Ribosomal protein S6 kinase beta-1 gene variants cause hypertrophic cardiomyopathy.

Autor:	Jain PK; Cardiovascular Biology and Disease Theme, Institute for Stem Cell Science and Regenerative Medicine, Bangalore, Karnataka, India.; The University of Trans-Disciplinary Health Sciences and Technology, Bangalore, Karnataka, India., Jayappa S; Cardiovascular Biology and Disease Theme, Institute for Stem Cell Science and Regenerative Medicine, Bangalore, Karnataka, India., Sairam T; Cardiovascular Biology and Disease Theme, Institute for Stem Cell Science and Regenerative Medicine, Bangalore, Karnataka, India., Mittal A; Cardiovascular Biology and Disease Theme, Institute for Stem Cell Science and Regenerative Medicine, Bangalore, Karnataka, India.; Current address: Department of Translational and Regenerative Medicine, PGIMER, Chandigarh, Chandigarh, India., Paul S; Cardiovascular Biology and Disease Theme, Institute for Stem Cell Science and Regenerative Medicine, Bangalore, Karnataka, India., Rao VJ; Cardiovascular Biology and Disease Theme, Institute for Stem Cell Science and Regenerative Medicine, Bangalore, Karnataka, India., Chittora H; Cardiovascular Biology and Disease Theme, Institute for Stem Cell Science and Regenerative Medicine, Bangalore, Karnataka, India.; National Centre for Biological Sciences, Tata Institute of Fundamental Research, GKVK Campus, Bangalore, India., Kashyap DK; Cardiovascular Biology and Disease Theme, Institute for Stem Cell Science and Regenerative Medicine, Bangalore, Karnataka, India.; CSIR-Center for Cellular and Molecular Biology, Hyderabad, India., Palakodeti D; Integrative Chemical Biology Theme, Institute for Stem Cell Science and Regenerative Medicine, Bangalore, Karnataka, India., Thangaraj K; CSIR-Center for Cellular and Molecular Biology, Hyderabad, India.; Centre for DNA Fingerprinting and Diagnostics, Hyderabad, Telangana, India., Shenthar J; Department of Cardiology, Sri Jayadeva Institute of Cardiovascular Sciences and Research, Bangalore, Karnataka, India., Koranchery R; Department of Cardiology, Government Medical College Calicut, Kozhikode, Kerala, India., Rajendran R; Department of Cardiology, Government Medical College Calicut, Kozhikode, Kerala, India., Alireza H; Department of Medicine, Brigham and Women's Hospital Department of Medicine, Boston, Massachusetts, USA.; Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.; Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA., Mohanan KS; Department of Cardiology, Government Medical College Calicut, Kozhikode, Kerala, India., Rathinavel A; Department of Cardio Vascular Thoracic Surgery, Madurai Medical College, Madurai, Tamil Nadu, India.; Government Sivagangai Medical College and Hospital, Sivagangai, Tamil Nadu, India., Dhandapany PS; Cardiovascular Biology and Disease Theme, Institute for Stem Cell Science and Regenerative Medicine, Bangalore, Karnataka, India dhan@instem.res.in.; Knight Cardiovascular Institute, Oregon Health & Science University, Portland, Oregon, USA.; Departments of Medicine, Molecular, and Medical Genetics, Oregon Health and Science University, Portland, Oregon, USA.
Jazyk:	angličtina
Zdroj:	Journal of medical genetics [J Med Genet] 2022 Oct; Vol. 59 (10), pp. 984-992. Date of Electronic Publication: 2021 Dec 16.
DOI:	10.1136/jmedgenet-2021-107866
Abstrakt:	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 ( RPS6KB1 or S6K1 ) 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 S6K1 gene are associated with HCM, and early detection of the S6K1 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 S6K1 gene variants. Competing Interests: Competing interests: None declared. (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu