Functional Differences in MYH7b That Contribute to Distinct Biological Roles across Species and in Health and Disease

Abstract

Myosin heavy chain 7b (MYH7b) is a recently identified sarcomeric myosin gene family member that has a unique expression pattern in mammals. MYH7b protein is absent from the heart and skeletal muscle of mammals and is only expressed in specialized muscles and, surprisingly, in the inner ear and brain. Additionally, compound heterozygous mutations in MYH7b (one in the motor domain and one in the rod domain) cause hearing loss in humans by an unknown mechanism (Haraksingh et al., BMC Genomics, 2014) indicating that MYH7b has an important yet undefined role in mammalian non-muscle tissue. Intriguingly, in snakes, MYH7b protein is abundant in cardiac and skeletal muscles. Despite these divergent roles in mammals and reptiles, MYH7b shares high sequence identity between these vertebrate classes, so it is unclear how mammalian MYH7b function may deviate in non-muscle tissues from its expected sarcomeric role. To address this question, we have generated recombinant protein for human MYH7b, human MYH7b with the motor domain hearing loss mutation (D515N), and python MYH7b, and have measured their biochemical and biophysical properties. We have observed differences in the steady-state actin-activated ATPase activities and actin translocation as assessed by in vitro motility assays between these three recombinant proteins. Comparing the motor activity of human MYH7b and python MYH7b provides both an evolutionary perspective and functional analysis of highly conserved myosins that operate in different cell types. Further, comparing the function of human wild type MYH7b and D515N MYH7b provides greater insight into the etiology of human hearing loss.