Hypertrophic cardiomyopathy (HCM) is predominantly a hereditary condition affecting the heart muscles, characterized by a preserved or enhanced ejection fraction without any secondary underlying causes. HCM is widely caused by mutations in genes that encode sarcomeric proteins. Nevertheless, there is limited knowledge regarding the genetic influence of non-sarcomeric proteins on HCM. In my study, we outlined our discovery of two novel non-sarcomeric HCM genes and their critical regulatory mechanisms in the disease pathogenesis.

1) Ribosomal protein S6 kinase beta-1 gene variants cause HCM by activating S6K1/rpS6/ERK signaling

Using the above NGS methods, we discovered identical mutations (p.G47W) in the gene encoding ribosomal protein S6 kinase beta-1 (RPS6KB1 or S6K1) in two Indian families. We further identified two heterozygous variants (p.Q49K and p.Y62H) from the UK cardiomyopathy cohort in replication association studies. These variations are absent in both region-specific controls and various population genomic datasets. Further, we detected additional S6K1 mutation (p.P445S) in an Arab HCM patient. The functional effects of these mutants were assessed in cellular models by comparing representative mutant proteins of S6K1 with the wild type. The mutated proteins activated the S6K1 and hyperphosphorylated the rpS6/ERK signaling cascades, suggesting a gain-of-function effect.

In conclusion, our study demonstrates for the first time that the TTL and S6K1 genes are associated with HCM and underscores the importance of non-sarcomeric gene roles in HCM.

Dr. Pratul Kumar Jain

PhD Student (2019-2024)