Mucolipidosis II-Related Mutations Inhibit the Exit from the Endoplasmic Reticulum and Proteolytic Cleavage of GlcNAc-1-Phosphotransferase Precursor Protein (GNPTAB)

• Tipo: Artigo em Revista Científica Internacional
• Data: 2014

Autores

Raffaella De Pace (Autor) Outra; Maria Francisca Coutinho (Autor) Outra; Friedrich Koch Nolte (Autor) Outra; Friedrich Haag (Autor) Outra; Maria Joao Prata (Autor) FCUP; Sandra Alves (Autor) Outra; Thomas Braulke (Autor) Outra; Sandra Pohl (Autor) Outra

Revista

Título: Human Mutation

Vol. 35

Páginas: 368-376

ISSN: 1059-7794

Editora: Wiley-Blackwell

Indexação

ISI Web of Knowledge - 17 Citações

Scopus - 18 Citações

Classificação Científica

FOS: Ciências exactas e naturais > Ciências da terra e ciências do ambiente

Outras Informações

ID Authenticus: P-009-5G3

DOI: 10.1002/humu.22502

Abstract (EN): Mucolipidosis (ML) II and MLIII alpha/beta are two pediatric lysosomal storage disorders caused by mutations in the GNPTAB gene, which encodes an alpha/beta-subunit precursor protein of GlcNAc-1-phosphotransferase. Considerable variations in the onset and severity of the clinical phenotype in these diseases are observed. We report here on expression studies of two missense mutations c.242G>T (p.Trp81Leu) and c.2956C>T (p.Arg986Cys) and two frameshift mutations c.3503_3504delTC (p.Leu1168GlnfsX5) and c.3145insC (p.Gly1049ArgfsX16) present in severely affected MLII patients, as well as two missense mutations c.1196C>T (p.Ser399Phe) and c.3707A>T (p.Lys1236Met) reported in more mild affected individuals. We generated a novel alpha-subunit-specific monoclonal antibody, allowing the analysis of the expression, subcellular localization, and proteolytic activation of wild-type and mutant alpha/beta-subunit precursor proteins by Western blotting and immunofluorescence microscopy. In general, we found that both missense and frameshift mutations that are associated with a severe clinical phenotype cause retention of the encoded protein in the endoplasmic reticulum and failure to cleave the alpha/beta-subunit precursor protein are associated with a severe clinical phenotype with the exception of p.Ser399Phe found in MLIII alpha/beta. Our data provide new insights into structural requirements for localization and activity of GlcNAc-1-phosphotransferase that may help to explain the clinical phenotype of MLII patients. Hum Mutat 35:368-376, 2014. (C) 2013 Wiley Periodicals, Inc.

Idioma: Inglês

Tipo (Avaliação Docente): Científica

Nº de páginas: 9