Different degree of loss‐of‐function among four missense mutations in the EDAR gene responsible for autosomal recessive hypohidrotic ectodermal dysplasia may be associated with the phenotypic severity
Different degree of loss‐of‐function among four missense mutations in the EDAR gene responsible for autosomal recessive hypohidrotic ectodermal dysplasia may be associated with the phenotypic severity
复制标题
导致常染色体隐性遗传性少汗性外胚层发育不良的 EDAR 基因四种错义突变的不同程度的功能丧失可能与表型严重程度相关
DOI：
10.1111/1346-8138.16610
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Shimomura Yutaka
中科院分区：
文献类型：
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作者：
Yagi Sasagu;Yasuno Shuichiro;Ansai Osamu;Hayashi Ryota;Shimomura Yutaka
少汗性外胚层发育不良是一种罕见疾病，其特征为少汗、牙齿发育不全和少毛症。该疾病可表现出X连锁隐性、常染色体显性或常染色体隐性遗传特征。其中，常染色体形式是由 EDA 或 EDARADD 突变引起的。迄今为止，常染色体形式的潜在病理机制或基因型-表型相关性尚未完全公开。在本研究中，我们对 EDAR 蛋白死亡结构域的四种错义突变进行了一系列体外研究：p.R358Q、p.G382S、p.I388T 和 p.T403M。结果显示，p.R358Q 和 p.T403M 突变体 EDAR 在蛋白质印迹和免疫染色中均显示出与野生型 EDAR 不同的表达模式。 NF-κB 报告基因检测表明，所有突变型 EDAR 均表现出 NF-κB 活化降低，但 p.G382S- 和 p.I388T- 突变型 EDAR 的降低程度中等。免疫共沉淀分析表明，p.R358Q-和p.T403M-突变体EDAR根本不与EDARADD结合，而p.G382S-和p.I388T-突变体EDAR在一定程度上保持了亲和力。此外，我们证明所有分析的突变 EDAR 蛋白均与 TRAF6 异常结合。数据总和表明，突变型 EDAR 蛋白的功能丧失程度不同，这可能与疾病的严重程度有关。
Hypohidrotic ectodermal dysplasia is a rare condition characterized by hypohidrosis, hypodontia, and hypotrichosis. The disease can show X‐linked recessive, autosomal dominant or autosomal recessive inheritance trait. Of these, the autosomal forms are caused by mutations in eitherEDARorEDARADD. To date, the underlying pathomechanisms or genotype–phenotype correlations for autosomal forms have not completely been disclosed. In this study, we performed a series of in vitro studies for four missense mutations in the death domain of EDAR protein: p.R358Q, p.G382S, p.I388T, and p.T403M. The results revealed that p.R358Q‐ and p.T403M‐mutant EDAR showed different expression patterns from wild‐type EDAR in both western blots and immunostainings. NF‐κB reporter assays demonstrated that all the mutant EDAR showed reduced activation of NF‐κB, but the reduction by p.G382S‐ and p.I388T‐mutant EDAR was moderate. Co‐immunoprecipitation assays showed that p.R358Q‐ and p.T403M‐mutant EDAR did not bind with EDARADD at all, whereas p.G382S‐ and p.I388T‐mutant EDAR maintained the affinity to some extent. Furthermore, we demonstrated that all the mutant EDAR proteins analyzed aberrantly bound with TRAF6. Sum of the data suggest that the degree of loss‐of‐function is different among the mutant EDAR proteins, which may be associated with the severity of the disease.