Isfahan University of Medical Sciences

Science Communicator Platform

Stay connected! Follow us on X network (Twitter):
Share this content! On (X network) By
Mutations in Gmppb Cause Congenital Myasthenic Syndrome and Bridge Myasthenic Disorders With Dystroglycanopathies Publisher Pubmed



Belaya K1 ; Rodriguez Cruz PM1, 2 ; Liu WW1 ; Maxwell S1 ; Mcgowan S3 ; Farrugia ME4 ; Petty R4 ; Walls TJ5 ; Sedghi M6 ; Basiri K7 ; Yue WW8 ; Sarkozy A9, 10 ; Bertoli M9 ; Pitt M11 Show All Authors
Authors
  1. Belaya K1
  2. Rodriguez Cruz PM1, 2
  3. Liu WW1
  4. Maxwell S1
  5. Mcgowan S3
  6. Farrugia ME4
  7. Petty R4
  8. Walls TJ5
  9. Sedghi M6
  10. Basiri K7
  11. Yue WW8
  12. Sarkozy A9, 10
  13. Bertoli M9
  14. Pitt M11
  15. Kennett R2
  16. Schaefer A5
  17. Bushby K9
  18. Parton M10
  19. Lochmuller H9
  20. Palace J2
  21. Muntoni F12
  22. Beeson D1
Show Affiliations
Authors Affiliations
  1. 1. Neurosciences Group, Nuffield Department of Clinical Neurosciences, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, OX3 9DS, United Kingdom
  2. 2. Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, Oxford, OX3 9DU, United Kingdom
  3. 3. Computational Biology Research Group, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, OX3 9DS, United Kingdom
  4. 4. Department of Neurology, Institute of Neurological Sciences, Southern General Hospital, Glasgow, United Kingdom
  5. 5. Department of Neurology, Royal Victoria Infirmary, Newcastle upon Tyne, NE1 4LP, United Kingdom
  6. 6. Medical Genetics Laboratory, Alzahra University Hospital, Isfahan University of Medical Sciences, Isfahan, Iran
  7. 7. Neurology Department, Neuroscience Research Centre, Isfahan University of Medical Sciences, Isfahan, Iran
  8. 8. Structural Genomics Consortium, University of Oxford, Oxford, OX3 7DQ, United Kingdom
  9. 9. Institute of Genetic Medicine, John Walton Muscular Dystrophy Research Centre, MRC Centre for Neuromuscular Diseases, Newcastle University, Newcastle upon Tyne, NE1 3BZ, United Kingdom
  10. 10. MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, National Hospital for Neurology and Neurosurgery, Queen Square, London, United Kingdom
  11. 11. Department of Clinical Neurophysiology, Great Ormond Street Hospital for Children, NHS Foundation Trust, London, WC1N 3JH, United Kingdom
  12. 12. Dubowitz Neuromuscular Centre, MRC Centre for Neuromuscular Diseases, UCL Institute of Child Health, London, WC1N 1EH, United Kingdom

Source: Brain Published:2015


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. © 2015 The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain.
Related Docs
View other Related Docs
1. Clinical Features of the Myasthenic Syndrome Arising From Mutations in Gmppb, Journal of Neurology, Neurosurgery and Psychiatry (2016)
2. Clinical Features in a Large Iranian Family With a Limb-Girdle Congenital Myasthenic Syndrome Due to a Mutation in Dpagt1, Neuromuscular Disorders (2013)
3. Humans With Inherited T Cell Cd28 Deficiency Are Susceptible to Skin Papillomaviruses But Are Otherwise Healthy, Cell (2021)
4. Detection of Intragenic Smn1 Mutations in Spinal Muscular Atrophy Patients With a Single Copy of Smn1, Journal of Child Neurology (2015)
5. Genome-Wide Association Scan of Serum Urea in European Populations Identifies Two Novel Loci, American Journal of Nephrology (2019)
6. Whole-Transcriptome Sequencing–Based Concomitant Detection of Viral and Human Genetic Determinants of Cutaneous Lesions, JCI Insight (2022)
7. In Silico Post Genome-Wide Association Studies Analysis of C-Reactive Protein Loci Suggests an Important Role for Interferons, Circulation: Cardiovascular Genetics (2015)
8. Use of in Silico Tools for Classification of Novel Missense Mutations Identified in Dystrophin Gene in Developing Countries, Gene (2014)
Experts (# of related papers)
View all Related Experts
Mohammad Amin Tabatabaiefar (6)
Keivan Basiri (5)
Other Related Docs
9. Predicting Deleterious Missense Genetic Variants Via Integrative Supervised Nonnegative Matrix Tri-Factorization, Scientific Reports (2021)
10. A Novel Mutation in Gjc2 Associated With Hypomyelinating Leukodystrophy Type 2 Disorder, Genomics and Informatics (2022)
11. Two Novel Mutations in Aldh18a1 and Spg11 Genes Found by Wholeexome Sequencing in Spastic Paraplegia Disease Patients in Iran, Genomics and Informatics (2022)
12. A Homozygous Nonsense Variant in Uvssa Causes Uv‑Sensitive Syndrome From Very Large Kindred: The First Report From Iran, Advanced Biomedical Research (2023)
13. On Genotype-Phenotype Relationship of Dystrophinopathies Among Iranian Population, Current Journal of Neurology (2023)
14. Novel In-Frame Duplication Variant Characterization in Late Infantile Metachromatic Leukodystrophy Using Whole-Exome Sequencing and Molecular Dynamics Simulation, PLoS ONE (2023)
15. Screening of Dfnb3 in Iranian Families With Autosomal Recessive Non-Syndromic Hearing Loss Reveals a Novel Pathogenic Mutation in the Myth4 Domain of the Myo15a Gene in a Linked Family, Iranian Journal of Basic Medical Sciences (2016)
16. Homozygous Tfg Gene Variants Expanding the Mutational and Clinical Spectrum of Hereditary Spastic Paraplegia 57 and a Review of Literature, Journal of Human Genetics (2021)
17. Causative Variants Linked With Limb Girdle Muscular Dystrophy in an Iranian Population: 6 Novel Variants, Molecular Genetics and Genomic Medicine (2023)
18. Genetic Screening in Adolescents With Steroid-Resistant Nephrotic Syndrome, Kidney International (2013)
19. A Recurrent Homozygous Missense Dpm3 Variant Leads to Muscle and Brain Disease, Clinical Genetics (2022)
20. Griscelli Syndrome Type 1: A Novel Pathogenic Variant, and Review of Literature, Molecular Genetics and Genomics (2023)
21. Jagn1 Deficiency Causes Aberrant Myeloid Cell Homeostasis and Congenital Neutropenia, Nature Genetics (2014)
22. Phenotypic But Not Genetically Predicted Heart Rate Variability Associated With All-Cause Mortality, Communications Biology (2023)
23. Genetic Analysis of a Cohort of 275 Patients With Hyper-Ige Syndromes And/Or Chronic Mucocutaneous Candidiasis, Journal of Clinical Immunology (2021)
24. Identification of Novel Mutations in Tpk1 and Slc19a3 Genes in Families Exhibiting Thiamine Metabolism Dysfunction Syndrome, Heliyon (2024)
25. Novel Kiaa0753 Mutations Extend the Phenotype of Skeletal Ciliopathies, Scientific Reports (2017)
26. In Silico Analysis of Slc3a1 and Slc7a9 Mutations in Iranian Patients With Cystinuria, Molecular Biology Reports (2018)
27. Clinical and Genetic Profile of Children With Unexplained Intellectual Disability/Developmental Delay and Epilepsy, Epilepsy Research (2021)
28. Bioinformatic Prioritization and Functional Annotation of Gwas-Based Candidate Genes for Primary Open-Angle Glaucoma, Genes (2022)