Discovery of Novel Hypertrophic Cardiomyopathy Genes and Their Functional Implications Using Multi Model Approach

Abstract

Hypertrophic cardiomyopathy (HCM) is predominately 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 talk, I will outline our discovery of two novel non-sarcomeric HCM genes and their critical regulatory mechanisms in the disease pathogenesis. newline1) TTL variant causes HCM by inducing oxidative stress in patient-specific iPSC-derived cardiomyocytes. newlineWe used Next Generation sequencing techniques to examine two cohorts of Indian HCM patients and their respective controls. We identified an HCM patient-carrying tubulin tyrosine ligase (TTL) gene variant (p.G219S) that is absent in controls. TTL is involved in post-translational modification of alpha-tubulin by adding tyrosine residue to its C-terminal tail. This absence leads to an abnormal de-tyrosinated and tyrosinated tubulin ratio, affecting the contractility in cardiomyocytes. Our biochemical study suggests that TTL mutant proteins displayed delayed activity in tubulin tyrosination compared to the wild type. We modeled the patient HCM phenotypes by generating and characterizing the TTL mutant patient-specific iPSCs-derived cardiomyocytes (iPSC-CMs). The iPSC-CMs recapitulated hypertrophy, contractile dysfunction, and sarcomeric disarray due to increased de-tyrosinated alpha-tubulin. Furthermore, transcriptomic analysis from iPSCs-CMs revealed perturbed redox homeostasis, specifically activating NRF2 pathways leading to oxidative stress. newline2) Ribosomal protein S6 kinase beta-1 gene variants cause HCM by activating S6K1/rpS6/ERK signaling newlineUsing 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