期刊
HUMAN MUTATION
卷 35, 期 3, 页码 368-376出版社
WILEY
DOI: 10.1002/humu.22502
关键词
GNPTAB; mannose 6-phosphate; site-1 protease; lysosomal storage disorder; Golgi
资金
- Fundacao para a Ciencia e a Tecnologia (FCT) [PIC/IC/83252/2007, SFRH/BD/48103/2008]
- Deutsche Forschungsgemeinschaft [GRK1459, SFB877]
- Fundação para a Ciência e a Tecnologia [PIC/IC/83252/2007, SFRH/BD/48103/2008] Funding Source: FCT
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.
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