Publication
Mucolipidosis II-Related Mutations Inhibit the Exit from the Endoplasmic Reticulum and Proteolytic Cleavage of GlcNAc-1-Phosphotransferase Precursor Protein (GNPTAB)
| dc.contributor.author | De Pace, Raffaella | |
| dc.contributor.author | Coutinho, Maria Francisca | |
| dc.contributor.author | Koch-Nolte, Friedrich | |
| dc.contributor.author | Haag, Friedrich | |
| dc.contributor.author | Prata, Maria João | |
| dc.contributor.author | Alves, Sandra | |
| dc.contributor.author | Braulke, Thomas | |
| dc.contributor.author | Pohl, Sandra | |
| dc.date.accessioned | 2014-03-14T16:09:34Z | |
| dc.date.available | 2014-03-14T16:09:34Z | |
| dc.date.issued | 2014-03 | |
| dc.description.abstract | Mucolipidosis (ML) II and MLIII alpha/beta are two pediatric lysosomal storage disorders caused by mutations in the GNPTAB gene, which encodes an α/β-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 α-subunit-specific monoclonal antibody, allowing the analysis of the expression, subcellular localization, and proteolytic activation of wild-type and mutant α/β-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 α/β-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 | por |
| dc.description.sponsorship | Contract grant sponsors: Fundac¸ao para a Ciência e a Tecnologia (FCT) (PIC/IC/83252/2007, SFRH/BD/48103/2008); Deutsche Forschungsgemeinschaft (GRK1459, SFB877). | por |
| dc.identifier.citation | Hum Mutat. 2014 Mar;35(3):368-76. doi: 10.1002/humu.22502. Epub 2014 Jan 15 | por |
| dc.identifier.other | doi: 10.1002/humu.22502. | |
| dc.identifier.uri | http://hdl.handle.net/10400.18/2136 | |
| dc.language.iso | eng | por |
| dc.peerreviewed | yes | por |
| dc.publisher | Wiley/ Human Genome Variation Society | por |
| dc.relation.publisherversion | http://onlinelibrary.wiley.com/doi/10.1002/humu.22502/full | por |
| dc.subject | GNPTAB | por |
| dc.subject | Golgi | por |
| dc.subject | Lysosomal Storage Disorder | por |
| dc.subject | Mannose 6-phosphate | por |
| dc.subject | Site-1 Protease | por |
| dc.subject | Doenças Genéticas | por |
| dc.title | Mucolipidosis II-Related Mutations Inhibit the Exit from the Endoplasmic Reticulum and Proteolytic Cleavage of GlcNAc-1-Phosphotransferase Precursor Protein (GNPTAB) | por |
| dc.type | journal article | |
| dspace.entity.type | Publication | |
| oaire.citation.endPage | 376 | por |
| oaire.citation.startPage | 368 | por |
| oaire.citation.title | Human Mutation | por |
| oaire.citation.volume | 35(3) | por |
| rcaap.rights | restrictedAccess | por |
| rcaap.type | article | por |