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 (ADIPOR1) as risk factors for HCM. Biochemical studies showed that ADIPOR1 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 ADIPOR1 variant displayed cardiomyopathy that recapitulated the cellular findings, and these features were rescued by rapamycin. Our results provide the first evidence that ADIPOR1 variants can cause HCM and provide new insights into ADIPOR1 regulation.
journal_name
Sci Advjournal_title
Science advancesauthors
Dhandapany PS,Kang S,Kashyap DK,Rajagopal R,Sundaresan NR,Singh R,Thangaraj K,Jayaprakash S,Manjunath CN,Shenthar J,Lebeche Ddoi
10.1126/sciadv.abb3991subject
Has Abstractpub_date
2021-01-06 00:00:00issue
2issn
2375-2548pii
7/2/eabb3991journal_volume
7pub_type
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