, are limited. In the present study, we report the novel NM_198056.2:c.1111C>T (p.Gln371*) heterozygous variant in the SCN5A gene, as well as its segregation with BrS in a large family. The results herein suggest a pathogenic effect of this variant. Functional studies are certainly warranted to characterize the molecular effects of this variant. Full article
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Open AccessArticle
Type IV Collagen Is Essential for Proper Function of Integrin-Mediated Adhesion in Drosophila Muscle Fibers
Int. J. Mol. Sci. 2019, 20(20), 5124; https://doi.org/10.3390/ijms20205124 - 16 Oct 2019
Abstract
Congenital muscular dystrophy (CMD), a subgroup of myopathies is a genetically and clinically heterogeneous group of inherited muscle disorders and is characterized by progressive muscle weakness, fiber size variability, fibrosis, clustered necrotic fibers, and central myonuclei present in regenerating muscle. Type IV collagen [...] Read more.
Congenital muscular dystrophy (CMD), a subgroup of myopathies is a genetically and clinically heterogeneous group of inherited muscle disorders and is characterized by progressive muscle weakness, fiber size variability, fibrosis, clustered necrotic fibers, and central myonuclei present in regenerating muscle. Type IV collagen (COL4A1) mutations have recently been identified in patients with intracerebral, vascular, renal, ophthalmologic pathologies and congenital muscular dystrophy, consistent with diagnoses of Walker–Warburg Syndrome or Muscle–Eye–Brain disease. Morphological characteristics of muscular dystrophy have also been demonstrated Col4a1 mutant mice. Yet, several aspects of the pathomechanism of COL4A1-associated muscle defects remained largely uncharacterized. Based on the results of genetic, histological, molecular, and biochemical analyses in an allelic series of Drosophila col4a1 mutants, we provide evidence that col4a1 mutations arise by transitions in glycine triplets, associate with severely compromised muscle fibers within the single-layer striated muscle of the common oviduct, characterized by loss of sarcomere structure, disintegration and streaming of Z-discs, indicating an essential role for the COL4A1 protein. Features of altered cytoskeletal phenotype include actin bundles traversing over sarcomere units, amorphous actin aggregates, atrophy, and aberrant fiber size. The mutant COL4A1-associated defects appear to recapitulate integrin-mediated adhesion phenotypes observed in RNA-inhibitory Drosophila. Our results provide insight into the mechanistic details of COL4A1-associated muscle disorders and suggest a role for integrin-collagen interaction in the maintenance of sarcomeres. Full article
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Open AccessArticle
Stabilization of c-KIT G-Quadruplex DNA Structures by the RNA Polymerase I Inhibitors BMH-21 and BA-41
Int. J. Mol. Sci. 2019, 20(19), 4927; https://doi.org/10.3390/ijms20194927 - 04 Oct 2019
Abstract
The stabilization of G-quadruplex DNA structures by small molecules with affinity to oncogene promoters has emerged as a promising anticancer strategy, due to a potential role in gene expression regulation. We explored the ability of BMH-21 (1) and its analogue BA-41 [...] Read more.
The stabilization of G-quadruplex DNA structures by small molecules with affinity to oncogene promoters has emerged as a promising anticancer strategy, due to a potential role in gene expression regulation. We explored the ability of BMH-21 (1) and its analogue BA-41 (2) to bind the G-quadruplex structure present in the c-KIT promoter by biophysical methods and molecular modeling. We provide evidence that both compounds interact with the c-KIT 21-mer sequence. The stable monomeric intramolecular parallel G-quadruplex obtained by the mutation of positions 12 and 21 allowed the precise determination of the binding mode by NMR and molecular dynamics studies. Both compounds form a complex characterized by one ligand molecule positioned over the tetrad at the 3′-end, stabilized by an extensive network of π–π interactions. The binding constants (Kb) obtained with fluorescence are similar for both complexes (around 106 M−1). Compound BA-41 (2) showed significant antiproliferative activity against a human lymphoma cell line, SU-DHL4, known to express substantial levels of c-KIT. However, the partial inhibition of c-KIT expression by Western blot analysis suggested that the interaction of compound 2 with the c-KIT promoter is not the primary event and that multiple effects provide a contribution as determinants of biological activity. Full article
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Open AccessCase Report
Novel SCN5A p.W697X Nonsense Mutation Segregation in a Family with Brugada Syndrome
Int. J. Mol. Sci. 2019, 20(19), 4920; https://doi.org/10.3390/ijms20194920 - 04 Oct 2019
Abstract
Brugada syndrome (BrS) is marked by an elevated ST-segment elevation and increased risk of sudden cardiac death. Variants in the SCN5A gene are considered to be molecular confirmation of the syndrome in about one third of cases, while the genetics remain a mystery [...] Read more.
Brugada syndrome (BrS) is marked by an elevated ST-segment elevation and increased risk of sudden cardiac death. Variants in the SCN5A gene are considered to be molecular confirmation of the syndrome in about one third of cases, while the genetics remain a mystery in about half of the cases, with the remaining cases being attributed to variants in any of a number of genes. Before research models can be developed, it is imperative to understand the genetics in patients. Even data from humans is complicated, since variants in the most common gene in BrS, SCN5A, are associated with a number of pathologies, or could even be considered benign, depending on the variant. Here, we provide crucial human data on a novel NM_198056.2:c.2091G>A (p.Trp697X) point-nonsense heterozygous variant in the SCN5A gene, as well as its segregation with BrS. The results herein suggest a pathogenic effect of this variant. These results could be used as a stepping stone for functional studies to better understand the molecular effects of this variant in BrS. Full article
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Open AccessArticle
Mitochondrial Genomes of Two Thaparocleidus Species (Platyhelminthes: Monogenea) Reveal the First rRNA Gene Rearrangement among the Neodermata
Int. J. Mol. Sci. 2019, 20(17), 4214; https://doi.org/10.3390/ijms20174214 - 28 Aug 2019
Abstract
Phylogenetic framework for the closely related Ancylodiscoidinae and Ancyrocephalinae subfamilies remains contentious. As this issue was never studied using a large molecular marker, we sequenced the first two Ancylodiscoidinae mitogenomes: Thaparocleidus asoti and Thaparocleidus varicus. Both mitogenomes had two non-coding regions (NCRs) [...] Read more.
Phylogenetic framework for the closely related Ancylodiscoidinae and Ancyrocephalinae subfamilies remains contentious. As this issue was never studied using a large molecular marker, we sequenced the first two Ancylodiscoidinae mitogenomes: Thaparocleidus asoti and Thaparocleidus varicus. Both mitogenomes had two non-coding regions (NCRs) that contained a number of repetitive hairpin-forming elements (RHE). Due to these, the mitogenome of T. asoti (16,074 bp) is the longest among the Monogenea; especially large is its major NCR, with 3500 bp, approximately 1500 bp of which could not be sequenced (thus, the total mitogenome size is ≈ 17,600 bp). Although RHEs have been identified in other monopisthocotyleans, they appear to be independently derived in different taxa. The presence of RHEs may have contributed to the high gene order rearrangement rate observed in the two mitogenomes, including the first report of a transposition of rRNA genes within the Neodermata. Phylogenetic analyses using mitogenomic dataset produced Dactylogyrinae embedded within the Ancyrocephalinae (paraphyly), whereas Ancylodiscoidinae formed a sister-group with them. This was also supported by the gene order analysis. 28S rDNA dataset produced polyphyletic Dactylogyridae and Ancyrocephalinae. The phylogeny of the two subfamilies shall have to be further evaluated with more data. Full article
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