GNPTAB – Mucolipidosis

Autosomal recessive mutations in GNPTAB underlie mucolipidosis (MONDO:0019248), a lysosomal storage disorder characterized by aberrant trafficking of hydrolases and consequent multisystem pathology. Clinical sequencing and linkage analyses have distinguished mucolipidosis from mucopolysaccharidosis by identifying loss-of-function variants in GNPTAB, confirming genetic diagnoses and guiding clinical management.

In a Chinese family with ambiguous mucopolysaccharidosis versus mucolipidosis presentation, linkage and sequencing revealed compound heterozygosity for c.1090C>T (p.Arg364Ter) and c.2715+1G>A in GNPTAB, definitively diagnosing MLIII (1 proband) ([PMID:21549105]).

A multi-center study of 69 unrelated Indian MLII/III families identified 38 pathogenic GNPTAB variants, including missense, frameshift, splice, and deletion alleles, with a recurrent c.3503_3504delTC in MLII, supporting a broad allelic spectrum (69 probands) ([PMID:32651481]).

A clinical-laboratory correlation in 18 pedigrees confirmed 15 distinct GNPTAB mutations causing MLII or MLIIIA; genotypes correlated with residual GlcNAc-phosphotransferase activity and splicing defects, demonstrating definitive recessive segregation (18 pedigrees) ([PMID:16465621]).

Functional assays in patient fibroblasts and animal models demonstrate that truncating and splice-site mutations abolish enzyme activity and impair mannose 6-phosphate tagging, leading to lysosomal enzyme misrouting. A Gnptab-mutant mouse recapitulates human MLII phenotypes—skeletal dysplasia, neurodegeneration, elevated enzyme secretion—and validates the haploinsufficiency mechanism ([PMID:25107912]).

Together, these genetic and functional data establish a Strong clinical validity for GNPTAB–mucolipidosis association. Owing to consistent autosomal recessive inheritance, genotype–enzyme activity correlations, and robust animal models, genetic testing of GNPTAB enables definitive diagnosis, informs prognosis, and underpins therapeutic research. Key Take-home: GNPTAB sequencing is clinically essential for accurate diagnosis and management of mucolipidosis.

References

• Clinica chimica acta; international journal of clinical chemistry • 2011 • Mucolipidosis in a Chinese family with compound heterozygous mutations at the GNPTAB gene PMID:21549105
• Journal of human genetics • 2020 • Identification and characterization of 30 novel pathogenic variations in 69 unrelated Indian patients with Mucolipidosis Type II and Type III PMID:32651481
• 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
• The Journal of biological chemistry • 2014 • A novel mouse model of a patient mucolipidosis II mutation recapitulates disease pathology PMID:25107912

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