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Original research
Ribosomal protein S6 kinase beta-1 gene variants cause hypertrophic cardiomyopathy
  1. Pratul Kumar Jain1,2,
  2. Shashank Jayappa1,
  3. Thiagarajan Sairam1,
  4. Anupam Mittal1,3,
  5. Sayan Paul1,
  6. Vinay J Rao1,
  7. Harshil Chittora1,4,
  8. Deepak K Kashyap1,5,
  9. Dasaradhi Palakodeti6,
  10. Kumarasamy Thangaraj5,7,
  11. Jayaprakash Shenthar8,
  12. Rakesh Koranchery9,
  13. Ranjith Rajendran9,
  14. Haghighi Alireza10,11,12,
  15. Kurukkanparampil Sreedharan Mohanan9,
  16. Andiappan Rathinavel13,14,
  17. Perundurai S Dhandapany1,15,16
  1. 1Cardiovascular Biology and Disease Theme, Institute for Stem Cell Science and Regenerative Medicine, Bangalore, Karnataka, India
  2. 2The University of Trans-Disciplinary Health Sciences and Technology, Bangalore, Karnataka, India
  3. 3Current address: Department of Translational and Regenerative Medicine, PGIMER, Chandigarh, Chandigarh, India
  4. 4National Centre for Biological Sciences, Tata Institute of Fundamental Research, GKVK Campus, Bangalore, India
  5. 5CSIR-Center for Cellular and Molecular Biology, Hyderabad, India
  6. 6Integrative Chemical Biology Theme, Institute for Stem Cell Science and Regenerative Medicine, Bangalore, Karnataka, India
  7. 7Centre for DNA Fingerprinting and Diagnostics, Hyderabad, Telangana, India
  8. 8Department of Cardiology, Sri Jayadeva Institute of Cardiovascular Sciences and Research, Bangalore, Karnataka, India
  9. 9Department of Cardiology, Government Medical College Calicut, Kozhikode, Kerala, India
  10. 10Department of Medicine, Brigham and Women's Hospital Department of Medicine, Boston, Massachusetts, USA
  11. 11Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA
  12. 12Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
  13. 13Department of Cardio Vascular Thoracic Surgery, Madurai Medical College, Madurai, Tamil Nadu, India
  14. 14Government Sivagangai Medical College and Hospital, Sivagangai, Tamil Nadu, India
  15. 15Knight Cardiovascular Institute, Oregon Health & Science University, Portland, Oregon, USA
  16. 16Departments of Medicine, Molecular, and Medical Genetics, Oregon Health and Science University, Portland, Oregon, USA
  1. Correspondence to Dr Perundurai S Dhandapany, Cardiovascular Biology and Disease Theme, Institute for Stem Cell Science and Regenerative Medicine, Bangalore, Karnataka 560065, India; dhan{at}instem.res.in

Abstract

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.

  • cardiomyopathies
  • genetics
  • medical
  • human genetics
  • genomics
  • sequence analysis
  • DNA

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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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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Footnotes

  • Twitter @Dhan_inStem

  • 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.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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