Mutations leading to X-linked hypohidrotic ectodermal dysplasia affect three major functional domains in the tumor necrosis factor family member ectodysplasin-A
Mutations leading to X-linked hypohidrotic ectodermal dysplasia affect three major functional domains in the tumor necrosis factor family member ectodysplasin-A
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DOI：
10.1074/jbc.m101280200
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发表时间：
2001-06-01
影响因子：
4.8
通讯作者：
Zonana, J
中科院分区：
文献类型：
--
作者：
Schneider, P;Street, SL;Zonana, J
上皮性形态原外胚层异常蛋白-A(EDA)是肿瘤坏死因子(TNF)家族的成员，它的突变是人类X连锁少汗性外胚叶发育不良(XLHED)的原因，其特征是毛发、汗腺和牙齿发育不良。EDA-A1和EDA-A2是EDA的两个剪接变异体，与不同的EDA-A1和X连锁的EDA-A2受体结合。我们在XLHED家系中发现了一系列新的EDA突变，从而能够鉴定EDA中的以下三个重要功能区域：C-末端的肿瘤坏死因子同源域、胶原域和Furin蛋白酶识别序列。肿瘤坏死因子同源域的突变会削弱两种剪接变异体与其受体的结合，胶原域的突变会抑制肿瘤坏死因子同源区的多聚化，而共同的Furin识别序列中的突变会阻止EDA的蛋白水解性切割。最后，预测影响内含子剪接供体位点的突变将特异性地消除EDA-A1，但不会消除EDA-A2剪接变异体。因此，在体内需要一种经过蛋白质降解处理的低聚形式的EDA-A1才能正常的形态发生。
Mutations in the epithelial morphogen ectodysplasin-A (EDA), a member of the tumor necrosis factor (TNF) family, are responsible for the human disorder X-linked hypohidrotic ectodermal dysplasia (XLHED) characterized by impaired development of hair, eccrine sweat glands, and teeth. EDA-A1 and EDA-A2 are two splice variants of EDA, which bind distinct EDA-A1 and X-linked EDA-A2 receptors. We identified a series of novel EDA mutations in families with XLHED, allowing the identification of the following three functionally important regions in EDA: a C-terminal TNF homology domain, a collagen domain, and a furin protease recognition sequence. Mutations in the TNF homology domain impair binding of both splice variants to their receptors, Mutations in the collagen domain can inhibit multimerization of the TNF homology region, whereas those in the consensus furin recognition sequence prevent proteolytic cleavage of EDA. Finally, a mutation affecting an intron splice donor site is predicted to eliminate specifically the EDA-A1 but not the EDA-A2 splice variant. Thus a proteolytically processed, oligomeric form of EDA-A1 is required in vivo for proper morphogenesis.