Osborn, DPS;
Emrahi, L;
Clayton, J;
Tabrizi, MT;
Wan, AYB;
Maroofian, R;
Yazdchi, M;
Garcia, MLE;
Galehdari, H;
Hesse, C;
et al.
Osborn, DPS; Emrahi, L; Clayton, J; Tabrizi, MT; Wan, AYB; Maroofian, R; Yazdchi, M; Garcia, MLE; Galehdari, H; Hesse, C; Shariati, G; Mazaheri, N; Sedaghat, A; Goullée, H; Laing, N; Jamshidi, Y; Tajsharghi, H
(2021)
Autosomal recessive cardiomyopathy and sudden cardiac death associated with variants in MYL3.
Genet Med, 23 (4).
pp. 787-792.
ISSN 1530-0366
https://doi.org/10.1038/s41436-020-01028-2
SGUL Authors: Jamshidi, Yalda Maroofian, Reza
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Abstract
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 Ca2+ 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.
Item Type: | Article | ||||||||
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Additional Information: | 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) andthe 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 licenseand 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/. © The Author(s) 2020 | ||||||||
Keywords: | Genetics & Heredity, 0604 Genetics, 1103 Clinical Sciences | ||||||||
SGUL Research Institute / Research Centre: | Academic Structure > Molecular and Clinical Sciences Research Institute (MCS) | ||||||||
Journal or Publication Title: | Genet Med | ||||||||
ISSN: | 1530-0366 | ||||||||
Language: | eng | ||||||||
Dates: |
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Publisher License: | Creative Commons: Attribution-Noncommercial-No Derivative Works 4.0 | ||||||||
PubMed ID: | 33288880 | ||||||||
Go to PubMed abstract | |||||||||
URI: | https://openaccess.sgul.ac.uk/id/eprint/112698 | ||||||||
Publisher's version: | https://doi.org/10.1038/s41436-020-01028-2 |
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