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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