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

• Type: Article in International Scientific Journal
• Date: 2014

Authors

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

Journal

Title: Human Mutation

Vol. 35

Pages: 368-376

ISSN: 1059-7794

Publisher: Wiley-Blackwell

Indexing

ISI Web of Knowledge - 17 Citations

Scopus - 18 Citations

Scientific classification

FOS: Natural sciences > Earth and related Environmental sciences

Other information

Authenticus ID: 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.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 9