title: Mutations in GMPPB cause congenital myasthenic syndrome and bridge myasthenic disorders with dystroglycanopathies.
abstract: Congenital myasthenic syndromes are inherited disorders that arise from impaired signal transmission at the neuromuscular junction. Mutations in at least 20 genes are known to lead to the onset of these conditions. Four of these, ALG2, ALG14, DPAGT1 and GFPT1, are involved in glycosylation. Here we identify a fifth glycosylation gene, GMPPB, where mutations cause congenital myasthenic syndrome. First, we identified recessive mutations in seven cases from five kinships defined as congenital myasthenic syndrome using decrement of compound muscle action potentials on repetitive nerve stimulation on electromyography. The mutations were present through the length of the GMPPB, and segregation, in silico analysis, exon trapping, cell transfection followed by western blots and immunostaining were used to determine pathogenicity. GMPPB congenital myasthenic syndrome cases show clinical features characteristic of congenital myasthenic syndrome subtypes that are due to defective glycosylation, with variable weakness of proximal limb muscle groups while facial and eye muscles are largely spared. However, patients with GMPPB congenital myasthenic syndrome had more prominent myopathic features that were detectable on muscle biopsies, electromyography, muscle magnetic resonance imaging, and through elevated serum creatine kinase levels. Mutations in GMPPB have recently been reported to lead to the onset of muscular dystrophy dystroglycanopathy. Analysis of four additional GMPPB-associated muscular dystrophy dystroglycanopathy cases by electromyography found that a defective neuromuscular junction component is not always present. Thus, we find mutations in GMPPB can lead to a wide spectrum of clinical features where deficit in neuromuscular transmission is the major component in a subset of cases. Clinical recognition of GMPPB-associated congenital myasthenic syndrome may be complicated by the presence of myopathic features, but correct diagnosis is important because affected individuals can respond to appropriate treatments.
authors.affiliation: 1 Neurosciences Group, Nuffield Department of Clinical Neurosciences, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, OX3 9DS, UK.
authors.forename: Katsiaryna
authors.initials: K
authors.lastname: Belaya
authors.affiliation: 1 Neurosciences Group, Nuffield Department of Clinical Neurosciences, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, OX3 9DS, UK 2 Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, Oxford, OX3 9DU, UK.
authors.forename: Pedro M
authors.initials: PM
authors.lastname: Rodríguez Cruz
authors.affiliation: 1 Neurosciences Group, Nuffield Department of Clinical Neurosciences, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, OX3 9DS, UK.
authors.forename: Wei Wei
authors.initials: WW
authors.lastname: Liu
authors.affiliation: 1 Neurosciences Group, Nuffield Department of Clinical Neurosciences, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, OX3 9DS, UK.
authors.forename: Susan
authors.initials: S
authors.lastname: Maxwell
authors.affiliation: 3 Computational Biology Research Group, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, OX3 9DS, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: McGowan
authors.affiliation: 4 Department of Neurology, Institute of Neurological Sciences, Southern General Hospital, Glasgow, UK.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Farrugia
authors.affiliation: 4 Department of Neurology, Institute of Neurological Sciences, Southern General Hospital, Glasgow, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Petty
authors.affiliation: 5 Department of Neurology, Royal Victoria Infirmary, Newcastle upon Tyne, NE1 4LP, UK.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Walls
authors.affiliation: 6 Medical Genetics Laboratory, Alzahra University Hospital, Isfahan University of Medical Sciences, Isfahan, Iran.
authors.forename: Maryam
authors.initials: M
authors.lastname: Sedghi
authors.affiliation: 7 Neurology Department, Neuroscience Research Centre, Isfahan University of Medical Sciences, Isfahan, Iran.
authors.forename: Keivan
authors.initials: K
authors.lastname: Basiri
authors.affiliation: 8 Structural Genomics Consortium, University of Oxford, Oxford, OX3 7DQ, UK.
authors.forename: Wyatt W
authors.initials: WW
authors.lastname: Yue
authors.affiliation: 9 Institute of Genetic Medicine, John Walton Muscular Dystrophy Research Centre, MRC Centre for Neuromuscular Diseases, Newcastle University, Newcastle upon Tyne, NE1 3BZ, UK 10 MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology and National Hospital for Neurology and Neurosurgery, Queen Square, London, UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Sarkozy
authors.affiliation: 9 Institute of Genetic Medicine, John Walton Muscular Dystrophy Research Centre, MRC Centre for Neuromuscular Diseases, Newcastle University, Newcastle upon Tyne, NE1 3BZ, UK.
authors.forename: Marta
authors.initials: M
authors.lastname: Bertoli
authors.affiliation: 11 Department of Clinical Neurophysiology, Great Ormond Street Hospital for children NHS foundation trust, London WC1N 3JH.
authors.forename: Matthew
authors.initials: M
authors.lastname: Pitt
authors.affiliation: 2 Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, Oxford, OX3 9DU, UK.
authors.forename: Robin
authors.initials: R
authors.lastname: Kennett
authors.affiliation: 5 Department of Neurology, Royal Victoria Infirmary, Newcastle upon Tyne, NE1 4LP, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Schaefer
authors.affiliation: 9 Institute of Genetic Medicine, John Walton Muscular Dystrophy Research Centre, MRC Centre for Neuromuscular Diseases, Newcastle University, Newcastle upon Tyne, NE1 3BZ, UK.
authors.forename: Kate
authors.initials: K
authors.lastname: Bushby
authors.affiliation: 10 MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology and National Hospital for Neurology and Neurosurgery, Queen Square, London, UK.
authors.forename: Matt
authors.initials: M
authors.lastname: Parton
authors.affiliation: 9 Institute of Genetic Medicine, John Walton Muscular Dystrophy Research Centre, MRC Centre for Neuromuscular Diseases, Newcastle University, Newcastle upon Tyne, NE1 3BZ, UK.
authors.forename: Hanns
authors.initials: H
authors.lastname: Lochmüller
authors.affiliation: 2 Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, Oxford, OX3 9DU, UK.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Palace
authors.affiliation: 12 Dubowitz Neuromuscular Centre and MRC Centre for Neuromuscular Diseases, UCL Institute of Child Health, London, WC1N 1EH, UK.
authors.forename: Francesco
authors.initials: F
authors.lastname: Muntoni
authors.affiliation: 1 Neurosciences Group, Nuffield Department of Clinical Neurosciences, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, OX3 9DS, UK david.beeson@ndcn.ox.ac.uk.
authors.forename: David
authors.initials: D
authors.lastname: Beeson
mesh_terms: D000293:Adolescent; D000328:Adult; D004252:DNA Mutational Analysis; D049030:Dystroglycans / Q000378:metabolism*; D005192:Family Health; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D018482:Muscle, Skeletal / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D020294:Myasthenic Syndromes, Congenital / Q000235:genetics* / Q000473:pathology; D009469:Neuromuscular Junction / Q000473:pathology / Q000503:physiopathology*; D009713:Nucleotidyltransferases / Q000235:genetics* / Q000378:metabolism; D014162:Transfection; D055815:Young Adult
chemical_list: D049030:Dystroglycans; D009713:Nucleotidyltransferases; C026917:mannose 1-phosphate guanylyltransferase
keywords: GMPPB; congenital myasthenic syndrome; dystroglycan; glycosylation; neurotransmission defect