Key result
Expression of the DNM2-S619L mutation impaired BIN1-dependent tubule formation, with only 19% of mutant cells exhibiting long tubules compared to 69% of wild-type cells.
The DNM2-S619L mutation associated with centronuclear myopathy causes disease by interfering with membrane tubulation and excitation-contraction coupling.
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Suggests DNM2-S619L drives centronuclear myopathy via tubulation defects; leaves open human cardiac translation and therapeutic targeting.
DNM2 is a ubiquitously expressed GTPase that regulates multiple subcellular processes. Mutations in DNM2 are a common cause of centronuclear myopathy, a severe disorder characterized by altered skeletal muscle structure and function. The precise mechanisms underlying disease-associated DNM2 mutations are unresolved. We examined the common DNM2-S619L mutation using both in vitro and in vivo approaches. Expression of DNM2-S619L in zebrafish led to the accumulation of aberrant vesicular structures and to defective excitation-contraction coupling. Expression of DNM2-S619L in COS7 cells resulted in defective BIN1-dependent tubule formation. These data suggest that DNM2-S619L causes disease, in part, by interfering with membrane tubulation.
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Gibbs et al. (2013) studied Centronuclear myopathy. DNM2-S619L mutation expression vs. DNM2-WT expression was evaluated on Formation of long tubules in BIN1-induced COS7 cells. Expression of the DNM2-S619L mutation impaired BIN1-dependent tubule formation, with only 19% of mutant cells exhibiting long tubules compared to 69% of wild-type cells.
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