GNPTAB

The GNPTAB gene provides instructions for making two different parts, the alpha and beta subunits, of an enzyme called GlcNAc-1-phosphotransferase. This enzyme is made up of two alpha (α), two beta (β), and two gamma (γ) subunits. The gamma subunit is produced from a different gene, called GNPTG. GlcNAc-1-phosphotransferase helps prepare certain newly made enzymes for transport to lysosomes. Lysosomes are compartments within the cell that use digestive enzymes called hydrolases to break down large molecules into smaller ones that can be reused by cells.

GlcNAc-1-phosphotransferase is involved in the first step of making a molecule called mannose-6-phosphate (M6P). M6P acts as a tag that indicates a hydrolase should be transported to the lysosome. Specifically, GlcNAc-1-phosphotransferase transfers a molecule called GlcNAc-1-phosphate to a newly produced hydrolase. In the next step, a molecule is removed to reveal an M6P attached to the hydrolase. Once a hydrolase has an M6P tag, it can be transported to a lysosome.

mucolipidosis II alpha/beta - caused by mutations in the GNPTAB gene

Around 50 mutations in the GNPTAB gene have been found to cause mucolipidosis II alpha/beta. These mutations prevent the production of any functional GlcNAc-1-phosphotransferase. Without this enzyme, hydrolases cannot be tagged with M6P and transported to lysosomes. Instead, hydrolases end up outside the cell and have increased digestive activity. The lack of hydrolases within lysosomes causes large molecules to accumulate there. Conditions that cause molecules to build up inside lysosomes, including mucolipidosis II alpha/beta, are called lysosomal storage disorders. The signs and symptoms of mucolipidosis II alpha/beta are most likely caused by the lack of hydrolases within lysosomes and the effects these enzymes have outside the cell.

mucolipidosis III alpha/beta - caused by mutations in the GNPTAB gene

Mutations in the GNPTAB gene have also been found to cause mucolipidosis III alpha/beta. Affected individuals have mutations that result in reduced activity of GlcNAc-1-phosphotransferase, which disrupts tagging of hydrolases with M6P. Digestive enzymes that do not receive the M6P tag end up outside the cell, where they have increased activity. The shortage of these digestive enzymes within lysosomes causes large molecules to accumulate there. Mucolipidosis III alpha/beta is also considered to be a lysosomal storage disorder. The signs and symptoms of mucolipidosis III alpha/beta are most likely due to the shortage of hydrolases inside lysosomes and the effects these enzymes have outside the cell.