Mutations of the POMT1 gene found in patients with Walker-Warburg syndrome lead to a defect of protein O-mannosylation.

Abstract

Walker-Warburg syndrome (WWS) is an autosomal recessive developmental disorder characterized by congenital muscular dystrophy, brain malformation, and structural eye abnormalities. WWS is due to defects in protein O-mannosyltransferase 1 (POMT1), which catalyzes the transfer of mannose to protein to form O-mannosyl glycans. POMT1 has been shown to require co-expression of another homologue, POMT2, to have activity. In the present study, mutations in POMT1 genes observed in patients with WWS were duplicated by site-directed mutagenesis. The mutant genes were co-expressed with POMT2 in Sf9 cells and assayed for protein O-mannosyltransferase activity. Expression of all mutant proteins was confirmed by Western blot, but the recombinant proteins did not show any protein O-mannosyltransferase activity. The results indicate that mutations in the POMT1 gene result in a defect of protein O-mannosylation in WWS patients. This may cause failure of binding between alpha-dystroglycan and laminin or other molecules in the extracellular matrix and interrupt normal muscular function and migration of neurons in developing brain.

• Authors: Keiko Akasaka-Manya, Hiroshi Manya, Tamao Endo
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 325 Issue 1 Pg. 75-9 (Dec 03 2004) ISSN: 0006-291X [Print] United States
• PMID: 15522202 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DAG1 protein, human
• Dystroglycans
• Mannosyltransferases
• protein O-mannosyltransferase

Topics

• Abnormalities, Multiple (genetics)
• Animals
• Brain (abnormalities)
• Cell Line
• Dystroglycans (metabolism)
• Eye Abnormalities (genetics)
• Genes, Recessive
• Humans
• Mannosyltransferases (genetics, metabolism)
• Muscular Dystrophies (genetics)
• Mutagenesis, Site-Directed
• Syndrome