Novel frameshift variant in MYL2 reveals molecular differences between dominant and recessive forms of hypertrophic cardiomyopathy

Autoři: Sathiya N. Manivannan aff001;  Sihem Darouich aff003;  Aida Masmoudi aff004;  David Gordon aff005;  Gloria Zender aff001;  Zhe Han aff006;  Sara Fitzgerald-Butt aff001;  Peter White aff005;  Kim L. McBride aff001;  Maher Kharrat aff003;  Vidu Garg aff001
Působiště autorů: Center for Cardiovascular Research, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, Ohio, United States of America aff001;  Heart Center, Nationwide Children’s Hospital, Columbus, Ohio, United States of America aff002;  University of Tunis El Manar, Faculty of Medicine of Tunis, LR99ES10 Laboratory of Human Genetics, Tunis, Tunisia aff003;  University of Tunis El Manar, Faculty of Medicine of Tunis, Department of Embryo-Fetopathology, Maternity and Neonatology Center, Tunis, Tunisia aff004;  Institute for Genomic Medicine at Nationwide Children’s Hospital, Columbus, Ohio, United States of America aff005;  Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, United States of America aff006;  Department of Pediatrics, The Ohio State University, Columbus, Ohio, United States of America aff007;  Department of Molecular Genetics, The Ohio State University, Columbus, Ohio, United States of America aff008
Vyšlo v časopise: Novel frameshift variant in MYL2 reveals molecular differences between dominant and recessive forms of hypertrophic cardiomyopathy. PLoS Genet 16(5): e32767. doi:10.1371/journal.pgen.1008639
Kategorie: Research Article
doi: 10.1371/journal.pgen.1008639


Hypertrophic cardiomyopathy (HCM) is characterized by thickening of the ventricular muscle without dilation and is often associated with dominant pathogenic variants in cardiac sarcomeric protein genes. Here, we report a family with two infants diagnosed with infantile-onset HCM and mitral valve dysplasia that led to death before one year of age. Using exome sequencing, we discovered that one of the affected children had a homozygous frameshift variant in Myosin light chain 2 (MYL2:NM_000432.3:c.431_432delCT: p.Pro144Argfs*57;MYL2-fs), which alters the last 20 amino acids of the protein and is predicted to impact the most C-terminal of the three EF-hand domains in MYL2. The parents are unaffected heterozygous carriers of the variant and the variant is absent in control cohorts from gnomAD. The absence of the phenotype in carriers and the infantile presentation of severe HCM is in contrast to HCM associated with dominant MYL2 variants. Immunohistochemical analysis of the ventricular muscle of the deceased patient with the MYL2-fs variant showed a marked reduction of MYL2 expression compared to an unaffected control. In vitro overexpression studies further indicate that the MYL2-fs variant is actively degraded. In contrast, an HCM-associated missense variant (MYL2:p.Gly162Arg) and three other MYL2 stop-gain variants (p.E22*, p.K62*, p.E97*) that result in loss of the EF domains are stably expressed but show impaired localization. The degradation of the MYL2-fs can be rescued by inhibiting the cell’s proteasome function supporting a post-translational effect of the variant. In vivo rescue experiments with a Drosophila MYL2-homolog (Mlc2) knockdown model indicate that neither the MYL2-fs nor the MYL2:p.Gly162Arg variant supports normal cardiac function. The tools that we have generated provide a rapid screening platform for functional assessment of variants of unknown significance in MYL2. Our study supports an autosomal recessive model of inheritance for MYL2 loss-of-function variants in infantile HCM and highlights the variant-specific molecular differences found in MYL2-associated cardiomyopathy.

Klíčová slova:

Alleles – Cardiac ventricles – Cardiomyopathies – Drosophila melanogaster – Hyperexpression techniques – Mouse models – Myocardium – Myosins


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