Dataset Information

Mucolipidosis III GNPTG Missense Mutations Cause Misfolding of the ? Subunit of GlcNAc-1-Phosphotransferase.

ABSTRACT: The lysosomal storage disorder ML III ? is caused by defects in the ? 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 ? subunit, have been reported in mucolipidosis III ? patients. However, in most cases, the impact of these mutations on ? 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 ? subunit, whereas another variant, c.857C>T (p.T286M), does not appear to alter ? subunit function. The misfolded ? subunits were retained in the ER and failed to rescue the lysosomal targeting of lysosomal acid glycosidases.

SUBMITTER: van Meel E

PROVIDER: S-EPMC4907843 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Mucolipidosis III GNPTG Missense Mutations Cause Misfolding of the γ Subunit of GlcNAc-1-Phosphotransferase.

van Meel Eline E Kornfeld Stuart S

Human mutation 20160422 7

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 ...[more]

PMID: 27038293

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Project description:Mucolipidosis II (MLII; I-cell disease) and mucolipidosis IIIA (MLIIIA; classical pseudo-Hurler polydystrophy) are diseases in which the activity of the uridine diphosphate (UDP)-N-acetylglucosamine:lysosomal enzyme N-acetylglucosamine-1-phosphotransferase (GlcNAc-phosphotransferase) is absent or reduced, respectively. In the absence of mannose phosphorylation, trafficking of lysosomal hydrolases to the lysosome is impaired. In these diseases, mistargeted lysosomal hydrolases are secreted into the blood, resulting in lysosomal deficiency of many hydrolases and a storage-disease phenotype. To determine whether these diseases are caused by mutations in the GlcNAc-phosphotransferase alpha / beta -subunits precursor gene (GNPTAB), we sequenced GNPTAB exons and flanking intronic sequences and measured GlcNAc-phosphotransferase activity in patient fibroblasts. We identified 15 different mutations in GNPTAB from 18 pedigrees with MLII or MLIIIA and demonstrated that these two diseases are allelic. Mutations in both alleles were identified in each case, which demonstrated that GNPTAB mutations are the cause of both diseases. Some pedigrees had identical mutations. One frameshift mutation (truncation at amino acid 1171) predominated and was found in both MLII and MLIIIA. This mutation was found in combination with severe mutations (i.e., mutations preventing the generation of active enzyme) in MLII and with mild mutations (i.e., mutations allowing the generation of active enzyme) in MLIIIA. Some cases of MLII and MLIIIA were the result of mutations that cause aberrant splicing. Substitutions were inside the invariant splice-site sequence in MLII and were outside it in MLIIIA. When the mutations were analyzed along with GlcNAc-phosphotransferase activity, it was possible to confidently distinguish these two clinically related but distinct diseases. We propose criteria for distinguishing these two disorders by a combination of mutation detection and GlcNAc-phosphotransferase activity determination.

Dataset Information

Mucolipidosis III GNPTG Missense Mutations Cause Misfolding of the ? Subunit of GlcNAc-1-Phosphotransferase.

Publications

Mucolipidosis III GNPTG Missense Mutations Cause Misfolding of the γ Subunit of GlcNAc-1-Phosphotransferase.

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