Adiponectin Receptor 1 Variants Contribute to Hypertrophic Cardiomyopathy That Can Be Reversed by Rapamycin

Overview

Journal Sci Adv

Specialties Biology
Science

Date 2021 Feb 1

PMID 33523960

Citations 7

Authors

Perundurai S Dhandapany

Soojeong Kang

Deepak K Kashyap

Raksha Rajagopal

Nagalingam R Sundaresan

Rajvir Singh

Kumarasamy Thangaraj

Shilpa Jayaprakash

Cholenahally N Manjunath

Jayaprakash Shenthar

Djamel Lebeche

Affiliations

Soon will be listed here.

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 () 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.

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