A dystroglycan mutation (p.Cys667Phe) associated to muscle-eye-brain disease with multicystic leucodystrophy results in ER-retention of the mutant protein
| Autor: | Viola Mönkemöller, Manuela Bozzi, Andrea Brancaccio, Petr V. Konarev, Giulia Signorino, Francesca Sciandra, Sonia Covaceuszach, Wolfgang Hübner, Alberto Cassetta |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Mutant confocal microscopy medicine.disease_cause dystroglycan Cell Line Dystroglycans 03 medical and health sciences Leukoencephalopathies Mutant protein dystroglycanopathy endoplasmic-reticulum retention Genetics medicine Dystroglycan Humans Settore BIO/10 - BIOCHIMICA Genetics (clinical) Mutation biology Endoplasmic reticulum multicystic leukodystrophy Walker-Warburg Syndrome ER retention SAXS Molecular biology site-directed mutagenesis super resolution microscopy 030104 developmental biology Ectodomain biology.protein Mutant Proteins |
| Zdroj: | Signorino, G, Covaceuszach, S, Bozzi, M, Hubner, W, Mönkemöller, V, Konarev, P V, Cassetta, A, Brancaccio, A & Sciandra, F 2018, ' A dystroglycan mutation (p.Cys667Phe) associated to muscle-eye-brain disease with multicystic leucodystrophy results in ER-retention of the mutant protein ', Human Mutation, vol. 39, no. 2, pp. 266-280 . https://doi.org/10.1002/humu.23370 Human mutation 39 (2018): 266–280. doi:10.1002/humu.23370 info:cnr-pdr/source/autori:Signorino, Giulia (1); Covaceuszach, Sonia (2); Bozzi, Manuela (1,3); Hubner, Wolfgang (4); Monkemoller, Viola (4); Konarev, Petr V (5,6); Cassetta, Alberto (2); Brancaccio, Andrea (3); Sciandra, Francesca (3)/titolo:A dystroglycan mutation (p.Cys667Phe) associated to muscle-eye-brain disease with multicystic leucodystrophy results in ER-retention of the mutant protein./doi:10.1002%2Fhumu.23370/rivista:Human mutation/anno:2018/pagina_da:266/pagina_a:280/intervallo_pagine:266–280/volume:39 |
| ISSN: | 1059-7794 |
| DOI: | 10.1002/humu.23370 |
| Popis: | Dystroglycan (DG) is a cell adhesion complex composed by two subunits, the highly glycosylated alpha-DG and the transmembrane beta-DG. In skeletal muscle, DG is involved in dystroglycanopathies, a group of heterogeneous muscular dystrophies characterized by a reduced glycosylation of alpha-DG. The genes mutated in secondary dystroglycanopathies are involved in the synthesis of O-mannosyl glycans and in the O-mannosylation pathway of alpha-DG. Mutations in the DG gene (DAG1), causing primary dystroglycanopathies, destabilize the alpha-DG core protein influencing its binding to modifying enzymes. Recently, a homozygous mutation (p.Cys699Phe) hitting the beta-DG ectodomain has been identified in a patient affected by muscle-eye-brain disease with multicystic leucodystrophy, suggesting that other mechanisms than hypoglycosylation of alpha-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 beta-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. |
| Databáze: | OpenAIRE |
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