@article{10.1172/jci.insight.126544, author = {Francisco J. Alvarado AND J. Martijn Bos AND Zhiguang Yuchi AND Carmen R. Valdivia AND Jonathan J. Hernández AND Yan-Ting Zhao AND Dawn S. Henderlong AND Yan Chen AND Talia R. Booher AND Cherisse A. Marcou AND Filip Van Petegem AND Michael J. Ackerman AND Héctor H. Valdivia}, journal = {JCI Insight}, publisher = {The American Society for Clinical Investigation}, title = {Cardiac hypertrophy and arrhythmia in mice induced by a mutation in ryanodine receptor 2}, year = {2019}, month = {4}, volume = {4}, url = {https://insight.jci.org/articles/view/126544}, abstract = {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 potentially novel mutation in 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 year of age, was accompanied by an increase in the expression of calmodulin (CaM). P1124L mice also showed higher susceptibility to arrhythmia at 8 months 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 it involves overexpression of CaM 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.}, number = {7}, doi = {10.1172/jci.insight.126544}, url = {https://doi.org/10.1172/jci.insight.126544}, }