Mucolipidosis III GNPTG Missense Mutations Cause Misfolding of the γ Subunit of GlcNAc‐1‐Phosphotransferase. Issue 7 (22nd April 2016)

• Record Type: Journal Article
• Authors: van Meel, Eline; Kornfeld, Stuart
• Is Part Of: Human mutation. Volume 37:Issue 7(2016)
• Page Start: 623
• Page End: 626
• Publication Date: 2016-04-22
• Subjects: GlcNAc‐1‐phosphotransferase -- GNPTG -- misfolding -- mucolipidosis III γ; Human chromosome abnormalities -- Periodicals; Mutation (Biology) -- Periodicals; 616.04205
• DOI: 10.1002/humu.22993
• Languages: English
• ISSNs: 1059-7794

Abstract

Abstract : Analysis of GlcNAc‐1‐phosphotransferase γ subunit variants that occur in mucolipidosis III γ patients 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.