Characterization of a Zebrafish Model of X-linked Centronuclear Myopathy for Therapeutic Drug Development

Abstract


X-linked centronuclear myopathy (XLCNM) is a congenital skeletal muscle disorder caused by mutations in MTM1. Despite being associated with a high rate of neonatal mortality there are currently no effective therapies for this disorder. MTM1 is a phosphoinositide 3-phosphatase that antagonizes class II and III phosphatidylinositol 3-kinases (PI3K). Loss of Pik3c2b, a class II PI3K, rescues lethality in Mtm1 knockout mice. Importantly, Pik3c2b knockout mice are viable and have no apparent phenotype. Therefore, pharmacological inhibitors of PIK3C2B have the potential to be highly effective in the treatment of XLCNM. I have characterized an mtm1 mutant using the zebrafish, Danio rerio, and found that PIK3C2B inhibition improves the mtm1 mutant phenotype. In parallel, a phenotypic drug screen identified valproic acid as a suppressor of an mtm1 mutant phenotype. The work presented herein demonstrates that PIK3C2B inhibitors and drugs like valproic acid may represent putative therapeutics for translation into MTM1 patients.