GNPTAB

GNPTAB stands for the gene encoding the alpha and beta subunits of UDP-N-acetylglucosamine-1-phosphotransferase, a Golgi-localized enzyme involved in lysosomal enzyme targeting. The encoded protein forms the catalytic alpha and beta components of GlcNAc-1-phosphotransferase, which initiates the attachment of mannose-6-phosphate (M6P) tags to lysosomal hydrolases, a modification required for their recognition by M6P receptors and delivery to lysosomes. The enzyme is expressed in the Golgi of most cell types that produce lysosomal enzymes and is processed into distinct polypeptides in the course of maturation.

GNPTAB mutations cause mucolipidosis II (I-cell disease) and mucolipidosis III alpha/beta. In these disorders, reduced or absent GlcNAc-1-phosphotransferase activity impairs M6P tagging, causing lysosomal hydrolases to be misdirected and secreted outside the cell rather than delivered to lysosomes. This leads to lysosomal substrate accumulation and a multisystemic clinical phenotype. Mucolipidosis II typically presents in infancy with severe developmental delay, skeletal abnormalities, coarse facial features, and failure to thrive, whereas mucolipidosis III alpha/beta usually has a later onset and a milder course.

Inheritance is autosomal recessive. Diagnosis combines clinical features with biochemical tests showing elevated lysosomal enzyme activity in plasma and reduced or absent GlcNAc-1-phosphotransferase activity, and is confirmed by GNPTAB gene sequencing. There is no cure, and management is supportive and multidisciplinary, focusing on symptom control and addressing organ-specific complications. A related gene, GNPTG, encodes the gamma subunit of the same enzyme complex.