title: A congenital muscular dystrophy with mitochondrial structural abnormalities caused by defective de novo phosphatidylcholine biosynthesis.
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.
authors.affiliation: National Institute of Neuroscience, Department of Neuromuscular Research, National Center of Neurology and Psychiatry, Tokyo 1878502, Japan.
authors.forename: Satomi
authors.initials: S
authors.lastname: Mitsuhashi
authors.affiliation: National Institute of Neuroscience, Department of Neuromuscular Research, National Center of Neurology and Psychiatry, Tokyo 1878502, Japan.
authors.forename: Aya
authors.initials: A
authors.lastname: Ohkuma
authors.affiliation: Department of Pediatrics, Pathology Unit, Hacettepe Children's Hospital, Ankara, 06100, Turkey.
authors.forename: Beril
authors.initials: B
authors.lastname: Talim
authors.affiliation: School of Pharmaceutical Sciences, Kitasato University, Tokyo, 1088641, Japan.
authors.forename: Minako
authors.initials: M
authors.lastname: Karahashi
authors.affiliation: School of Pharmaceutical Sciences, Kitasato University, Tokyo, 1088641, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Koumura
authors.affiliation: Department of Biochemistry, Dokkyo Medical University School of Medicine, Mibu, 3210293, Japan.
authors.forename: Chieko
authors.initials: C
authors.lastname: Aoyama
authors.affiliation: Department of Pediatrics, The Kanagawa Rehabilitation Center, Kanagawa, 2430121, Japan.
authors.forename: Mana
authors.initials: M
authors.lastname: Kurihara
authors.affiliation: Dubowitz Neuromuscular Centre, Great Ormond Street Hospital for Children NHS Trust, London, WC1N 3JH, UK; MRC Centre for Neuromuscular Disorders, National Hospital for Neurology and Neurosurgery, Queen Square, London, WC1N 3BG, UK.
authors.forename: Ros
authors.initials: R
authors.lastname: Quinlivan
authors.affiliation: Dubowitz Neuromuscular Centre, Great Ormond Street Hospital for Children NHS Trust, London, WC1N 3JH, UK; RJAH Orthopaedic Hospital, Oswestry, SY107AG, UK.
authors.forename: Caroline
authors.initials: C
authors.lastname: Sewry
authors.affiliation: National Institute of Neuroscience, Department of Neuromuscular Research, National Center of Neurology and Psychiatry, Tokyo 1878502, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Mitsuhashi
authors.affiliation: National Institute of Neuroscience, Department of Neuromuscular Research, National Center of Neurology and Psychiatry, Tokyo 1878502, Japan.
authors.forename: Kanako
authors.initials: K
authors.lastname: Goto
authors.affiliation: Department of Pediatrics, Pathology Unit, Hacettepe Children's Hospital, Ankara, 06100, Turkey.
authors.forename: Burcu
authors.initials: B
authors.lastname: Koksal
authors.affiliation: Department of Pediatrics, Pathology Unit, Hacettepe Children's Hospital, Ankara, 06100, Turkey.
authors.forename: Gulsev
authors.initials: G
authors.lastname: Kale
authors.affiliation: Department of Metabolome, Graduate School of Medicine, The University of Tokyo, Tokyo, 1130033, Japan.
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Ikeda
authors.affiliation: Department of Metabolome, Graduate School of Medicine, The University of Tokyo, Tokyo, 1130033, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Taguchi
authors.affiliation: National Institute of Neuroscience, Department of Neuromuscular Research, National Center of Neurology and Psychiatry, Tokyo 1878502, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Noguchi
authors.affiliation: National Institute of Neuroscience, Department of Neuromuscular Research, National Center of Neurology and Psychiatry, Tokyo 1878502, Japan.
authors.forename: Yukiko K
authors.initials: YK
authors.lastname: Hayashi
authors.affiliation: National Institute of Neuroscience, Department of Neuromuscular Research, National Center of Neurology and Psychiatry, Tokyo 1878502, Japan.
authors.forename: Ikuya
authors.initials: I
authors.lastname: Nonaka
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine, 04609, USA.
authors.forename: Roger B
authors.initials: RB
authors.lastname: Sher
authors.affiliation: Department of Biochemistry, Dokkyo Medical University School of Medicine, Mibu, 3210293, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Sugimoto
authors.affiliation: School of Pharmaceutical Sciences, Kitasato University, Tokyo, 1088641, Japan.
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Nakagawa
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine, 04609, USA.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Cox
authors.affiliation: Department of Pediatrics, Child Neurology Unit, Hacettepe Children's Hospital, 06100, Ankara, Turkey.
authors.forename: Haluk
authors.initials: H
authors.lastname: Topaloglu
authors.affiliation: National Institute of Neuroscience, Department of Neuromuscular Research, National Center of Neurology and Psychiatry, Tokyo 1878502, Japan. Electronic address: nishino@ncnp.go.jp.
authors.forename: Ichizo
authors.initials: I
authors.lastname: Nishino
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D002797:Choline Kinase / Q000235:genetics*; D005260:Female; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics; D008297:Male; D008931:Mitochondria, Muscle / Q000235:genetics / Q000473:pathology*; D009136:Muscular Dystrophies / Q000151:congenital* / Q000235:genetics / Q000473:pathology*; D009154:Mutation; D010375:Pedigree; D010713:Phosphatidylcholines / Q000096:biosynthesis* / Q000235:genetics; D011110:Polymorphism, Genetic; D055815:Young Adult
chemical_list: D010713:Phosphatidylcholines; C542592:CHKB protein, human; D002797:Choline Kinase