A R146N Hypertrophic Cardiomyopathy Myosin Mutation Disrupts Myosin Function, Myofibrillar Structure, and Cardiac Contraction in Drosophila

Abstract

A human K146N hypertrophic cardiomyopathy (HCM) myosin mutation localizes near the N-terminus of β-cardiac MHC, and molecular modeling of the analogous Drosophila R146 residue predicts its electrostatic interaction with an E774 residue of the lever arm during the pre-power stroke state. We expressed the R146N mutation in Drosophila to test whether disrupting this interaction alters myosin structure and function and causes HCM. R146N mutants exhibited defects in flight ability and progressive disruptions in indirect flight muscle (IFM) morphology.