A dystroglycan mutation (p.Cys66uPhe) associated to muscle-eye-brain disease with multicystic leukodystrophy results in ER-retention of the mutant protein
| العنوان: | A dystroglycan mutation (p.Cys66uPhe) associated to muscle-eye-brain disease with multicystic leukodystrophy results in ER-retention of the mutant protein |
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| المؤلفون: | Signorino G (1), Covaceuszach S (2), Bozzi M (1), (3), Hübner W (4), Mönkemöller V (4), Konarev PV (5), Cassetta A (2), Brancaccio A (3), (6), Sciandra F (3). |
| المصدر: | Human mutation 39 (2018): 266–280. info:cnr-pdr/source/autori:Signorino G (1), Covaceuszach S (2), Bozzi M (1),(3), Hübner W (4), Mönkemöller V (4), Konarev PV (5), Cassetta A (2), Brancaccio A (3),(6), Sciandra F (3)./titolo:A dystroglycan mutation (p.Cys66uPhe) associated to muscle-eye-brain disease with multicystic leukodystrophy results in ER-retention of the mutant protein/doi:/rivista:Human mutation/anno:2018/pagina_da:266/pagina_a:280/intervallo_pagine:266–280/volume:39 |
| بيانات النشر: | Wiley-Liss, New York , Stati Uniti d'America, 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | SAXS, confocal microscopy, dystroglycan, dystroglycanopathy, endoplasmic-reticulum retention, multicystic leukodystrophy, site-directed mutagenesis, super resolution microscopy |
| الوصف: | Dystroglycan (DG) is a cell adhesion complex composed by two subunits, the highly glycosylated ?-DG and the transmembrane ?-DG. In skeletal muscle, DG is involved in dystroglycanopathies, a group of heterogeneous muscular dystrophies characterized by a reduced glycosylation of ?-DG. The genes mutated in secondary dystroglycanopathies are involved in the synthesis of O-mannosyl glycans and in the O-mannosylation pathway of ?-DG. Mutations in the DG gene (DAG1), causing primary dystroglycanopathies, destabilize the ?-DG core protein influencing its binding to modifying enzymes. Recently, a homozygous mutation (p.Cys699Phe) hitting the ?-DG ectodomain has been identified in a patient affected by muscle-eye-brain disease with multicystic leucodystrophy, suggesting that other mechanisms than hypoglycosylation of ?-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 ?-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. |
| اللغة: | English |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=cnr_________::adbed9846b9650783ff2d45322dc2d02 http://www.cnr.it/prodotto/i/390142 |
| رقم الأكسشن: | edsair.cnr...........adbed9846b9650783ff2d45322dc2d02 |
| قاعدة البيانات: | OpenAIRE |
| الوصف غير متاح. |