Mutations in GMPPB cause congenital myasthenic syndrome and bridge myasthenic disorders with dystroglycanopathies.

Katsiaryna Belaya,Maryam Sedghi,Matthew Pitt,Hanns Lochmüller,David Beeson,Wei Wei Liu,Keivan Basiri,Timothy J Walls,Pedro M Rodríguez Cruz,Wyatt W Yue,Francesco Muntoni,Jacqueline Palace,Richard Petty,Kate Bushby,Susan Maxwell,Matt Parton,Simon J Mcgowan ,Andrew M Schaefer ,Marta Bértoli ,Roger H Kennett ,Maria Elena Farrugia ,Anna Sárközy

doi:10.1093/brain/awv185

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.

Highlights

Congenital myasthenic syndromes (CMS) are a rare and heterogeneous group of inherited disorders caused by mutations in genes encoding proteins that are essential for neuromuscular transmission
GMPPB encodes GDP-mannose pyrophosphorylase B—an enzyme involved in glycosylation
We identify mutations in GMPPB, an enzyme involved in glycosylation, as a new cause of CMS

Summary

Introduction

Congenital myasthenic syndromes (CMS) are a rare and heterogeneous group of inherited disorders caused by mutations in genes encoding proteins that are essential for neuromuscular transmission. ALG2, ALG14, DPAGT1 and GFPT1, are recently identified genes encoding proteins involved in glycosylation (Fig. 1) (Senderek et al, 2011; Belaya et al, 2012; Cossins et al, 2013). GFPT1 is involved in the synthesis of UDP-GlcNAc, a nucleotide sugar used as a building block by several glycosylation pathways, including N- and O-linked glycosylation. These four subtypes of glycosylation-CMS have characteristic clinical features that help to distinguish them from other CMS subtypes. Other neuromuscular junction proteins are likely to be affected by abnormal glycosylation and might further contribute to the phenotype (Selcen et al, 2014)

Methods

Results

Conclusion