Mutations in the O-mannosyltransferase gene POMT1 give rise to the severe neuronal migration disorder Walker-Warburg syndrome
Mutations in the O-mannosyltransferase gene POMT1 give rise to the severe neuronal migration disorder Walker-Warburg syndrome
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DOI：
10.1086/342975
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发表时间：
2002-11-01
影响因子：
9.8
通讯作者：
Brunner, HG
中科院分区：
文献类型：
--
作者：
Beltran-Valero de Bernabé, D;Currier, S;Brunner, HG
沃克 - 瓦尔堡综合征（WWS）是一种常染色体隐性发育障碍，其特征为先天性肌营养不良以及复杂的脑和眼异常。另外两种人类疾病，即肌 - 眼 - 脑疾病（MEB）和福山先天性肌营养不良（FCMD）也呈现出类似的症状组合。尽管FCMD（福库廷蛋白基因）和MEB（蛋白O - 甘露糖基 - β - 1,2 - N - 乙酰氨基葡萄糖基转移酶1基因，POMGnT1）的相关基因已被克隆，但WWS的基因位点仍然难以确定。POMGnT1和福库廷蛋白的产物都与蛋白质糖基化有关。为了揭示WWS的遗传基础，我们首先在10个患有WWS的近亲家族中进行了全基因组连锁分析。结果表明至少存在三个WWS基因位点。随后，我们在15个患有WWS的近亲家族中采用候选基因方法并结合纯合性定位。候选基因是根据FCMD和MEB基因的作用来选择的。由于POMGnT1编码一种O - 甘露糖苷N - 乙酰氨基葡萄糖基转移酶，我们分析了O - 甘露糖聚糖合成在WWS中的可能影响。对O - 甘露糖基转移酶1（POMT1）基因位点的分析显示，15个家族中有5个家族存在纯合性。对POMT1基因进行测序，在30名无亲缘关系的WWS患者中有6名发现了突变。在鉴定出的5种突变中，2种是无义突变，2种是移码突变，1种是错义突变。对具有POMT1突变的患者的肌肉进行免疫组织化学分析，证实了O - 甘露糖基化缺陷，这是通过α - dystroglycan糖基化缺失来判断的。O - 甘露糖基化在MEB和WWS中的作用为理解神经元迁移的分子基础提供了新的研究方向。
Walker-Warburg syndrome (WWS) is an autosomal recessive developmental disorder characterized by congenital muscular dystrophy and complex brain and eye abnormalities. A similar combination of symptoms is presented by two other human diseases, muscle-eye-brain disease (MEB) and Fukuyama congenital muscular dystrophy (FCMD). Although the genes underlying FCMD (Fukutin) and MEB (POMGnT1) have been cloned, loci for WWS have remained elusive. The protein products of POMGnT1 and Fukutin have both been implicated in protein glycosylation. To unravel the genetic basis of WWS, we first performed a genomewide linkage analysis in 10 consanguineous families with WWS. The results indicated the existence of at least three WWS loci. Subsequently, we adopted a candidate-gene approach in combination with homozygosity mapping in 15 consanguineous families with WWS. Candidate genes were selected on the basis of the role of the FCMD and MEB genes. Since POMGnT1 encodes an O-mannoside N-acetylglucosaminyltransferase, we analyzed the possible implication of O-mannosyl glycan synthesis in WWS. Analysis of the locus for O-mannosyltransferase 1 (POMT1) revealed homozygosity in 5 of 15 families. Sequencing of the POMT1 gene revealed mutations in 6 of the 30 unrelated patients with WWS. Of the five mutations identified, two are nonsense mutations, two are frameshift mutations, and one is a missense mutation. Immunohistochemical analysis of muscle from patients with POMT1 mutations corroborated the O-mannosylation defect, as judged by the absence of glycosylation of alpha-dystroglycan. The implication of O-mannosylation in MEB and WWS suggests new lines of study in understanding the molecular basis of neuronal migration.