A congenital muscular dystrophy with mitochondrial structural abnormalities caused by defective de novo phosphatidylcholine biosynthesis

Am J Hum Genet. 2011 Jun 10;88(6):845-851. doi: 10.1016/j.ajhg.2011.05.010.

Satomi Mitsuhashi ¹, Aya Ohkuma ¹, Beril Talim ², Minako Karahashi ³, Tomoko Koumura ³, Chieko Aoyama ⁴, Mana Kurihara ⁵, Ros Quinlivan ⁶, Caroline Sewry ⁷, Hiroaki Mitsuhashi ¹, Kanako Goto ¹, Burcu Koksal ², Gulsev Kale ², Kazutaka Ikeda ⁸, Ryo Taguchi ⁸, Satoru Noguchi ¹, Yukiko K Hayashi ¹, Ikuya Nonaka ¹, Roger B Sher ⁹, Hiroyuki Sugimoto ⁴, Yasuhito Nakagawa ³, Gregory A Cox ⁹, Haluk Topaloglu ¹⁰, Ichizo Nishino ¹¹

Affiliations

1 National Institute of Neuroscience, Department of Neuromuscular Research, National Center of Neurology and Psychiatry, Tokyo 1878502, Japan.
2 Department of Pediatrics, Pathology Unit, Hacettepe Children's Hospital, Ankara, 06100, Turkey.
3 School of Pharmaceutical Sciences, Kitasato University, Tokyo, 1088641, Japan.
4 Department of Biochemistry, Dokkyo Medical University School of Medicine, Mibu, 3210293, Japan.
5 Department of Pediatrics, The Kanagawa Rehabilitation Center, Kanagawa, 2430121, Japan.
6 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.
7 Dubowitz Neuromuscular Centre, Great Ormond Street Hospital for Children NHS Trust, London, WC1N 3JH, UK; RJAH Orthopaedic Hospital, Oswestry, SY107AG, UK.
8 Department of Metabolome, Graduate School of Medicine, The University of Tokyo, Tokyo, 1130033, Japan.
9 The Jackson Laboratory, Bar Harbor, Maine, 04609, USA.
10 Department of Pediatrics, Child Neurology Unit, Hacettepe Children's Hospital, 06100, Ankara, Turkey.
11 National Institute of Neuroscience, Department of Neuromuscular Research, National Center of Neurology and Psychiatry, Tokyo 1878502, Japan. Electronic address: [email protected].

PMID: 21665002 DOI: 10.1016/j.ajhg.2011.05.010

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.

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