The transmembrane protein meckelin (MKS3) is mutated in Meckel-Gruber syndrome and the wpk rat
The transmembrane protein meckelin (MKS3) is mutated in Meckel-Gruber syndrome and the wpk rat
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DOI：
10.1038/ng1713
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发表时间：
2006-02-01
期刊：
影响因子：
30.8
通讯作者：
Johnson, CA
中科院分区：
文献类型：
--
作者：
Smith, UM;Consugar, M;Johnson, CA
Meckel-Gruber综合征是一种严重的常染色体隐性遗传疾病，其特征为双侧肾囊性发育不良、中枢神经系统发育缺陷（最常见的是枕部脑膨出）、肝导管发育不良、囊肿和多趾畸形（1-3）。MKS具有遗传异质性，有三个位点：MKS1, 17q21-24（参考文献4）；MKS2, 11q13 （ref. 5）和MKS3 （ref. 6）。我们将MKS3定位到12.67 mb的区间（8q21.13-q22.1），这与大鼠的Wpk位点一致，大鼠是多囊肾病、胼胝体发育和脑积水的模型（7,8）。Wpk基因的定位克隆提示了一个MKS3候选基因TMEM67，我们在5个MKS3连锁的近亲家族中发现了致病突变。MKS3是一种以前未被发现的、进化上保守的基因，在胎儿的大脑、肝脏和肾脏中以中等水平表达，但具有广泛的低水平表达。它编码一种由995个氨基酸组成的七跨膜受体蛋白，这种蛋白的功能未知，我们称之为麦胶蛋白。
Meckel-Gruber syndrome is a severe autosomal, recessively inherited disorder characterized by bilateral renal cystic dysplasia, developmental defects of the central nervous system ( most commonly occipital encephalocele), hepatic ductal dysplasia and cysts and polydactyly(1-3). MKS is genetically heterogeneous, with three loci mapped: MKS1, 17q21-24 (ref. 4); MKS2, 11q13 ( ref. 5) and MKS3 ( ref. 6). We have refined MKS3 mapping to a 12.67-Mb interval (8q21.13-q22.1) that is syntenic to the Wpk locus in rat, which is a model with polycystic kidney disease, agenesis of the corpus callosum and hydrocephalus(7,8). Positional cloning of the Wpk gene suggested a MKS3 candidate gene, TMEM67, for which we identified pathogenic mutations for five MKS3-linked consanguineous families. MKS3 is a previously uncharacterized, evolutionarily conserved gene that is expressed at moderate levels in fetal brain, liver and kidney but has widespread, low levels of expression. It encodes a 995 - amino acid seven-transmembrane receptor protein of unknown function that we have called meckelin.