A dystroglycan mutation (p.Cys667Phe) associated to Muscle-Eye-Brain disease with multicystic leucodystrophy results in ER-retention of the mutant protein

Manuela Bozzi, Giulia Signorino, Andrea Brancaccio, Francesca Sciandra, Sonia Covaceuszach, Wolfgang Hübner, Viola Mönkemöller, Petr V. Konarev, Alberto Cassetta

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)

Abstract

Dystroglycan (DG) is a cell adhesion complex composed by two subunits, the highly glycosylated α-DG and the transmembrane β-DG. In skeletal muscle, DG is involved in dystroglycanopathies, a group of heterogeneous muscular dystrophies characterized by a reduced glycosylation of α-DG. The genes mutated in secondary dystroglycanopathies are involved in the synthesis of O-mannosyl glycans and in the O-mannosylation pathway of α-DG. Mutations in the DG gene (DAG1), causing primary dystroglycanopathies, destabilize the α-DG core protein influencing its binding to modifying enzymes. Recently, a homozygous mutation (p.Cys699Phe) hitting the β-DG ectodomain has been identified in a patient affected by Muscle-Eye-Brain disease with multicystic leucodystrophy, suggesting that other mechanisms than hypoglycosylation of α-DG could be implicated in dystroglycanopathies. Herein, we have characterized the DG murine mutant counterpart by transfection in cellular systems and high-resolution microscopy. We observed that the mutation alters the DG processing leading to retention of its uncleaved precursor in the endoplasmic reticulum. Accordingly, small-angle X-ray scattering (SAXS) data, corroborated by biochemical and biophysical experiments, revealed that the mutation provokes an alteration in the β-DG ectodomain overall folding, resulting in disulfide-associated oligomerization. Our data provide the first evidence of a novel intracellular mechanism, featuring an anomalous endoplasmic reticulum-retention, underlying dystroglycanopathy. This article is protected by copyright. All rights reserved.
Original languageEnglish
Pages (from-to)266-280
Number of pages15
JournalHuman Mutation
Volume2018/39
DOIs
Publication statusPublished - 2017

Keywords

  • SAXS
  • confocal microscopy
  • dystroglycan
  • dystroglycanopathy
  • endoplasmic-reticulum retention
  • multicystic leukodystrophy
  • site-directed mutagenesis
  • super resolution microscopy

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