GNPTAB – Mucolipidosis II

Mucolipidosis type II (ML II) or I-cell disease is an autosomal recessive lysosomal storage disorder caused by biallelic pathogenic variants in GNPTAB leading to deficiency of GlcNAc-1-phosphotransferase and resultant mis-sorting of lysosomal hydrolases. Clinically, ML II presents in the prenatal or neonatal period with intrauterine growth retardation, dysostosis multiplex, coarse facial features, hyperparathyroidism, and cardiopulmonary involvement.

Genetic evidence includes compound heterozygous and homozygous loss-of-function variants identified in hundreds of unrelated ML II patients, encompassing nonsense, frameshift, and splice-site mutations that abolish enzyme activity. A landmark systematic review described 388 GNPTAB-mutated individuals across 301 publications, supporting a strong genetic association (PMID:34172897). Segregation of pathogenic variants in at least 18 independent pedigrees confirms autosomal recessive inheritance with consistent co-segregation of disease (PMID:16465621).

Representative case reports document variants such as c.3456_3459dup (p.Ile1154GlnfsTer3) in an infant with prenatal skeletal dysplasia and severe neonatal secondary hyperparathyroidism (PMID:23227064). The variant spectrum comprises recurrent deletions (e.g., c.3503_3504del (p.Leu1168GlnfsTer5)), splice defects (e.g., c.3335+1G>A), and missense mutations distributed across critical domains, with founder alleles identified in Mediterranean and Pakistani populations.

Functional studies demonstrate that loss-of-function GNPTAB mutations result in endoplasmic reticulum retention of the α/β-subunit precursor, failure of Golgi-mediated cleavage by Site-1 protease, and absence of mannose 6-phosphate tagging, as shown by retroviral transduction restoring enzyme activity in patient fibroblasts (PMID:16200072). Detailed domain analyses of missense mutations have elucidated catalytic and hydrolase-recognition motifs essential for enzyme function.

A GNPTAB patient-mutation mouse model recapitulates human ML II pathology, including growth retardation, skeletal and craniofacial abnormalities, Purkinje cell loss, and impaired motor function, thereby validating the pathogenic mechanism and providing a platform for therapeutic development (PMID:25107912).

Collectively, extensive familial segregation, large patient cohorts, functional rescue data, and animal modeling establish a definitive gene–disease relationship. GNPTAB genetic testing enables early diagnosis, prognostication, genetic counseling, and consideration of emerging enzyme-targeted therapies.

Key Take-Home: Biallelic GNPTAB variants cause ML II by disrupting mannose 6-phosphate–mediated lysosomal targeting, with definitive clinical validity and established diagnostic utility.

References

• Nature Medicine • 2005 • Mucolipidosis II is caused by mutations in GNPTA encoding the alpha/beta GlcNAc-1-phosphotransferase. PMID:16200072
• Genetics in Medicine • 2021 • Mucolipidosis type II and type III: a systematic review of 843 published cases. PMID:34172897
• Korean journal of pediatrics • 2012 • A case of mucolipidosis II presenting with prenatal skeletal dysplasia and severe secondary hyperparathyroidism at birth. PMID:23227064
• 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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