Biological functions of O-mannosyl glycans

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The O-mannosyl glycan is present in a limited number of glycoproteins of brain, nerve, and skeletal muscle. α-Dystroglycan is one of the O-mannosylated proteins and is a central component of the dystrophin-glycoprotein complex that has been shown to be related to the onset of muscular dystrophy. We have identified and characterized glycosyltransferases, protein O-mannose β1,2-N-acetylglucosaminyltransferase (POMGnT1) and protein O-mannosyltransferase 1 (POMT1) and POMT2, involved in the biosynthesis of O-mannosyl glycans. We subsequently found that loss of function of the POMGnT1 gene is responsible for muscle-eye-brain disease (MEB). It has also been reported that the POMT1/2 genes are responsible for Walker-Warburg syndrome (WWS). We show that POMT1 forms a complex with POMT2, and the complex possesses protein O-mannosyltransferase activity. Results indicate that POMT1 and POMT2 associate physically and functionally in vivo. Recently, three mutations were reported in the POMP gene of patients who showed milder phenotypes than typical WWS. We coexpressed these mutant POMT1s with POMT2 and found that none of them had any activity. However, all POMT1 mutants including previously identified POMT1 mutants coprecipitated with POMT2. These results indicate that the mutant POMTls could form heterocomplexes with POMT2 but that such complexes are insufficient for enzymatic activity. We also show that, in Drosophila, both dPOMT1 and dPOMT2 are required for functional enzymatic activity to contribute to normal muscle development in vivo. Finally, we demonstrate an interaction between fukutin and POMGnT1. Decreases in the POMGnT1 activity in fukutin-deficient tissues may indicate that the formation of the fukutin-POMGnT1 complex is crucial for functional glycosylation of α-dystroglycan. These results indicate that O-mannosylation of α-dystroglycan is important in muscle and brain development.