Key result
The RyR2-P1124L mutation induces a cytosolic loss-of-function and luminal gain-of-function phenotype, triggering mild cardiac hypertrophy and increased susceptibility to arrhythmias in mice.
Why the study?
A significant proportion of patients with HCM lack a genetic diagnosis, prompting investigation into whether a novel RyR2-P1124L mutation identified in genotype-negative HCM triggers functional and structural cardiac alterations.
The RyR2-P1124L mutation triggers arrhythmias and structural cardiac remodeling in mice, highlighting a potential mechanism for genotype-negative hypertrophic cardiomyopathy.
Hypertrophic cardiomyopathy (HCM) is triggered mainly by mutations in genes encoding sarcomeric proteins, but a significant proportion of patients lack a genetic diagnosis. We identified a novel mutation in the ryanodine receptor 2, RyR2-P1124L, in a patient from a genotype-negative HCM cohort. The aim of this study was to determine whether RyR2-P1124L triggers functional and structural alterations in isolated RyR2 channels and whole hearts. We found that P1124L induces significant conformational changes in the SPRY2 domain of RyR2. Recombinant RyR2-P1124L channels displayed a cytosolic loss-of-function phenotype, which contrasted with a higher sensitivity to luminal [Ca2+], indicating a luminal gain-of-function. Homozygous mice for RyR2-P1124L showed mild cardiac hypertrophy, similar to the human patient. This phenotype, evident at 1 yr of age, was accompanied by an increase in the expression of calmodulin (CaM). P1124L mice also showed higher susceptibility to arrhythmia at 8 mo of age, before the onset of hypertrophy. RyR2-P1124L has a distinct cytosolic loss-of-function and a luminal gain-of-function phenotype. This bifunctionally-divergent behavior triggers arrhythmias and structural cardiac remodeling, and involves overexpression of calmodulin as a potential hypertrophic mediator. This study is relevant to continue elucidating the possible causes of genotype-negative HCM and the role of RyR2 in cardiac hypertrophy.
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Alvarado et al. (2019) studied Hypertrophic cardiomyopathy. RyR2-P1124L mutation vs. Wild-type (WT) was evaluated on Cardiac hypertrophy and arrhythmia susceptibility. The RyR2-P1124L mutation induces a cytosolic loss-of-function and luminal gain-of-function phenotype, triggering mild cardiac hypertrophy and increased susceptibility to arrhythmias in mice.
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