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GNPTAB missense mutations cause loss of GlcNAc-1-phosphotransferase activity in mucolipidosis type II through distinct mechanisms.
- Source :
-
International Journal of Biochemistry & Cell Biology . Nov2017, Vol. 92, p90-94. 5p. - Publication Year :
- 2017
-
Abstract
- Mucolipidoses (ML) II and III alpha/beta are lysosomal storage diseases caused by pathogenic mutations in GNPTAB encoding the α⁄β-subunit precursor of GlcNAc-1-phosphotransferase. To determine genotype-phenotype correlation and functional analysis of mutant GlcNAc-1-phosphotransferase, 13 Brazilian patients clinically and biochemical diagnosed for MLII or III alpha/beta were studied. By sequencing of genomic GNPTAB of the MLII and MLIII alpha/beta patients we identified six novel mutations: p.D76G, p.S385L, p.Q278K fs *3, p.H588Q fs *27, p.N642L fs *10 and p.Y1111*. Expression analysis by western blotting and immunofluorescence microscopy revealed that the mutant α⁄β-subunit precursor p.D76G is retained in the endoplasmic reticulum whereas the mutant p.S385L is correctly transported to the cis -Golgi apparatus and proteolytically processed. Both mutations lead to complete loss of GlcNAc-1-phosphotransferase activity, consistent with the severe clinical MLII phenotype of the patients. Our study expands the genotypic spectrum of MLII and provides novel insights into structural requirements to ensure GlcNAc-1-phosphotransferase activity. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 13572725
- Volume :
- 92
- Database :
- Academic Search Index
- Journal :
- International Journal of Biochemistry & Cell Biology
- Publication Type :
- Academic Journal
- Accession number :
- 125945254
- Full Text :
- https://doi.org/10.1016/j.biocel.2017.09.006