GNPTAB missense mutations cause loss of GlcNAc-1-phosphotransferase activity in mucolipidosis type II through distinct mechanisms |
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| Affiliation: | 1. Servicio de Hematología y Oncología Médica, Hospital Universitario Morales Meseguer, Centro Regional de Hemodonación, Universidad de Murcia, IMIB-Arrixaca, CIBERER, Murcia, Spain;2. Servicio de Hematología. Hospital Virgen del Castillo de Yecla, Murcia, Spain;1. Department of Pediatrics, PUMC Hospital, CAMS&PUMC, Beijing 100730, PR China;2. Clinical Research Laboratory, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, PR China;3. Department of Medical Genetics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, PR China;1. Department of Biochemical Genetics, Division of Human Genetics and Genome Research, National Research Centre, Dokki12311, Cairo, Egypt;2. Department of Biochemistry, Faculty of pharmacy (Girls), Al Azhar University, Cairo, Egypt;3. Department of Medical Molecular Genetics, Division of Human Genetics and Genome Research, National Research Centre, Dokki12311, Cairo, Egypt;4. Department of Clinical Genetics, Division of Human Genetics and Genome Research, National Research Centre, Dokki12311, Cairo, Egypt |
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| 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.Q278Kfs*3, p.H588Qfs*27, p.N642Lfs*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. |
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| Keywords: | Lysosomal storage disorder Mannose 6-phosphate Genotype-phenotype relation Missense mutations Site-1 protease |
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