Characterization of EDARADD gene mutations responsible for hypohidrotic ectodermal dysplasia

被引:12
|
作者
Asano, Nobuyuki [1 ]
Yasuno, Shuichiro [1 ]
Hayashi, Ryota [2 ]
Shimomura, Yutaka [1 ]
机构
[1] Yamaguchi Univ, Dept Dermatol, Grad Sch Med, 1-1-1 Minami Kogushi, Ube, Yamaguchi 7558505, Japan
[2] Niigata Univ, Div Dermatol, Grad Sch Med & Dent Sci, Niigata, Japan
来源
JOURNAL OF DERMATOLOGY | 2021年 / 48卷 / 10期
基金
日本学术振兴会;
关键词
death domain; EDAR; EDARADD; hypohidrotic ectodermal dysplasia; TRAF6; MISSENSE MUTATION; ECTODYSPLASIN-A; TNF-RECEPTOR; DEATH DOMAIN; EDA GENE; KAPPA-B; HOMOLOG; TRAF6; PHENOTYPE; ENCODES;
D O I
10.1111/1346-8138.16044
中图分类号
R75 [皮肤病学与性病学];
学科分类号
100206 ;
摘要
Hypohidrotic ectodermal dysplasia (HED) is a genetic disorder characterized by hypohidrosis, hypodontia, and hypotrichosis. Autosomal forms of the disease are caused by mutations in either EDAR or EDARADD. To date, the underlying pathomechanisms for HED resulting from EDARADD mutations have not fully been disclosed. In this study, we performed detailed in vitro analyses in order to characterize three dominantly inherited missense mutations, p.D120Y, p.L122R, and p.D123N, and one recessively inherited missense mutation, p.E152K, in the EDARADD gene. Nuclear factor (NF)-kappa B reporter assays demonstrated that all the mutant EDARADD showed reduction in activation of NF-kappa B. Importantly, p.D120Y-, p.L122R-, and p.D123N-mutant EDARADD slightly reduced the NF-kappa B activity induced by wild-type EDARADD in a dominant negative manner. Co-immunoprecipitation assays showed that all of the mutant EDARADD were capable of binding to EDAR and wild-type EDARADD. Additional co-immunoprecipitation assays revealed that p.D120Y-, p.L122R-, and p.D123N-mutant EDARADD markedly prevented the interaction between EDAR and wild-type EDARADD, which further indicated a dominant negative effect by these mutations. Finally, we found that p.D120Y-, p.L122R-, and p.D123N-mutant EDARADD completely lost the ability to bind with TRAF6, while p.E152K-mutant EDARADD showed a mild reduction in the affinity. Our findings will provide crucial information toward unraveling the molecular mechanisms how EDARADD gene mutations cause the disease.
引用
收藏
页码:1533 / 1541
页数:9
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