PDF(Pubmed)
Abstract：
Deficiency of ectodysplasin A1 (EDA1) due to variants of the gene EDA causes X-linked hypohidrotic ectodermal dysplasia (XLHED), a rare genetic condition characterized by abnormal development of ectodermal structures. XLHED is defined by the triad of hypotrichosis, hypo- or anhidrosis, and hypo- or anodontia. Anhidrosis may lead to life-threatening hyperthermia. A definite genetic diagnosis is, thus, important for the patients\' management and amenability to a novel prenatal treatment option. Here, we describe five familial EDA variants segregating with the disease in three families, for which different prediction tools yielded discordant results with respect to their significance. Functional properties in vitro and levels of circulating serum EDA were compared with phenotypic data on skin, hair, eyes, teeth, and sweat glands. EDA1-Gly176Val, although associated with relevant hypohidrosis, still bound to the EDA receptor (EDAR). Subjects with EDA1-Pro389LeufsX27, -Ter392GlnfsX30, -Ser125Cys, and an EDA1 splice variant (c.924+7A > G) showed complete absence of pilocarpine-induced sweating. EDA1-Pro389LeufsX27 was incapable of binding to EDAR and undetectable in serum. EDA1-Ter392GlnfsX30, produced in much lower amounts than wild-type EDA1, could still bind to EDAR, and so did EDA1-Ser125Cys that was, however, undetectable in serum. The EDA splice variant c.924+7A > G resulted experimentally in a mix of wild-type EDA1 and EDA molecules truncated in the middle of the receptor-binding domain, with reduced EDA serum concentration. Thus, in vitro assays reflected the clinical phenotype in two of these difficult cases, but underestimated it in three others. Absence of circulating EDA seems to predict the full-blown phenotype of XLHED, while residual EDA levels may also be found in anhidrotic patients. This indicates that unborn subjects carrying variants of uncertain significance could benefit from an upcoming prenatal medical treatment even if circulating EDA levels or tests in vitro suggest residual EDA1 activity.
摘要：
由于基因EDA的变异而导致的外胚层发育不良蛋白A1（EDA1）的缺乏导致X连锁的多汗性外胚层发育不良（XLHED），一种以外胚层结构发育异常为特征的罕见遗传病。XLHED是由毛癣症三联征定义的，下汗症或无汗症，和牙齿不足或无牙齿。无汗症可能导致危及生命的高热。一个明确的基因诊断是,因此，对于患者管理和适应新的产前治疗选择很重要。这里,我们描述了三个家庭中与疾病分离的五个家族性EDA变体，不同的预测工具在其意义上产生了不一致的结果。将体外功能特性和循环血清EDA水平与皮肤表型数据进行比较，头发,眼睛,牙齿,和汗腺。EDA1-Gly176Val,尽管与相关的多汗症有关，仍然与EDA受体（EDAR）结合。受试者EDA1-Pro389LeufsX27,-Ter392GlnfsX30,-Ser125Cys,EDA1剪接变体（c.9247A>G）显示完全不存在毛果芸香碱诱导的出汗。EDA1-Pro389LeufsX27不能与EDAR结合并且在血清中检测不到。EDA1-Ter392GlnfsX30的产量远低于野生型EDA1，仍然可以与EDAR结合，EDA1-Ser125Cys也是如此，然而,在血清中检测不到。EDA剪接变体c.924+7A>G在实验上导致野生型EDA1和EDA分子在受体结合域中间截短的混合物，降低EDA血清浓度。因此，体外分析反映了其中两个困难病例的临床表型，但在其他三个人中低估了它。缺乏循环EDA似乎可以预测XLHED的完整表型，而残留的EDA水平也可能在无汗症患者中发现。这表明，即使循环EDA水平或体外测试表明残留的EDA1活性，携带不确定意义变体的未出生受试者也可以从即将进行的产前医学治疗中受益。
