ArticleThe Journal of biological chemistry2015
Analysis of mucolipidosis II/III GNPTAB missense mutations identifies domains of UDP-GlcNAc:lysosomal enzyme GlcNAc-1-phosphotransferase involved in catalytic function and lysosomal enzyme recognition.
Article in The Journal of biological chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 45 citations in OpenAlex.
- Relevance of functional studies for assessing an antisense oligonucleotide-mediated exon skipping therapeutic strategy for mucolipidosis type II.Orphanet journal of rare diseases · 2026Article
- Multi-omic analysis of a mucolipidosis II neuronal cell model uncovers involvement of pathways related to neurodegeneration and drug metabolism.Molecular genetics and metabolism · 2024Article
- Multiplex tandem mass spectrometry enzymatic activity assay for the screening and diagnosis of Mucolipidosis type II and III.Molecular genetics and metabolism reports · 2023Article
- Zebra-Sphinx: Modeling Sphingolipidoses in Zebrafish.International journal of molecular sciences · 2023Review
- Outcomes after HSCT for mucolipidosis II (I-cell disease) caused by novel compound heterozygous GNPTAB mutations.Frontiers in pediatrics · 2023Article
- GCAF(TMEM251) regulates lysosome biogenesis by activating the mannose-6-phosphate pathway.Nature communications · 2022Article
- Structures of the mannose-6-phosphate pathway enzyme, GlcNAc-1-phosphotransferase.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Structure of the human GlcNAc-1-phosphotransferase αβ subunits reveals regulatory mechanism for lysosomal enzyme glycan phosphorylation.Nature structural & molecular biology · 2022Article
- Identification and characterization of 30 novel pathogenic variations in 69 unrelated Indian patients with Mucolipidosis Type II and Type III.Journal of human genetics · 2020Article
- Mucolipidoses Overview: Past, Present, and Future.International journal of molecular sciences · 2020Review
- Disease-causing missense mutations within the N-terminal transmembrane domain of GlcNAc-1-phosphotransferase impair endoplasmic reticulum translocation or Golgi retention.Human mutation · 2020Article
- Upregulation of Sortilin, a Lysosomal Sorting Receptor, Corresponds with Reduced Bioavailability of Latent TGFβ in Mucolipidosis II Cells.Biomolecules · 2020Article
- Modeling Lysosomal Storage Diseases in the Zebrafish.Frontiers in molecular biosciences · 2020Review
- Identification of predominant GNPTAB gene mutations in Eastern Chinese patients with mucolipidosis II/III and a prenatal diagnosis of mucolipidosis II.Acta pharmacologica Sinica · 2019Article
- Clinical implementation of gene panel testing for lysosomal storage diseases.Molecular genetics & genomic medicine · 2019Article
- Compound heterozygousInternational journal of clinical and experimental pathology · 2019Article
- Recycling of Golgi glycosyltransferases requires direct binding to coatomer.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- Altered Met receptor phosphorylation and LRP1-mediated uptake in cells lacking carbohydrate-dependent lysosomal targeting.The Journal of biological chemistry · 2017Article
- Article
- Pharmaceutical Chaperones and Proteostasis Regulators in the Therapy of Lysosomal Storage Disorders: Current Perspective and Future Promises.Frontiers in pharmacology · 2017Review
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
UDP-GlcNAc:lysosomal enzyme GlcNAc-1-phosphotransferase tags newly synthesized lysosomal enzymes with mannose 6-phosphate recognition markers, which are required for their targeting to the endolysosomal system. GNPTAB encodes the α and β subunits of GlcNAc-1-phosphotransferase, and mutations in this gene cause the lysosomal storage disorders mucolipidosis II and III αβ. Prior investigation of missense mutations in GNPTAB uncovered amino acids in the N-terminal region and within the DMAP domain involved in Golgi retention of GlcNAc-1-phosphotransferase and its ability to specifically recognize lysosomal hydrolases, respectively. Here, we undertook a comprehensive analysis of the remaining missense mutations in GNPTAB reported in mucolipidosis II and III αβ patients using cell- and zebrafish-based approaches. We show that the Stealth domain harbors the catalytic site, as some mutations in these regions greatly impaired the activity of the enzyme without affecting its Golgi localization and proteolytic processing. We also demonstrate a role for the Notch repeat 1 in lysosomal hydrolase recognition, as missense mutations in conserved cysteine residues in this domain do not affect the catalytic activity but impair mannose phosphorylation of certain lysosomal hydrolases. Rescue experiments using mRNA bearing Notch repeat 1 mutations in GNPTAB-deficient zebrafish revealed selective effects on hydrolase recognition that differ from the DMAP mutation. Finally, the mutant R587P, located in the spacer between Notch 2 and DMAP, was partially rescued by overexpression of the γ subunit, suggesting a role for this region in γ subunit binding. These studies provide new insight into the functions of the different domains of the α and β subunits.
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