TY - JOUR T1 - Adiponectin receptor 1 variants contribute to hypertrophic cardiomyopathy that can be reversed by rapamycin. JF - Sci Adv Y1 - 2021 A1 - Dhandapany, Perundurai S A1 - Kang, Soojeong A1 - Kashyap, Deepak K A1 - Rajagopal, Raksha A1 - Sundaresan, Nagalingam R A1 - Singh, Rajvir A1 - Thangaraj, Kumarasamy A1 - Jayaprakash, Shilpa A1 - Manjunath, Cholenahally N A1 - Shenthar, Jayaprakash A1 - Lebeche, Djamel AB -

Hypertrophic cardiomyopathy (HCM) is a heterogeneous genetic heart muscle disease characterized by hypertrophy with preserved or increased ejection fraction in the absence of secondary causes. However, recent studies have demonstrated that a substantial proportion of individuals with HCM also have comorbid diabetes mellitus (~10%). Whether genetic variants may contribute a combined phenotype of HCM and diabetes mellitus is not known. Here, using next-generation sequencing methods, we identified novel and ultrarare variants in adiponectin receptor 1 () as risk factors for HCM. Biochemical studies showed that variants dysregulate glucose and lipid metabolism and cause cardiac hypertrophy through the p38/mammalian target of rapamycin and/or extracellular signal-regulated kinase pathways. A transgenic mouse model expressing an variant displayed cardiomyopathy that recapitulated the cellular findings, and these features were rescued by rapamycin. Our results provide the first evidence that variants can cause HCM and provide new insights into regulation.

VL - 7 IS - 2 ER -