Abstract:

Congenital muscular dystrophy is a heterogeneous group of inherited muscle diseases characterized clinically by muscle weakness and hypotonia in early infancy. A number of genes harboring causative mutations have been identified, but several cases of congenital muscular dystrophy remain molecularly unresolved. We examined 15 individuals with a congenital muscular dystrophy characterized by early-onset muscle wasting, mental retardation, and peculiar enlarged mitochondria that are prevalent toward the periphery of the fibers but are sparse in the center on muscle biopsy, and we have identified homozygous or compound heterozygous mutations in the gene encoding choline kinase beta (CHKB). This is the first enzymatic step in a biosynthetic pathway for phosphatidylcholine, the most abundant phospholipid in eukaryotes. In muscle of three affected individuals with nonsense mutations, choline kinase activities were undetectable, and phosphatidylcholine levels were decreased. We identified the human disease caused by disruption of a phospholipid de novo biosynthetic pathway, demonstrating the pivotal role of phosphatidylcholine in muscle and brain.

日本語要旨:

ミトコンドリア形態異常を伴う新たな先天性筋ジストロフィーを見出し、その原因遺伝子を世界で初めて明らかにした。この遺伝子は、リン脂質の一つホスファチジルコリンを合成する酵素、コリンキナーゼ・ベータ(CHKB)をコードしており、この酵素が骨格筋で欠損することで重篤な筋ジストロフィーを引き起こすことが、初めて明らかになった。これは、ホスファチジルコリン合成酵素欠損による初めてのヒトの疾患である。