Adiponectin receptor 1 variants contribute to hypertrophic cardiomyopathy that can be reversed by rapamycin

Abstract

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 (<i>ADIPOR1</i>) as risk factors for HCM. Biochemical studies showed that <i>ADIPOR1</i> 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 <i>ADIPOR1</i> variant displayed cardiomyopathy that recapitulated the cellular findings, and these features were rescued by rapamycin. Our results provide the first evidence that <i>ADIPOR1</i> variants can cause HCM and provide new insights into <i>ADIPOR1</i> regulation.