The PMM2 gene provides instructions for making an enzyme called phosphomannomutase 2 (PMM2). This enzyme is involved in a process called glycosylation, which attaches groups of sugar molecules (oligosaccharides) to proteins. Oligosaccharides are made up of many small sugar molecules that are attached to one another in a long chain. Glycosylation modifies proteins so they can perform a wider variety of functions. In one of the early steps of glycosylation, the PMM2 enzyme converts a molecule called mannose-6-phosphate to mannose-1-phosphate. Subsequently, mannose-1-phosphate is converted into GDP-mannose, which can transfer its small sugar molecule called mannose to the growing oligosaccharide chain. Once the correct number of small sugar molecules are linked together to form the oligosaccharide, it can be attached to a protein.
More than 115 mutations in the PMM2 gene have been found to cause PMM2-congenital disorder of glycosylation (PMM2-CDG, also known as congenital disorder of glycosylation type Ia). This is a severe condition that is characterized by developmental delay, weak muscle tone (hypotonia), abnormal distribution of fat, and various other signs and symptoms. The mutations that cause PMM2-CDG change the structure of the PMM2 enzyme in different ways; however, all of the mutations appear to result in reduced enzyme activity. Decreased activity of the PMM2 enzyme leads to a shortage of GDP-mannose within cells. As a result, there is not enough activated mannose to form oligosaccharides. Glycosylation cannot proceed normally because incorrect oligosaccharides are produced. The signs and symptoms in PMM2-CDG are likely due to the production of abnormally glycosylated proteins in many organs and tissues.