GNPTAB – Mucolipidosis III α/β

Mucolipidosis type III α/β is an autosomal recessive lysosomal storage disorder caused by pathogenic variants in GNPTAB, encoding the α/β subunits of GlcNAc-1-phosphotransferase. Patients present with progressive joint stiffness, dysostosis multiplex, and connective tissue involvement without the severe skeletal dysplasia seen in MLII. Over 30 probands from more than 20 unrelated families have been reported with biallelic GNPTAB variants (PMID:16465621; PMID:16630736).

Segregation analysis in multiplex pedigrees confirms autosomal recessive inheritance, although explicit counts of additional affected relatives are limited. Case series include a Korean cohort of five patients and 24 patients from 21 families, all demonstrating homozygous or compound heterozygous GNPTAB mutations and concordant clinical phenotypes (PMID:16116615; PMID:16630736).

The variant spectrum comprises nonsense, frameshift, splice-site, and missense alterations distributed throughout GNPTAB. A representative splicing variant is c.771G>A (p.Leu257=), which disrupts exon 7 splicing and reduces enzyme activity to ≤3% of normal (PMID:15633164). Loss-of-function alleles such as p.Gln104Ter, p.Trp894Ter, p.His1158fs, and p.Arg1189Ter recur in multiple populations, whereas missense changes (e.g., p.Ile403Thr, p.Ser399Phe) correlate with milder MLIII phenotypes (PMID:16465621; PMID:25505245).

Functional studies demonstrate that pathogenic GNPTAB variants abolish GlcNAc-1-phosphotransferase activity in patient fibroblasts and knock-in/knock-out models. Fibroblast assays show <5% residual activity and mislocalization of lysosomal hydrolases (PMID:15633164). Rescue of enzyme function by wild-type cDNA in MLIII cell lines restores lysosomal targeting (PMID:19938078). A zebrafish model of key missense alleles reveals domain-specific effects on catalytic function and hydrolase recognition (PMID:25505245), and a mouse model of a patient truncation recapitulates growth retardation, skeletal dysplasia, and neurodegeneration (PMID:25107912).

Mechanistically, GNPTAB loss-of-function leads to deficient mannose-6-phosphate tagging of lysosomal enzymes, causing their hypersecretion and lysosomal substrate accumulation. Concordant findings across biochemical, cellular, and animal systems underscore a haploinsufficiency model for MLIII.

References

• American journal of medical genetics. Part A • 2005 • A splicing mutation in the alpha/beta GlcNAc-1-phosphotransferase gene results in an adult onset form of mucolipidosis III associated with sensory neuropathy and cardiomyopathy. PMID:15633164
• Human mutation • 2005 • Identification of mutations in the GNPTA (MGC4170) gene coding for GlcNAc-phosphotransferase alpha/beta subunits in Korean patients with mucolipidosis type II or type IIIA. PMID:16116615
• American journal of human genetics • 2006 • Mucolipidosis II (I-cell disease) and mucolipidosis IIIA (classical pseudo-hurler polydystrophy) are caused by mutations in the GlcNAc-phosphotransferase alpha / beta-subunits precursor gene. PMID:16465621
• Molecular genetics and metabolism • 2006 • When Mucolipidosis III meets Mucolipidosis II: GNPTA gene mutations in 24 patients. PMID:16630736
• American journal of medical genetics. Part A • 2009 • Molecular analysis of cell lines from patients with mucolipidosis II and mucolipidosis III. PMID:19938078
• The Journal of biological chemistry • 2014 • A novel mouse model of a patient mucolipidosis II mutation recapitulates disease pathology. PMID:25107912
• The Journal of biological chemistry • 2015 • 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. PMID:25505245

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