POMT2 mutations cause alpha-dystroglycan hypoglycosylation and Walker-Warburg syndrome
POMT2 mutations cause alpha-dystroglycan hypoglycosylation and Walker-Warburg syndrome
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POMT2 突变导致 α-肌营养不良聚糖低糖基化和 Walker-Warburg 综合征
DOI：
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发表时间：
2005
期刊：
影响因子：
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通讯作者：
Van Bokhoven
中科院分区：
文献类型：
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作者：
van Reeuwijk;V. Elzen;Denis Bernabé;Van Bokhoven
背景：Walker-Warburg综合征(WWS)是一种常染色体隐性遗传性疾病，以先天性肌营养不良、结构性脑缺陷和眼畸形为特征。典型的脑部异常包括脑积水、无脑、胼胝体发育不全、两半球融合、小脑发育不良和神经元过度迁移，导致鹅卵石皮质。眼部异常包括白内障、小眼球、眼球和彼得斯畸形。肌萎缩侧索硬化症患者表现出α-营养不良多糖的O-糖基化缺陷，它在肌肉和中枢神经系统细胞骨架与细胞外基质蛋白之间起着关键的桥梁作用，对肌肉的完整性和神经元的迁移非常重要。在20%的WWS患者中，低糖基化是由蛋白O-甘露糖基转移酶1(POMT1)、Fukutin或Fukutin相关蛋白(FKRP)基因突变引起的。这种高度异质性疾病的其他基因仍有待识别。目的：寻找POMT2突变作为WWS的原因，因为POMT1和POMT2都是获得蛋白O-甘露糖基转移酶活性所必需的。方法：候选基因定位与纯合子定位相结合。结果：在11个有血缘关系的WWS家系中，有4个家系的POMT2基因14q24.3存在纯合子。在这些家系中的两个以及来自六个WWS家系的另一个队列中的一名患者中，存在POMT2纯合子突变。在肌肉中的免疫组织化学显示糖基化的α-DG水平严重降低，这与POMT2在O-甘露糖化途径中的假设作用一致。结论：发现了WWS的第四个致病基因。这些基因约占WWS病例的三分之一。预计还会有更多的基因，它们可能在a-DG的糖基化过程中发挥作用。
Background: Walker-Warburg syndrome (WWS) is an autosomal recessive condition characterised by congenital muscular dystrophy, structural brain defects, and eye malformations. Typical brain abnormalities are hydrocephalus, lissencephaly, agenesis of the corpus callosum, fusion of the hemispheres, cerebellar hypoplasia, and neuronal overmigration, which causes a cobblestone cortex. Ocular abnormalities include cataract, microphthalmia, buphthalmos, and Peters anomaly. WWS patients show defective O-glycosylation of a -dystroglycan ( a -DG), which plays a key role in bridging the cytoskeleton of muscle and CNS cells with extracellular matrix proteins, important for muscle integrity and neuronal migration. In 20% of the WWS patients, hypoglycosylation results from mutations in either the protein O-mannosyltransferase 1 ( POMT1 ), fukutin , or fukutin related protein ( FKRP ) genes. The other genes for this highly heterogeneous disorder remain to be identified. Objective: To look for mutations in POMT2 as a cause of WWS, as both POMT1 and POMT2 are required to achieve protein O-mannosyltransferase activity. Methods: A candidate gene approach combined with homozygosity mapping. Results: Homozygosity was found for the POMT2 locus at 14q24.3 in four of 11 consanguineous WWS families. Homozygous POMT2 mutations were present in two of these families as well as in one patient from another cohort of six WWS families. Immunohistochemistry in muscle showed severely reduced levels of glycosylated a -DG, which is consistent with the postulated role for POMT2 in the O-mannosylation pathway. Conclusions: A fourth causative gene for WWS was uncovered. These genes account for approximately one third of the WWS cases. Several more genes are anticipated, which are likely to play a role in glycosylation of a -DG.
影响因子：
9.8
作者：
Beltran-Valero de Bernabé, D;Currier, S;Brunner, HG
通讯作者：
Brunner, HG