Investigation of ADPRHL1 (ARH2), a disease modifier in hypertrophic cardiomyopathy
- 1 November 2023 to 30 September 2024
- Awards: Pump-priming Awards
In this study we will investigate the effect of a novel modifier variant in the gene ADPRHL1 in inherited hypertrophic cardiomyopathy (HCM). The L294R missense variant in the protein ADP-ribosylhydrolase-like-protein1 (ARH2) is present in ~3% of the global population and is enriched in HCM patients suggesting its involvement in increasing the severity of the disease and contributing to polygenic risk in non-familial HCM. Very little is known about ARH2 other than potential involvement with myofibrillogenesis in frogs and an association with muscle filament actin. We have made recombinant protein and viral vectors, to test the intrinsic function of the protein and define novel binding partners with mass spectroscopy and generated CRISPr modified iPS cells with the variant on both a WT and HCM mutant (MYH7R403Q) background. We will measure the contraction and Ca2+ transients of differentiated iPSC cardiomyocytes to define ARH2 involvement in HCM disease pathogenesis.
Ribbon structure of ARH2 protein, position of L294R mutation and schematic of ARH1 activity in homeostasis of ADP-ribose post-translational modification.