title: 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.affiliation: Glycobiology Research Group, Tokyo Metropolitan Institute of Gerontology, Foundation for Research on Aging and Promotion of Human Welfare, 35-2 Sakaecho, Itabashi-ku, Tokyo 173-0015, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Akasaka-Manya
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Manya
authors.forename: Tamao
authors.initials: T
authors.lastname: Endo
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D000818:Animals; D001921:Brain / Q000002:abnormalities; D002460:Cell Line; D049030:Dystroglycans / Q000378:metabolism; D005124:Eye Abnormalities / Q000235:genetics; D005808:Genes, Recessive; D006801:Humans; D008364:Mannosyltransferases / Q000235:genetics* / Q000378:metabolism*; D009136:Muscular Dystrophies / Q000235:genetics; D016297:Mutagenesis, Site-Directed; D013577:Syndrome
chemical_list: C483081:DAG1 protein, human; D049030:Dystroglycans; D008364:Mannosyltransferases; C082696:protein O-mannosyltransferase