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 - TY - JOUR T1 - Ribosomal protein S6 kinase beta-1 gene variants cause hypertrophic cardiomyopathy. JF - J Med Genet Y1 - 2021 A1 - Jain, Pratul Kumar A1 - Jayappa, Shashank A1 - Sairam, Thiagarajan A1 - Mittal, Anupam A1 - Paul, Sayan A1 - Rao, Vinay J A1 - Chittora, Harshil A1 - Kashyap, Deepak K A1 - Palakodeti, Dasaradhi A1 - Thangaraj, Kumarasamy A1 - Shenthar, Jayaprakash A1 - Koranchery, Rakesh A1 - Rajendran, Ranjith A1 - Alireza, Haghighi A1 - Mohanan, Kurukkanparampil Sreedharan A1 - Rathinavel, Andiappan A1 - Dhandapany, Perundurai S AB -

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is a genetic heart muscle disease with preserved or increased ejection fraction in the absence of secondary causes. Mutations in the sarcomeric protein-encoding genes predominantly cause HCM. However, relatively little is known about the genetic impact of signalling proteins on HCM.

METHODS AND RESULTS: Here, using exome and targeted sequencing methods, we analysed two independent cohorts comprising 401 Indian patients with HCM and 3521 Indian controls. We identified novel variants in ribosomal protein S6 kinase beta-1 () gene in two unrelated Indian families as a potential candidate gene for HCM. The two unrelated HCM families had the same heterozygous missense S6K1 variant (p.G47W). In a replication association study, we identified two S6K1 heterozygotes variants (p.Q49K and p.Y62H) in the UK Biobank cardiomyopathy cohort (n=190) compared with matched controls (n=16 479). These variants are neither detected in region-specific controls nor in the human population genome data. Additionally, we observed an S6K1 variant (p.P445S) in an Arab patient with HCM. Functional consequences were evaluated using representative S6K1 mutated proteins compared with wild type in cellular models. The mutated proteins activated the S6K1 and hyperphosphorylated the rpS6 and ERK1/2 signalling cascades, suggesting a gain-of-function effect.

CONCLUSIONS: Our study demonstrates for the first time that the variants in the gene are associated with HCM, and early detection of the variant carriers can help to identify family members at risk and subsequent preventive measures. Further screening in patients with HCM with different ethnic populations will establish the specificity and frequency of gene variants.

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