Mechanistic Understanding of the Involvement of MyBP-C Slow in the Development of Distal Arthrogryposis

Myosin Binding Protein-C (MyBP-C), expressed in striated muscles, is a thick filament associated protein that plays important roles in thick filament assembly and stabilization, and the modulation of actomyosin cross-bridges formation. Several studies have implicated MyBP-C in the development of cardiac and recently skeletal myopathies, underlining its importance in normal sarcomeric function. Mutations in the slow skeletal isoform of MyBP-C (sMyBP-C) have been causally linked to severe and lethal forms of arthrogryposis, a family of neuromuscular diseases. Two missense mutations within MYBPC1, the gene that encodes sMyBP-C, located within the NH2-terminal M-motif (W236R) and the COOH-terminal immunoglobulin (Ig) C8 domain (Y856H) have been linked to the development of distal arthrogryposis type-1 (DA-1), a skeletal muscle disorder characterized by contractures of the distal limbs. Here we explore the molecular defects that underlie the development of DA-1. using a combination of in vitro binding and motility assays, we show that the presence of the W236R mutation abolishes the ability of the NH2-terminus to modulate the formation of actomyosin cross-bridges, while the presence of the Y856H mutation inhibits Ig domains C8-C10 from interacting with native myosin filaments. Our findings therefore suggest that distinct mechanisms may underlie the pathogenesis of DA-1 myopathy depending on the location of the individual mutation within sMyBP-C. We are currently examining the effects of overexpressing mutant sMyBP-C proteins carrying either the W236R or the Y856H mutation in a sMyBP-C-null background, via in vivo gene transfer. In summary, our studies are the first to provide a mechanistic interpretation of the pathogenesis of distal arthrogryposis.