Congenital myopathy results from misregulation of a muscle Ca2+ channel by mutant Stac3.

Abstract

Skeletal muscle contractions are initiated by an increase in Ca²⁺ released during excitation-contraction (EC) coupling, and defects in EC coupling are associated with human myopathies. EC coupling requires communication between voltage-sensing dihydropyridine receptors (DHPRs) in transverse tubule membrane and Ca²⁺ release channel ryanodine receptor 1 (RyR1) in the sarcoplasmic reticulum (SR). Stac3 protein (SH3 and cysteine-rich domain 3) is an essential component of the EC coupling apparatus and a mutation in human STAC3 causes the debilitating Native American myopathy (NAM), but the nature of how Stac3 acts on the DHPR and/or RyR1 is unknown. Using electron microscopy, electrophysiology, and dynamic imaging of zebrafish muscle fibers, we find significantly reduced DHPR levels, functionality, and stability in stac3 mutants. Furthermore, stac3^NAM myofibers exhibited increased caffeine-induced Ca²⁺ release across a wide range of concentrations in the absence of altered caffeine sensitivity as well as increased Ca²⁺ in internal stores, which is consistent with increased SR luminal Ca²⁺ These findings define critical roles for Stac3 in EC coupling and human disease.