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Molecular Effects of Mutations in Human Genetic Diseases 2.0
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Molecular Effects of Mutations in Human Genetic Diseases 2.0

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

Deadline for manuscript submissions: closed (15 July 2023) | Viewed by 15392

Special Issue Editors

Dr. Giovanni Minervini

E-Mail Website
Guest Editor
Department of Biomedical Science, University of Padua, 35121 Padua, Italy
Interests: von Hippel-Lindau disease; cancer bioinformatics; computational biology; protein characterization; computational biophysics; molecular dynamic simulations
Special Issues, Collections and Topics in MDPI journals
Dr. Emanuela Leonardi

E-Mail Website
Guest Editor
1. Department of Woman and Child Health, University of Padua, 35121 Padua, Italy
2. Pediatric Research Institute, Città della Speranza, 35127 Padova, Italy
Interests: neurodevelopmental disorders; Rett syndrome; human genetics; next generation sequencing; mutations; genome interpretation; bioinformatics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Interpreting the millions of human genetic variants identified by high-throughput sequencing presents one of the greatest scientific challenges of our time. Variants can be classified by their location in genomic DNA, as well as their evolutionary, physicochemical, structural, and functional properties, and their impact on transcripts, proteins, and molecular interactions. Knowledge of the molecular effects of causal mutations emerges at the interface of human genetics, computational biology, molecular biology, and biophysics. It can provide insights into the pathogenic mechanisms underlying diseases and will help pave the way for mechanism-based drug development strategies.

The aim of this Special Issue is to attract high-quality studies describing computational and experimental approaches for investigating the molecular effects of novel genetic mutations, and providing a useful framework for understanding the molecular defects underlying human diseases. Contributors are also encouraged to submit articles describing use cases, models, and methodological innovations.

This Special Issue will include (1) human genetics studies on genome/exome or targeted sequencing panels that allow either identification of disease–gene associations, characterization of rare diseases with significant genetic heterogeneity, or differential clustering of disease mutations associated with distinct phenotypes; (2) experimental studies investigating how a genetic variant causes disease at the molecular, cellular, and organismal levels; and (3) computational methods devised to predict the impact of genetic variations and their assessment, large-scale statistical studies dissecting key features of disease mutations, or well-curated data repositories of genetic variation and/or disease associations.

Dr. Giovanni Minervini
Dr. Emanuela Leonardi
Guest Editors

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.

Keywords

  • variant interpretation
  • institutional review board statement
  • personalized medicine
  • disease-causing mutations
  • disease–gene association
  • molecular mechanisms
  • pathogenicity prediction
  • protein stability

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Related Special Issue

Published Papers (6 papers)

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Research

11 pages, 1794 KiB  
Article
Spinocerebellar Ataxia in a Hungarian Female Patient with a Novel Variant of Unknown Significance in the CCDC88C Gene
by Fanni Annamária Boros, László Szpisjak, Renáta Bozó, Evelyn Kelemen, Dénes Zádori, András Salamon, Judit Danis, Tibor Kalmár, Zoltán Maróti, Mária Judit Molnár, Péter Klivényi, Márta Széll and Éva Ádám
Int. J. Mol. Sci. 2023, 24(3), 2617; https://doi.org/10.3390/ijms24032617 - 30 Jan 2023
Cited by 5 | Viewed by 2303
Abstract
Spinocerebellar ataxia (SCA) 40 is an extremely rare subtype of the phenotypically and genetically diverse autosomal dominant ataxias caused by mutations of the CCDC88C gene. Most reported cases of SCA40 are characterized by late-onset cerebellar ataxia and variable extrapyramidal features; however, there is [...] Read more.
Spinocerebellar ataxia (SCA) 40 is an extremely rare subtype of the phenotypically and genetically diverse autosomal dominant ataxias caused by mutations of the CCDC88C gene. Most reported cases of SCA40 are characterized by late-onset cerebellar ataxia and variable extrapyramidal features; however, there is a report of a patient with early-onset spastic paraparesis as well. Here, we describe a novel missense CCDC88C mutation (p.R203W) in the hook domain of the DAPLE protein encoded by the CCDC88C gene that was identified in a female patient who developed late-onset ataxia, dysmetria and intention tremor. To explore the molecular consequences of the newly identified and previously described CCDC88C mutations, we carried out in vitro functional tests. The CCDC88C alleles were expressed in HEK293 cells, and the impact of the mutant DAPLE protein variants on JNK pathway activation and apoptosis was assessed. Our results revealed only a small-scale activation of the JNK pathway by mutant DAPLE proteins; however, increased JNK1 phosphorylation could not be detected. Additionally, none of the examined mutations triggered proapoptotic effect. In conclusion, we identified a novel mutation of the CCDC88C gene from a patient with spinocerebellar ataxia. Our results are not in accord with previous observations and do not support the primary role of the CCDC88C mutations in induction of JNK pathway activation in ataxia. Therefore, we propose that CCDC88C mutations may exert their effects through different and possibly in much broader, yet unexplored, biological processes. Full article
(This article belongs to the Special Issue Molecular Effects of Mutations in Human Genetic Diseases 2.0)
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19 pages, 2195 KiB  
Article
Increased Levels of the Parkinson’s Disease-Associated Gene ITPKB Correlate with Higher Expression Levels of α-Synuclein, Independent of Mutation Status
by Francesca Di Leva, Michele Filosi, Lisa Oyston, Erica Silvestri, Anne Picard, Alexandros A. Lavdas, Evy Lobbestael, Veerle Baekelandt, G. Gregory Neely, Peter P. Pramstaller, Andrew A. Hicks and Corrado Corti
Int. J. Mol. Sci. 2023, 24(3), 1984; https://doi.org/10.3390/ijms24031984 - 19 Jan 2023
Cited by 2 | Viewed by 2626
Abstract
Autosomal dominant mutations in the gene encoding α-synuclein (SNCA) were the first to be linked with hereditary Parkinson’s disease (PD). Duplication and triplication of SNCA has been observed in PD patients, together with mutations at the N-terminal of the protein, among [...] Read more.
Autosomal dominant mutations in the gene encoding α-synuclein (SNCA) were the first to be linked with hereditary Parkinson’s disease (PD). Duplication and triplication of SNCA has been observed in PD patients, together with mutations at the N-terminal of the protein, among which A30P and A53T influence the formation of fibrils. By overexpressing human α-synuclein in the neuronal system of Drosophila, we functionally validated the ability of IP3K2, an ortholog of the GWAS identified risk gene, Inositol-trisphosphate 3-kinase B (ITPKB), to modulate α-synuclein toxicity in vivo. ITPKB mRNA and protein levels were also increased in SK-N-SH cells overexpressing wild-type α-synuclein, A53T or A30P mutants. Kinase overexpression was detected in the cytoplasmatic and in the nuclear compartments in all α-synuclein cell types. By quantifying mRNAs in the cortex of PD patients, we observed higher levels of ITPKB mRNA when SNCA was expressed more (p < 0.05), compared to controls. A positive correlation was also observed between SNCA and ITPKB expression in the cortex of patients, which was not seen in the controls. We replicated this observation in a public dataset. Our data, generated in SK-N-SH cells and in cortex from PD patients, show that the expression of α-synuclein and ITPKB is correlated in pathological situations. Full article
(This article belongs to the Special Issue Molecular Effects of Mutations in Human Genetic Diseases 2.0)
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20 pages, 3089 KiB  
Article
Functional Characterization of a Spectrum of Novel Romano-Ward Syndrome KCNQ1 Variants
by Susanne Rinné, Annemarie Oertli, Claudia Nagel, Philipp Tomsits, Tina Jenewein, Stefan Kääb, Silke Kauferstein, Axel Loewe, Britt Maria Beckmann and Niels Decher
Int. J. Mol. Sci. 2023, 24(2), 1350; https://doi.org/10.3390/ijms24021350 - 10 Jan 2023
Cited by 2 | Viewed by 2173
Abstract
The KCNQ1 gene encodes the α-subunit of the cardiac voltage-gated potassium (Kv) channel KCNQ1, also denoted as Kv7.1 or KvLQT1. The channel assembles with the ß-subunit KCNE1, also known as minK, to generate the slowly activating cardiac delayed rectifier current IKs, [...] Read more.
The KCNQ1 gene encodes the α-subunit of the cardiac voltage-gated potassium (Kv) channel KCNQ1, also denoted as Kv7.1 or KvLQT1. The channel assembles with the ß-subunit KCNE1, also known as minK, to generate the slowly activating cardiac delayed rectifier current IKs, a key regulator of the heart rate dependent adaptation of the cardiac action potential duration (APD). Loss-of-function variants in KCNQ1 cause the congenital Long QT1 (LQT1) syndrome, characterized by delayed cardiac repolarization and a QT interval prolongation in the surface electrocardiogram (ECG). Autosomal dominant loss-of-function variants in KCNQ1 result in the LQT syndrome called Romano-Ward syndrome (RWS), while autosomal recessive variants affecting function, lead to Jervell and Lange-Nielsen syndrome (JLNS), associated with deafness. The aim of this study was the characterization of novel KCNQ1 variants identified in patients with RWS to widen the spectrum of known LQT1 variants, and improve the interpretation of the clinical relevance of variants in the KCNQ1 gene. We functionally characterized nine human KCNQ1 variants using the voltage-clamp technique in Xenopus laevis oocytes, from which we report seven novel variants. The functional data was taken as input to model surface ECGs, to subsequently compare the functional changes with the clinically observed QTc times, allowing a further interpretation of the severity of the different LQTS variants. We found that the electrophysiological properties of the variants correlate with the severity of the clinically diagnosed phenotype in most cases, however, not in all. Electrophysiological studies combined with in silico modelling approaches are valuable components for the interpretation of the pathogenicity of KCNQ1 variants, but assessing the clinical severity demands the consideration of other factors that are included, for example in the Schwartz score. Full article
(This article belongs to the Special Issue Molecular Effects of Mutations in Human Genetic Diseases 2.0)
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18 pages, 3224 KiB  
Article
Whole Exome Sequencing Identifies a Heterozygous Variant in the Cav1.3 Gene CACNA1D Associated with Familial Sinus Node Dysfunction and Focal Idiopathic Epilepsy
by Susanne Rinné, Birgit Stallmeyer, Alexandra Pinggera, Michael F. Netter, Lina A. Matschke, Sven Dittmann, Uwe Kirchhefer, Ulrich Neudorf, Joachim Opp, Jörg Striessnig, Niels Decher and Eric Schulze-Bahr
Int. J. Mol. Sci. 2022, 23(22), 14215; https://doi.org/10.3390/ijms232214215 - 17 Nov 2022
Cited by 7 | Viewed by 2537
Abstract
Cav1.3 voltage-gated L-type calcium channels (LTCCs) are involved in cardiac pacemaking, hearing and hormone secretion, but are also expressed postsynaptically in neurons. So far, homozygous loss of function mutations in CACNA1D encoding the Cav1.3 α1-subunit are described in congenital sinus node [...] Read more.
Cav1.3 voltage-gated L-type calcium channels (LTCCs) are involved in cardiac pacemaking, hearing and hormone secretion, but are also expressed postsynaptically in neurons. So far, homozygous loss of function mutations in CACNA1D encoding the Cav1.3 α1-subunit are described in congenital sinus node dysfunction and deafness. In addition, germline mutations in CACNA1D have been linked to neurodevelopmental syndromes including epileptic seizures, autism, intellectual disability and primary hyperaldosteronism. Here, a three-generation family with a syndromal phenotype of sinus node dysfunction, idiopathic epilepsy and attention deficit hyperactivity disorder (ADHD) is investigated. Whole genome sequencing and functional heterologous expression studies were used to identify the disease-causing mechanisms in this novel syndromal disorder. We identified a heterozygous non-synonymous variant (p.Arg930His) in the CACNA1D gene that cosegregated with the combined clinical phenotype in an autosomal dominant manner. Functional heterologous expression studies showed that the CACNA1D variant induces isoform-specific alterations of Cav1.3 channel gating: a gain of ion channel function was observed in the brain-specific short CACNA1D isoform (Cav1.3S), whereas a loss of ion channel function was seen in the long (Cav1.3L) isoform. The combined gain-of-function (GOF) and loss-of-function (LOF) induced by the R930H variant are likely to be associated with the rare combined clinical and syndromal phenotypes in the family. The GOF in the Cav1.3S variant with high neuronal expression is likely to result in epilepsy, whereas the LOF in the long Cav1.3L variant results in sinus node dysfunction. Full article
(This article belongs to the Special Issue Molecular Effects of Mutations in Human Genetic Diseases 2.0)
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20 pages, 2526 KiB  
Article
Characterization of 22q12 Microdeletions Causing Position Effect in Rare NF2 Patients with Complex Phenotypes
by Viviana Tritto, Marica Eoli, Rosina Paterra, Serena Redaelli, Marco Moscatelli, Francesco Rusconi and Paola Riva
Int. J. Mol. Sci. 2022, 23(17), 10017; https://doi.org/10.3390/ijms231710017 - 2 Sep 2022
Cited by 1 | Viewed by 2443
Abstract
Neurofibromatosis type 2 is an autosomal dominant tumor-prone disorder mainly caused by NF2 point mutations or intragenic deletions. Few individuals with a complex phenotype and 22q12 microdeletions have been described. The 22q12 microdeletions’ pathogenic effects at the genetic and epigenetic levels are currently [...] Read more.
Neurofibromatosis type 2 is an autosomal dominant tumor-prone disorder mainly caused by NF2 point mutations or intragenic deletions. Few individuals with a complex phenotype and 22q12 microdeletions have been described. The 22q12 microdeletions’ pathogenic effects at the genetic and epigenetic levels are currently unknown. We here report on 22q12 microdeletions’ characterization in three NF2 patients with different phenotype complexities. A possible effect of the position was investigated by in silico analysis of 22q12 topologically associated domains (TADs) and regulatory elements, and by expression analysis of 12 genes flanking patients’ deletions. A 147 Kb microdeletion was identified in the patient with the mildest phenotype, while two large deletions of 561 Kb and 1.8 Mb were found in the other two patients, showing a more severe symptomatology. The last two patients displayed intellectual disability, possibly related to AP1B1 gene deletion. The microdeletions change from one to five TADs, and the 22q12 chromatin regulatory landscape, according to the altered expression levels of four deletion-flanking genes, including PIK3IP1, are likely associated with an early ischemic event occurring in the patient with the largest deletion. Our results suggest that the identification of the deletion extent can provide prognostic markers, predictive of NF2 phenotypes, and potential therapeutic targets, thus overall improving patient management. Full article
(This article belongs to the Special Issue Molecular Effects of Mutations in Human Genetic Diseases 2.0)
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17 pages, 2554 KiB  
Article
Hyperinsulinemic Hypoglycemia Associated with a CaV1.2 Variant with Mixed Gain- and Loss-of-Function Effects
by Sebastian Kummer, Susanne Rinné, Gunnar Seemann, Nadine Bachmann, Katherine Timothy, Paul S. Thornton, Frank Pillekamp, Ertan Mayatepek, Carsten Bergmann, Thomas Meissner and Niels Decher
Int. J. Mol. Sci. 2022, 23(15), 8097; https://doi.org/10.3390/ijms23158097 - 22 Jul 2022
Cited by 4 | Viewed by 2335
Abstract
The voltage-dependent L-type calcium channel isoform CaV1.2 is critically involved in many physiological processes, e.g., in cardiac action potential formation, electromechanical coupling and regulation of insulin secretion by beta cells. Gain-of-function mutations in the calcium voltage-gated channel subunit alpha 1 C [...] Read more.
The voltage-dependent L-type calcium channel isoform CaV1.2 is critically involved in many physiological processes, e.g., in cardiac action potential formation, electromechanical coupling and regulation of insulin secretion by beta cells. Gain-of-function mutations in the calcium voltage-gated channel subunit alpha 1 C (CACNA1C) gene, encoding the CaV1.2 α1-subunit, cause Timothy syndrome (TS), a multisystemic disorder that includes autism spectrum disorders and long QT (LQT) syndrome. Strikingly, TS patients frequently suffer from hypoglycemia of yet unproven origin. Using next-generation sequencing, we identified a novel heterozygous CACNA1C mutation in a patient with congenital hyperinsulinism (CHI) and associated hypoglycemic episodes. We characterized the electrophysiological phenotype of the mutated channel using voltage-clamp recordings and in silico action potential modeling experiments. The identified CaV1.2L566P mutation causes a mixed electrophysiological phenotype of gain- and loss-of-function effects. In silico action potential modeling supports that this mixed electrophysiological phenotype leads to a tissue-specific impact on beta cells compared to cardiomyocytes. Thus, CACNA1C variants may be associated with non-syndromic hyperinsulinemic hypoglycemia without long-QT syndrome, explained by very specific electrophysiological properties of the mutated channel. We discuss different biochemical characteristics and clinical impacts of hypoglycemia in the context of CACNA1C variants and show that these may be associated with significant morbidity for Timothy Syndrome patients. Our findings underline that the potential of hypoglycemia warrants careful attention in patients with CACNA1C variants, and such variants should be included in the differential diagnosis of non-syndromic congenital hyperinsulinism. Full article
(This article belongs to the Special Issue Molecular Effects of Mutations in Human Genetic Diseases 2.0)
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