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.
- human genetics
- sequence analysis
Data availability statement
Data are available upon reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information. Not applicable.
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Contributors PSD conceived, designed, analyzed and drafted the manuscript. PKJ performed, designed and analyzed the major functional studies. PSD, SJ, VJR, HC, DKK, SP screened and analyzed the various cardiomyopathy cases and controls. AM was involved in intial functional analysis. PSD, RK, RR, KSM, KT, JS, AR provided reagents for the study. TS performed data analysis and helped in drafting the manuscript. PSD is the guarantor.
Funding PSD is supported by the Wellcome Trust- Indian Alliance (IA/I/16/1/502367), Rajiv Gandhi University of Health Sciences (RGUHS), Scientist Development Grant (15SDG23250005) from American Heart Association (AHA), Department of Science and Technology (DST/CRG/2019/005401) and inStem core funding. PKJ is supported by DBT-JRF and ICMR-SRF fellowships (2020–6915/SCR-BMS). VJR is supported by ICMR-SRF (3/1/1 (8)/CVD/2020-NCD-1).
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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