Cardiac hypertrophy and arrhythmia in mice induced by a mutation in ryanodine receptor 2

• Published in: JCI insight Vol. 5; no. 7
• Main Authors: Alvarado, Francisco J, Bos, J Martijn, Yuchi, Zhiguang, Valdivia, Carmen R, Hernández, Jonathan J, Zhao, Yan-Ting, Henderlong, Dawn S, Chen, Yan, Booher, Talia R, Marcou, Cherisse A, Van Petegem, Filip, Ackerman, Michael J, Valdivia, Héctor H
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 04.04.2019
• Subjects: Cardiovascular disease; Calcium; Excitation contraction coupling; Cardiology
• ISSN: 2379-3708; 2379-3708
• DOI: 10.1172/jci.insight.126544

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.