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

Abstract

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 infantileonset 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 HCMassociated 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 PLOS GENETICS

Age and Sex-Dependent ADNP Regulation of Muscle Gene Expression Is Correlated with Motor Behavior: Possible Feedback Mechanism with PACAP

“…Interestingly, here, we also found sexually/developmentally differential expression of Myl2 and Myl9 in correlation with Adnp expression. In this respect, MYL2 is linked to cardiac development and function [51], while MYL9 is involved in smooth muscle and non-muscle cell contractile activity e.g., in the gut and urinary tract [52], with ADNP syndrome children suffering cardiac as well as gastrointestinal problems [17]. Furthermore, a recent study identified Myl9 as highly important for skeletal muscle development [53] as well as to bladder and gastrointestinal smooth muscle contraction, with homozygous deletion leading to megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS), a severe disease characterized by functional obstruction in the urinary and gastrointestinal tract [52,54].…”

Functional comparison of phosphomimetic S15D and T160D mutants of myosin regulatory light chain exchanged in cardiac muscle preparations of HCM and WT mice

“…A high restrictive filling pattern and atrial fibrillation incidence were observed ( 19 ). In the same year, the Garg group reported on another missense MYL2 variant (G162R) located in the vicinity of T160 in the C-terminus of RLC ( 20 ).…”

Heat shock proteins and small nucleolar RNAs are dysregulated in a Drosophila model for feline hypertrophic cardiomyopathy

“…The Homophila database ( http://homophila.sdsc.edu ) reports that the Act genes ( Act57B, Act79B , and Act88F ) and Mlc2 are close matches to the human ACTC1 gene (NP_005150) and MYL2 (NP_000423) genes, respectively. Mutations in both these genes have been associated with familial HCM ( van Waning et al 2019 ; Manivannan et al 2020 ). Next-generation sequencing of an Italian family with HCM revealed an Ala21Val mutation in ACTC1 resulted in myofibrillar disarray causing dis-anchorage of myofilaments ( Frustaci et al 2018 ).…”