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Autosomal recessive cardiomyopathy and sudden cardiac death associated with variants in MYL3
PURPOSE: Variants in genes encoding sarcomeric proteins are the most common cause of inherited cardiomyopathies. However, the underlying genetic cause remains unknown in many cases. We used exome sequencing to reveal the genetic etiology in patients with recessive familial cardiomyopathy. METHODS: E...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group US
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026398/ https://www.ncbi.nlm.nih.gov/pubmed/33288880 http://dx.doi.org/10.1038/s41436-020-01028-2 |
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author | Osborn, Daniel Peter Sayer Emrahi, Leila Clayton, Joshua Tabrizi, Mehrnoush Toufan Wan, Alex Yui Bong Maroofian, Reza Yazdchi, Mohammad Garcia, Michael Leon Enrique Galehdari, Hamid Hesse, Camila Shariati, Gholamreza Mazaheri, Neda Sedaghat, Alireza Goullée, Hayley Laing, Nigel Jamshidi, Yalda Tajsharghi, Homa |
author_facet | Osborn, Daniel Peter Sayer Emrahi, Leila Clayton, Joshua Tabrizi, Mehrnoush Toufan Wan, Alex Yui Bong Maroofian, Reza Yazdchi, Mohammad Garcia, Michael Leon Enrique Galehdari, Hamid Hesse, Camila Shariati, Gholamreza Mazaheri, Neda Sedaghat, Alireza Goullée, Hayley Laing, Nigel Jamshidi, Yalda Tajsharghi, Homa |
author_sort | Osborn, Daniel Peter Sayer |
collection | PubMed |
description | PURPOSE: Variants in genes encoding sarcomeric proteins are the most common cause of inherited cardiomyopathies. However, the underlying genetic cause remains unknown in many cases. We used exome sequencing to reveal the genetic etiology in patients with recessive familial cardiomyopathy. METHODS: Exome sequencing was carried out in three consanguineous families. Functional assessment of the variants was performed. RESULTS: Affected individuals presented with hypertrophic or dilated cardiomyopathy of variable severity from infantile- to early adulthood–onset and sudden cardiac death. We identified a homozygous missense substitution (c.170C>A, p.[Ala57Asp]), a homozygous translation stop codon variant (c.106G>T, p.[Glu36Ter]), and a presumable homozygous essential splice acceptor variant (c.482-1G>A, predicted to result in skipping of exon 5). Morpholino knockdown of the MYL3 orthologue in zebrafish, cmlc1, resulted in compromised cardiac function, which could not be rescued by reintroduction of MYL3 carrying either the nonsense c.106G>T or the missense c.170C>A variants. Minigene assay of the c.482-1G>A variant indicated a splicing defect likely resulting in disruption of the EF-hand Ca(2+) binding domains. CONCLUSIONS: Our data demonstrate that homozygous MYL3 loss-of-function variants can cause of recessive cardiomyopathy and occurrence of sudden cardiac death, most likely due to impaired or loss of myosin essential light chain function. |
format | Online Article Text |
id | pubmed-8026398 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group US |
record_format | MEDLINE/PubMed |
spelling | pubmed-80263982021-04-27 Autosomal recessive cardiomyopathy and sudden cardiac death associated with variants in MYL3 Osborn, Daniel Peter Sayer Emrahi, Leila Clayton, Joshua Tabrizi, Mehrnoush Toufan Wan, Alex Yui Bong Maroofian, Reza Yazdchi, Mohammad Garcia, Michael Leon Enrique Galehdari, Hamid Hesse, Camila Shariati, Gholamreza Mazaheri, Neda Sedaghat, Alireza Goullée, Hayley Laing, Nigel Jamshidi, Yalda Tajsharghi, Homa Genet Med Brief Communication PURPOSE: Variants in genes encoding sarcomeric proteins are the most common cause of inherited cardiomyopathies. However, the underlying genetic cause remains unknown in many cases. We used exome sequencing to reveal the genetic etiology in patients with recessive familial cardiomyopathy. METHODS: Exome sequencing was carried out in three consanguineous families. Functional assessment of the variants was performed. RESULTS: Affected individuals presented with hypertrophic or dilated cardiomyopathy of variable severity from infantile- to early adulthood–onset and sudden cardiac death. We identified a homozygous missense substitution (c.170C>A, p.[Ala57Asp]), a homozygous translation stop codon variant (c.106G>T, p.[Glu36Ter]), and a presumable homozygous essential splice acceptor variant (c.482-1G>A, predicted to result in skipping of exon 5). Morpholino knockdown of the MYL3 orthologue in zebrafish, cmlc1, resulted in compromised cardiac function, which could not be rescued by reintroduction of MYL3 carrying either the nonsense c.106G>T or the missense c.170C>A variants. Minigene assay of the c.482-1G>A variant indicated a splicing defect likely resulting in disruption of the EF-hand Ca(2+) binding domains. CONCLUSIONS: Our data demonstrate that homozygous MYL3 loss-of-function variants can cause of recessive cardiomyopathy and occurrence of sudden cardiac death, most likely due to impaired or loss of myosin essential light chain function. Nature Publishing Group US 2020-12-08 2021 /pmc/articles/PMC8026398/ /pubmed/33288880 http://dx.doi.org/10.1038/s41436-020-01028-2 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, and provide a link to the Creative Commons license. You do not have permission under this license to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/. |
spellingShingle | Brief Communication Osborn, Daniel Peter Sayer Emrahi, Leila Clayton, Joshua Tabrizi, Mehrnoush Toufan Wan, Alex Yui Bong Maroofian, Reza Yazdchi, Mohammad Garcia, Michael Leon Enrique Galehdari, Hamid Hesse, Camila Shariati, Gholamreza Mazaheri, Neda Sedaghat, Alireza Goullée, Hayley Laing, Nigel Jamshidi, Yalda Tajsharghi, Homa Autosomal recessive cardiomyopathy and sudden cardiac death associated with variants in MYL3 |
title | Autosomal recessive cardiomyopathy and sudden cardiac death associated with variants in MYL3 |
title_full | Autosomal recessive cardiomyopathy and sudden cardiac death associated with variants in MYL3 |
title_fullStr | Autosomal recessive cardiomyopathy and sudden cardiac death associated with variants in MYL3 |
title_full_unstemmed | Autosomal recessive cardiomyopathy and sudden cardiac death associated with variants in MYL3 |
title_short | Autosomal recessive cardiomyopathy and sudden cardiac death associated with variants in MYL3 |
title_sort | autosomal recessive cardiomyopathy and sudden cardiac death associated with variants in myl3 |
topic | Brief Communication |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026398/ https://www.ncbi.nlm.nih.gov/pubmed/33288880 http://dx.doi.org/10.1038/s41436-020-01028-2 |
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