Gökdere Sare, Schneider Holm, Hehr Ute, Willen Laure, Schneider Pascal, Maier-Wohlfart Sigrun
Department of Pediatrics, Center for Ectodermal Dysplasias, University Hospital Erlangen, Erlangen, Germany.
Center for Human Genetics, Regensburg, Germany.
Front Genet. 2022 Jul 18;13:934395. doi: 10.3389/fgene.2022.934395. eCollection 2022.
Deficiency of ectodysplasin A1 (EDA1) due to variants of the gene 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 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 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, 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 suggest residual EDA1 activity.
基因变异导致外胚层发育不全蛋白A1（EDA1）缺乏会引起X连锁少汗型外胚层发育不良（XLHED），这是一种罕见的遗传病，其特征为外胚层结构发育异常。XLHED由毛发稀疏、少汗或无汗、牙齿发育不全或无牙三联征定义。无汗可能导致危及生命的高热。因此，明确的基因诊断对于患者的治疗管理以及采用新的产前治疗方案至关重要。在此，我们描述了三个家族中与疾病共分离的五个家族性EDA变异，对于这些变异，不同的预测工具在其意义方面得出了不一致的结果。将循环血清EDA的功能特性和水平与皮肤、毛发、眼睛、牙齿和汗腺的表型数据进行了比较。EDA1 - Gly176Val虽然与相关的少汗有关，但仍能与EDA受体（EDAR）结合。携带EDA1 - Pro389LeufsX27、- Ter392GlnfsX30、- Ser125Cys以及一个EDA1剪接变异（c.924 + 7A > G）的受试者显示毛果芸香碱诱导的出汗完全缺失。EDA1 - Pro389LeufsX27无法与EDAR结合且在血清中无法检测到。EDA1 - Ter392GlnfsX30的产生量比野生型EDA1低得多，但仍能与EDAR结合，EDA1 - Ser125Cys也是如此，不过在血清中无法检测到。剪接变异c.924 + 7A > G实验结果显示为野生型EDA1和在受体结合域中部截断的EDA分子的混合物，血清EDA浓度降低。因此，检测在其中两个疑难病例中反映了临床表型，但在另外三个病例中低估了表型。循环中EDA的缺失似乎预示着XLHED的典型表型，而无汗患者中也可能存在残余的EDA水平。这表明，即使循环EDA水平或检测提示存在残余的EDA1活性，携带意义不确定变异的未出生受试者也可能从即将出现的产前医学治疗中获益。
