A Congenital Muscular Dystrophy with Mitochondrial Structural Abnormalities Caused By Defective De Novo Phosphatidylcholine Biosynthesis
Tarih
2011Yazar
Mitsuhashi, Satomi
Ohkuma, Aya
Talim, Beril
Karahashi, Minako
Koumura, Tomoko
Aoyama, Chieko
Kurihara, Mana
Quinlivan, Ros
Sewry, Caroline
Mitsuhashi, Hiroaki
Goto, Kanako
Koksal, Burcu
Kale, Gulsev
Ikeda, Kazutaka
Taguchi, Ryo
Noguchi, Satoru
Hayashi, Yukiko K.
Nonaka, Ikuya
Sher, Roger B.
Sugimoto, Hiroyuki
Nakagawa, Yasuhito
Cox, Gregory A.
Topaloglu, Haluk
Nishino, Ichizo
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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.