Functional studies for a dominant mutation in the EDAR gene responsible for hypohidrotic ectodermal dysplasia

Abstract

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.

Comparative analysis of rare EDAR mutations and tooth agenesis pattern in EDAR ‐ and EDA ‐associated nonsyndromic oligodontia

“…The EDA/EDAR/NF‐κB pathway has been previously found to be required for normal embryogenesis, particularly in the development of tooth, hair, skin, and other ectodermal organs (Sadier, Viriot, Pantalacci, & Laudet, 2014). In this pathway, EDAR functions as a core member, interacting with its ligand, EDA, and its adaptor, EDARADD, which results in the downstream activation of NF‐κB signaling (Okita, Asano, Yasuno, & Shimomura, 2019). EDAR contains an extracellular ligand‐binding domain (LBD), a single transmembrane region, and an intracellular death domain (DD), enabling it to function as a transmembrane factor (Sadier et al, 2014).…”

Characterisation of a second gain of function EDAR variant, encoding EDAR380R, in East Asia

“…The death domain of EDAR is a highly conserved region of the protein, with mutations altering this domain commonly leading to a loss-of-function and thus clinically diagnosed hypohidrotic ectodermal dysplasia (Cluzeau et al, 2011), presumably due to altered or abrogated EDAR interaction with EDARADD (Okita et al, 2019). We identified SNV rs146567337 (EDAR:c.1138A>C) in EDAR in the gnomAD database (https://gnomad.broadinstitute.org/) (Karczewski et al, 2019).…”

A novel EDAR missense mutation identified by whole‐exome sequencing with non‐syndromic tooth agenesis in a Chinese family

“…EDAR interacts with extracellular EDA and intracellular EDARADD via the extra-and intracellular regions to form a complex. This, in turn, activates downstream NF-κB to mediate the transcription of the target gene (Kumar et al, 2001;Masui et al, 2011;Okita et al, 2019;Outi et al, 2001;Parveen et al, 2019). The c.338G>A p.( Cys113Tyr) mutation in exon 4 occurs in the LBD that binds to EDA.…”