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Research paper
Mobility shift of beta-dystroglycan as a marker of GMPPB gene-related muscular dystrophy
  1. Anna Sarkozy1,
  2. Silvia Torelli1,
  3. Rachael Mein2,
  4. Matt Henderson3,
  5. Rahul Phadke1,
  6. Lucy Feng1,
  7. Caroline Sewry1,4,
  8. Pierpaolo Ala1,
  9. Michael Yau2,
  10. Marta Bertoli5,6,
  11. Tracey Willis4,
  12. Simon Hammans7,
  13. Adnan Manzur1,
  14. Maria Sframeli1,
  15. Fiona Norwood8,
  16. Wojtek Rakowicz9,
  17. Aleksandar Radunovic10,
  18. Sujit S Vaidya10,
  19. Matt Parton11,
  20. Mark Walker12,
  21. Silvia Marino13,
  22. Curtis Offiah14,
  23. Maria Elena Farrugia15,
  24. Godwin Mamutse16,
  25. Chiara Marini-Bettolo5,
  26. Elizabeth Wraige17,
  27. David Beeson18,
  28. Hanns Lochmüller5,
  29. Volker Straub5,
  30. Kate Bushby5,
  31. Rita Barresi3,5,
  32. Francesco Muntoni1
  1. 1 Dubowitz Neuromuscular Centre, MRC Centre for Neuromuscular Diseases, UCL Great Ormond Street Institute of Child Health, London, UK
  2. 2 DNA Laboratory, Viapath, Guy’s Hospital, London, UK
  3. 3 Rare Diseases Advisory Group Service for Neuromuscular Diseases, Muscle Immunoanalysis Unit, Dental Hospital, Newcastle upon Tyne, UK
  4. 4 The Robert Jones and Agnes Hunt Orthopaedic Hospital, Oswestry, UK
  5. 5 The John Walton Muscular Dystrophy Research Centre, MRC Centre for Neuromuscular Diseases Institute of Genetic Medicine, University of Newcastle, Newcastle upon Tyne, UK
  6. 6 Northern Genetics Service, Newcastle upon Tyne NHS Trust, Newcastle upon Tyne, UK
  7. 7 Wessex Neurological Centre, University Hospital of Southampton, Southampton, UK
  8. 8 Department of Neurology, King’s College Hospital, London, UK
  9. 9 Department of Neurology, Hampshire Hospitals NHS Foundation Trust, Royal Hampshire County Hospital, Winchester, UK
  10. 10 The Royal London Hospital, London, UK
  11. 11 MRC Centre for Neuromuscular Diseases, Institute of Neurology, University College London, London, UK
  12. 12 Department of Cellular Pathology, Southampton University Hospitals, Southampton, UK
  13. 13 Queen Mary University of London, Barts and the London School of Medicine and Dentistry, London, UK
  14. 14 Department of Radiology, Royal London Hospital, London, UK
  15. 15 Department of Neurology, Institute of Neurological Sciences, Southern General Hospital, Glasgow, UK
  16. 16 Department of Neurology, Norfolk and Norwich University Hospital, Norwich, UK
  17. 17 Department of Paediatric Neurology, Neuromuscular Service, Evelina Children’s Hospital, St Thomas’ Hospital, London, UK
  18. 18 Neuromuscular Disorders Group, Nuffield Department of Clinical Neurosciences, Weatherall Institute of Molecular Medicine, Oxford, UK
  1. Correspondence to Professor Francesco Muntoni, Dubowitz Neuromuscular Centre, UCL Great Ormond Street Institute of Child Health, London WC1N 1EH, UK; f.muntoni{at}


Background Defects in glycosylation of alpha-dystroglycan (α-DG) cause autosomal-recessive disorders with wide clinical and genetic heterogeneity, with phenotypes ranging from congenital muscular dystrophies to milder limb girdle muscular dystrophies. Patients show variable reduction of immunoreactivity to antibodies specific for glycoepitopes of α-DG on a muscle biopsy. Recessive mutations in 18 genes, including guanosine diphosphate mannose pyrophosphorylase B (GMPPB), have been reported to date. With no specific clinical and pathological handles, diagnosis requires parallel or sequential analysis of all known genes.

Methods We describe clinical, genetic and biochemical findings of 21 patients with GMPPB-associated dystroglycanopathy.

Results We report eight novel mutations and further expand current knowledge on clinical and muscle MRI features of this condition. In addition, we report a consistent shift in the mobility of beta-dystroglycan (β-DG) on Western blot analysis of all patients analysed by this mean. This was only observed in patients with GMPPB in our large dystroglycanopathy cohort. We further demonstrate that this mobility shift in patients with GMPPB was due to abnormal N-linked glycosylation of β-DG.

Conclusions Our data demonstrate that a change in β-DG electrophoretic mobility in patients with dystroglycanopathy is a distinctive marker of the molecular defect in GMPPB.

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  • RB and FM contributed equally.

  • Contributors AS drafted the manuscript, reviewed clinical and MRI data and contributed to plan the study, ST planned the study and performed laboratory investigations; RM performed genetic testing; MH performed protein analysis; RP, LH and CS performed histopathological investigations and critical review of muscle biopsy data; PA performed laboratory investigations; MS collected and analysed clinical data; MY performed genetic testing; MB, TW, SH, AM, FN, WR, AR, SSV, MP, MEF, CO, GM, CMB, EW, DB, HL, VS, KB collected and clinically reviewed clinical and MRI data; MW, SM conducted further histopathogical investigations; RB designed the study, critically reviewed results, content of the work and manuscript as guarantor of the study; FM has reviewed the results, manuscript and is responsible for the overall content as guarantor.

  • Funding FM is supported by the National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London. DB is supported by the MRC programme (grant MR/M006824).

  • Disclaimer The opinions expressed in this manuscript are of the authors and not from NHS England or the NIHR.

  • Competing interests None declared.

  • Patient consent Obtained.

  • Ethics approval This study was approved by the Health Research Authority, NRES Committee East of England – Hatfield (REC 13/EE/0398).

  • Provenance and peer review Not commissioned; externally peer reviewed.

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