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Heterogeneous Distribution of Genetic Mutations in Myosin Binding Protein-C Paralogs
Myosin binding protein-C (MyBP-C) is a sarcomeric protein which regulates the force of contraction in striated muscles. Mutations in the MYBPC family of genes, including slow skeletal (MYBPC1), fast skeletal (MYBPC2) and cardiac (MYBPC3), can result in cardiac and skeletal myopathies. Nonetheless, t...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2022
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9272480/ https://www.ncbi.nlm.nih.gov/pubmed/35832193 http://dx.doi.org/10.3389/fgene.2022.896117 |
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author | Desai, Darshini A. Rao, Vinay J. Jegga, Anil G. Dhandapany, Perundurai S. Sadayappan, Sakthivel |
author_facet | Desai, Darshini A. Rao, Vinay J. Jegga, Anil G. Dhandapany, Perundurai S. Sadayappan, Sakthivel |
author_sort | Desai, Darshini A. |
collection | PubMed |
description | Myosin binding protein-C (MyBP-C) is a sarcomeric protein which regulates the force of contraction in striated muscles. Mutations in the MYBPC family of genes, including slow skeletal (MYBPC1), fast skeletal (MYBPC2) and cardiac (MYBPC3), can result in cardiac and skeletal myopathies. Nonetheless, their evolutionary pattern, pathogenicity and impact on MyBP-C protein structure remain to be elucidated. Therefore, the present study aimed to systematically assess the evolutionarily conserved and epigenetic patterns of MYBPC family mutations. Leveraging a machine learning (ML) approach, the Genome Aggregation Database (gnomAD) provided variants in MYBPC1, MYBPC2, and MYBPC3 genes. This was followed by an analysis with Ensembl’s variant effect predictor (VEP), resulting in the identification of 8,618, 3,871, and 3,071 variants in MYBPC1, MYBPC2, and MYBPC3, respectively. Missense variants comprised 61%–66% of total variants in which the third nucleotide positions in the codons were highly altered. Arginine was the most mutated amino acid, important because most disease-causing mutations in MyBP-C proteins are arginine in origin. Domains C5 and C6 of MyBP-C were found to be hotspots for most mutations in the MyBP-C family of proteins. A high percentage of truncated mutations in cMyBP-C cause cardiomyopathies. Arginine and glutamate were the top hits in fMyBP-C and cMyBP-C, respectively, and tryptophan and tyrosine were the most common among the three paralogs changing to premature stop codons and causing protein truncations at the carboxyl terminus. A heterogeneous epigenetic pattern was identified among the three MYBP-C paralogs. Overall, it was shown that databases using computational approaches can facilitate diagnosis and drug discovery to treat muscle disorders caused by MYBPC mutations. |
format | Online Article Text |
id | pubmed-9272480 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-92724802022-07-12 Heterogeneous Distribution of Genetic Mutations in Myosin Binding Protein-C Paralogs Desai, Darshini A. Rao, Vinay J. Jegga, Anil G. Dhandapany, Perundurai S. Sadayappan, Sakthivel Front Genet Genetics Myosin binding protein-C (MyBP-C) is a sarcomeric protein which regulates the force of contraction in striated muscles. Mutations in the MYBPC family of genes, including slow skeletal (MYBPC1), fast skeletal (MYBPC2) and cardiac (MYBPC3), can result in cardiac and skeletal myopathies. Nonetheless, their evolutionary pattern, pathogenicity and impact on MyBP-C protein structure remain to be elucidated. Therefore, the present study aimed to systematically assess the evolutionarily conserved and epigenetic patterns of MYBPC family mutations. Leveraging a machine learning (ML) approach, the Genome Aggregation Database (gnomAD) provided variants in MYBPC1, MYBPC2, and MYBPC3 genes. This was followed by an analysis with Ensembl’s variant effect predictor (VEP), resulting in the identification of 8,618, 3,871, and 3,071 variants in MYBPC1, MYBPC2, and MYBPC3, respectively. Missense variants comprised 61%–66% of total variants in which the third nucleotide positions in the codons were highly altered. Arginine was the most mutated amino acid, important because most disease-causing mutations in MyBP-C proteins are arginine in origin. Domains C5 and C6 of MyBP-C were found to be hotspots for most mutations in the MyBP-C family of proteins. A high percentage of truncated mutations in cMyBP-C cause cardiomyopathies. Arginine and glutamate were the top hits in fMyBP-C and cMyBP-C, respectively, and tryptophan and tyrosine were the most common among the three paralogs changing to premature stop codons and causing protein truncations at the carboxyl terminus. A heterogeneous epigenetic pattern was identified among the three MYBP-C paralogs. Overall, it was shown that databases using computational approaches can facilitate diagnosis and drug discovery to treat muscle disorders caused by MYBPC mutations. Frontiers Media S.A. 2022-06-27 /pmc/articles/PMC9272480/ /pubmed/35832193 http://dx.doi.org/10.3389/fgene.2022.896117 Text en Copyright © 2022 Desai, Rao, Jegga, Dhandapany and Sadayappan. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Genetics Desai, Darshini A. Rao, Vinay J. Jegga, Anil G. Dhandapany, Perundurai S. Sadayappan, Sakthivel Heterogeneous Distribution of Genetic Mutations in Myosin Binding Protein-C Paralogs |
title | Heterogeneous Distribution of Genetic Mutations in Myosin Binding Protein-C Paralogs |
title_full | Heterogeneous Distribution of Genetic Mutations in Myosin Binding Protein-C Paralogs |
title_fullStr | Heterogeneous Distribution of Genetic Mutations in Myosin Binding Protein-C Paralogs |
title_full_unstemmed | Heterogeneous Distribution of Genetic Mutations in Myosin Binding Protein-C Paralogs |
title_short | Heterogeneous Distribution of Genetic Mutations in Myosin Binding Protein-C Paralogs |
title_sort | heterogeneous distribution of genetic mutations in myosin binding protein-c paralogs |
topic | Genetics |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9272480/ https://www.ncbi.nlm.nih.gov/pubmed/35832193 http://dx.doi.org/10.3389/fgene.2022.896117 |
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