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A dystroglycan mutation (p.Cys667Phe) associated to muscle‐eye‐brain disease with multicystic leucodystrophy results in ER‐retention of the mutant protein
Author(s) -
Signorino Giulia,
Covaceuszach Sonia,
Bozzi Manuela,
Hübner Wolfgang,
Mönkemöller Viola,
Konarev Petr V.,
Cassetta Alberto,
Brancaccio Andrea,
Sciandra Francesca
Publication year - 2018
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.23370
Subject(s) - endoplasmic reticulum , biology , ectodomain , calnexin , mutant , mutation , microbiology and biotechnology , er retention , dystroglycan , biochemistry , gene , extracellular matrix , calreticulin , laminin , receptor
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 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.