A novel missense mutation in POMT1 modulates the severe congenital muscular dystrophy phenotype associated with POMT1 nonsense mutations期刊界 All Journals 搜尽天下杂志传播学术成果专业期刊搜索期刊信息化学术搜索

A novel missense mutation in POMT1 modulates the severe congenital muscular dystrophy phenotype associated with POMT1 nonsense mutations

Affiliation:	1. Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA, United States;2. Seattle Children’s Hospital, Seattle, WA, United States;3. Department of Laboratories, Seattle Children’s Hospital, Seattle, WA, United States;4. Prevention Genetics, Marshfield, WI, United States;5. Howard Hughes Medical Institute and Department of Molecular Physiology and Biophysics, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, United States;6. Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, United States;9. Department of Neurosciences University of California, San Diego, La Jolla, CA, United States;10. Department of Pediatrics, University of California, San Diego, La Jolla, CA, United States;11. Rady Children’s Hospital San Diego, CA, United States;12. Department of Pathology, Seattle Children’s Hospital, Seattle, WA, United States;13. Department of Neurology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, United States;14. Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, United States;15. Department of Pathology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, United States;p. Department of Neurology, University of Washington, Seattle, WA, United States;q. Department of Pediatrics, University of Washington, Seattle, WA, United States;r. Seattle Children’s Hospital, Seattle, WA, United States;1. Division of Hematology, Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA;2. Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC 27701, USA;3. Duke Center for the Study of Aging and Human Development, Duke University School of Medicine, Durham, NC 27701, USA;4. Division of Rheumatology, Duke University School of Medicine, Durham, NC 27701, USA;5. Division of Cardiology, Duke University School of Medicine, Durham, NC 27701, USA;6. Muscle Metabolism Discovery Performance Unit, Metabolic Pathways and Cardiovascular Therapeutic Area, GlaxoSmithKline, King of Prussia, PA 19406, USA;1. Graduate School of Life Science, Frontier Research Center for Advanced Material & Life Science, Hokkaido University, N21, W11, Sapporo 001-0021, Japan;2. Medicinal Chemistry Pharmaceuticals Co. Ltd., Sapporo, Japan;3. Sumitomo Bakelite Co., Ltd., Tokyo, Japan;1. Department of Obstetrics and Gynecology, Taipei City Hospital, Women and Children Campus, Taiwan;2. Department of Biomedical Engineering, National Yang Ming Chiao Tung University – Yang Ming Campus, Taiwan;3. School of Medicine for International Students, I-Shou University, Kaohsiung, Taiwan;4. Department of Bioscience Technology, Chung Yuan Christian University, Taiwan;5. Union Clinical Laboratory, Taiwan

Abstract:	Mutations in POMT1 lead to a group of neuromuscular conditions ranging in severity from Walker–Warburg syndrome to limb girdle muscular dystrophy. We report two male siblings, ages 19 and 14, and an unrelated 6-year old female with early onset muscular dystrophy and intellectual disability with minimal structural brain anomalies and no ocular abnormalities. Compound heterozygous mutations in POMT1 were identified including a previously reported nonsense mutation (c.2167dupG; p.Asp723Glyfs8) associated with Walker–Warburg syndrome and a novel missense mutation in a highly conserved region of the protein O-mannosyltransferase 1 protein (c.1958C>T; p.Pro653Leu). This novel variant reduces the phenotypic severity compared to patients with homozygous c.2167dupG mutations or compound heterozygous patients with a c.2167dupG mutation and a wide range of other mutant POMT1* alleles.

Keywords:	Protein O-mannosylation Dystroglycanopathy Walker–Warburg syndrome Congenital muscular dystrophy Limb girdle muscular dystrophy
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