Biological functions of O-mannosyl glycans

O-甘露糖聚糖存在于大脑、神经和骨骼肌中数量有限的糖蛋白中。α-抗肌营养不良蛋白是一种O-甘露糖化蛋白，是抗肌营养不良蛋白-糖蛋白复合体的中心成分，已被证明与肌营养不良症的发病有关。我们已经鉴定并鉴定了与O-甘露糖β1，2-N-乙酰氨基葡萄糖基转移酶、O-甘露糖基转移酶1和2有关的糖基转移酶，它们参与了O-甘露糖的生物合成。我们随后发现POMGNT1基因的功能丧失与肌肉-眼-脑疾病(MEB)有关。也有报道称POMT1/2基因与Walker-Warburg综合征(WWS)有关。我们发现POMT1与POMT2形成了一个复合体，该复合体具有蛋白O-甘露糖基转移酶活性。结果表明，POMT1和POMT2在体内具有物理和功能上的相关性。最近，据报道，与典型的WWS相比，表型较轻的患者的pomp基因发生了三个突变。我们将这些突变体POMT1与POMT2共表达，发现它们都没有任何活性。然而，所有的POMT1突变体，包括先前鉴定的POMT1突变体，都与POMT2共沉淀。这些结果表明，突变的POMT1可以与POMT2形成杂化络合物，但这种杂化络合物不足以发挥酶的活性。我们还表明，在果蝇中，dPOMT1和dPOMT2都是功能酶活动所必需的，有助于体内正常的肌肉发育。最后，我们展示了Fukutin和POMGNT1之间的相互作用。缺陷型组织中POMGNT1活性的降低可能表明，FUKUTIN-POMGNT1复合体的形成对α-DYSTROGAN的功能糖基化是至关重要的。这些结果表明，α-Dystroglan的O-甘露糖化在肌肉和脑的发育中是重要的。

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.