Hypohidrotic ectodermal dysplasia (HED) is a rare genetic disorder characterized by hypotrichosis, hypohidrosis and hypodontia. The disease shows X‐linked recessive, autosomal dominant or autosomal recessive inheritance traits. The X‐linked form of HED is caused by mutations in the EDA gene, while autosomal forms result from mutations in either EDAR or EDARADD genes. Regarding recessive mutations in the EDAR gene, the pathomechanisms have been well characterized. However, it has remained largely unknown how dominant mutations in the EDAR cause HED. In this study, we performed in vitro analyses for a dominant EDAR gene mutation, p.F398*, as a representative. We showed that the p.F398* mutant EDAR completely lost its affinity to EDARADD, and suppressed the downstream nuclear factor‐κB activation induced by wild‐type EDAR in a dominant‐negative manner. Furthermore, we demonstrated that the mutant EDAR was capable of binding with the wild‐type EDAR, which led to reduced interaction between the wild‐type EDAR and EDARADD. Our findings not only underscore an essential role of the interaction between EDAR and EDARADD in ectodermal development, but also disclose, in part, the molecular basis of autosomal dominant HED.
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)-κB reporter assays demonstrated that all the mutant EDARADD showed reduction in activation of NF-κB.Importantly, p.D120Y-, p.L122R-, and p.D123N-mutant EDARADD slightly reduced the NF-κB activity induced by wild-type EDARADD in a dominant negative manner. Coimmunoprecipitation 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.
Generalized pustular psoriasis (GPP) is the most severe form of psoriasis and is characterized by sudden onset of diffuse skin rushes with sterile pustule formation, high fever, high leukocyte count, and high levels of C reactive protein in the serum. 1,2 These episodic attacks can be induced by several distinct factors, such as pregnancy, infections, or medicines. It is known that psoriasis vulgaris (PV) can eventually progress to GPP.In recent years, the underlying genetic basis for GPP has gradually been disclosed. Firstly, Marrakchi et al. have reported that Tunisian patients with GPP carried bi-allelic loss-of-function mutations in IL36RN gene encoding interleukin (IL)-36 receptor antagonist, and thus, the disease caused by IL36RN gene mutations is also known as deficiency of interleukin 36 receptor antagonist (DITRA;Online Mendelian Inheritance in Man [OMIM] 614 204). 2 Mutations in the IL36RN gene have also been identified in Japanese patients with GPP, who tended to show an early onset and were not preceded by PV. 3 Soon after that, mono-allelic gain-of-function mutations in CARD14 gene have been reported to be a strong risk factor of GPP. 4 In the Japanese population, it has been demonstrated that a mono-allelic CARD14 gene variant c.526G>C (p.Asp176His) showed a significant association with GPP which progressed from PV. 5 Later on, mono-allelic loss-of-function mutations in AP1S3 gene have been identified in affected individuals with GPP (OMIM 616106). 6 Most recently, SERPINA3 and MPO have been reported as additional causative/susceptibility genes for GPP. [7][8][9] Of these, the MPO gene encodes myeloperoxidase (MPO) which is a lysosomal
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