title: Mucolipidosis III GNPTG Missense Mutations Cause Misfolding of the γ Subunit of GlcNAc-1-Phosphotransferase.
abstract: The lysosomal storage disorder ML III γ is caused by defects in the γ subunit of UDP-GlcNAc:lysosomal enzyme N-acetylglucosamine-1-phosphotransferase, the enzyme that tags lysosomal enzymes with the mannose 6-phosphate lysosomal targeting signal. In patients with this disorder, most of the newly synthesized lysosomal enzymes are secreted rather than being sorted to lysosomes, resulting in increased levels of these enzymes in the plasma. Several missense mutations in GNPTG, the gene encoding the γ subunit, have been reported in mucolipidosis III γ patients. However, in most cases, the impact of these mutations on γ subunit function has remained unclear. Here, we report that the variants c.316G>A (p.G106S), c.376G>A (p.G126S), and c.425G>A (p.C142Y) cause misfolding of the γ subunit, whereas another variant, c.857C>T (p.T286M), does not appear to alter γ subunit function. The misfolded γ subunits were retained in the ER and failed to rescue the lysosomal targeting of lysosomal acid glycosidases.
authors.affiliation: Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, 63110, USA.
authors.forename: Eline
authors.initials: E
authors.lastname: van Meel
authors.affiliation: Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, 63110, USA.
authors.forename: Stuart
authors.initials: S
authors.lastname: Kornfeld
mesh_terms: D004721:Endoplasmic Reticulum / Q000201:enzymology; D006367:HeLa Cells; D006801:Humans; D009081:Mucolipidoses / Q000235:genetics*; D020125:Mutation, Missense; D020641:Polymorphism, Single Nucleotide; D017510:Protein Folding; D017855:Transferases (Other Substituted Phosphate Groups) / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism
chemical_list: D017855:Transferases (Other Substituted Phosphate Groups); C504791:GNPTG protein, human
keywords: GNPTG; GlcNAc-1-phosphotransferase; misfolding; mucolipidosis III γ