Mutation identification in a canine model of X-linked ectodermal dysplasia
Mutation identification in a canine model of X-linked ectodermal dysplasia
复制标题
DOI：
10.1007/s00335-004-2463-4
复制
发表时间：
2005-07-01
期刊：
影响因子：
2.5
通讯作者：
Werner, P
中科院分区：
文献类型：
--
作者：
Casal, ML;Scheidt, JL;Werner, P
X连锁少汗性外胚叶发育不良(XHED)是一种在人类、小鼠和牛身上发现的遗传性疾病，其特征是毛少、汗腺数量减少或缺乏，以及牙齿缺失或畸形。在一组受影响的个体和动物中，已发现编码胞外异型蛋白的EDA基因(以前称为EDI)突变导致了这种表型。胞外障碍蛋白是一种具有细胞外肿瘤坏死因子样结构域的同源三聚体跨膜蛋白，已被证明参与了胎儿发育过程中毛囊和牙蕾的形态发生。一些人类XHED患者也有并发的免疫缺陷，原因是核因子-kappa B基本调节器蛋白(IKBKG；以前的NEMO)突变，该蛋白也在X染色体上编码。在一群患有XHED的繁殖犬中，免疫系统缺陷被怀疑是因为频繁的肺部感染和肺炎导致的意外死亡。为了确定EDA或IKBKG中的缺陷是否会导致犬的XHED，进行了连锁分析和测序实验。犬EDA基因附近的一个多态标记与XHED存在显著连锁。对犬EDA基因进行了测序，并在病犬中检测到内含子8剪接受体位置的核苷酸替换(G到A)。在A残基存在的情况下，外显子9内的隐蔽受体位点被使用，导致框架移位和使用过早终止密码子，从而截断两种异构体EDA-A1和EDA-A2的翻译，导致缺乏肿瘤坏死因子样的同源结构域，即外胚胞浆蛋白的受体结合部位。
X-linked hypohidrotic ectodermal dysplasia (XHED), an inherited disease recognized in humans, mice, and cattle, is characterized by hypotrichosis, a reduced number or absence of sweat glands, and missing or malformed teeth. in a subset of affected individuals and animals, mutations in the EDA gene (formerly EDI), coding for ectodysplasin, have been found to cause this phenotype. Ectodysplasin is a homotrimeric transmembrane protein with an extracellular TNF-like domain, which has been shown to be involved in the morphogenesis of hair follicles and tooth buds during fetal development. Some human XHED patients also have concurrent immunodeficiency, due to mutations in the NF-kappa B essential modulator protein (IKBKG; formerly NEMO), which is also encoded on the X chromosome. In a breeding colony of dogs with XHED, immune system defects had been suspected because of frequent pulmonary infections and unexpected deaths resulting from pneumonia. To determine if defects in EDA or IKBKG cause XHED in the dogs, linkage analysis and sequencing experiments were performed. A polymorphic marker near the canine EDA gene showed significant linkage to XHED. The canine EDA gene was sequenced and a nucleotide substitution (G to A) in the splice acceptor site of intron 8 was detected in affected dogs. In the presence of the A residue, a cryptic acceptor site within exon 9 is used, leading to a frame shift and use of a premature stop codon that truncates the translation of both isoforms, EDA-A1 and EDA-A2, resulting in the absence of the TNF-like homology domain, the receptor-binding site of ectodysplasin.