[New congenital muscular dystrophy due to CHKB mutations].

Congenital muscular dystrophy with mitochondrial structural abnormalities (MIM #602541), or also called megaconial congenital muscular dystrophy, is characterized clinically by early-onset muscle wasting and severe mental retardation, and pathologically by peculiar enlarged mitochondria that are prevalent toward the periphery of the fibers but are sparse in the center on muscle biopsy. Based upon the similarity in the pathological features to rmd mouse which has a recessive mutation in Chkb gene encoding the choline kinase β that catalyzes first enzymatic step in a biosynthetic pathway for phosphatidylcholine, we have sequenced the CHKB gene in 15 patients with the disease and identified identified biallelic mutations in all patients. In muscle of three affected individuals with nonsense mutations, choline kinase activities were undetectable, and phosphatidylcholine levels were decreased while phosphatidylethanolamine levels were unchanged. Recombinant CHKB with identified missense mutations also showed reduced choline kinase activity, indicating that the disease is caused by the loss-of-function mutations in CHKB. Furthermore, mitochondria in the center of muscle fibers were subjected to autophagy on electron microscopy and these mitochondria did not have cytochrome c oxidase activity. The expression of parkin, PINK1, LC3, polyubiquitin, and p62 was upregulated in rmd muscles, indicating that mitochondria are eliminated by mitophagy.