A Novel Missense Mutation at EDA2R Gene Identified in a Case Study Associated with Hypohidrotic Ectodermal Dysplasia

Article A Novel Missense Mutation at EDA2R Gene Identified in a Case Study Associated with Hypohidrotic Ectodermal Dysplasia Wan Yang 1,†, Siyu Jin 1,†, Jie Jiang 1, Wei Ji 1,2,*,‡ and Qing He 1,*,‡ 1 State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430000, China 2 Department of Implantology, School & Hospital of Stomatology, Wuhan University, Wuhan 430000, China * Correspondence: [email protected] (W.J.); [email protected] (Q.H.); Tel.: +86-131-0061-5376 (W.J.); +86-183-2719-2492 (Q.H.) † These authors contributed equally as first authors. ‡ These authors share equal senior authorships. Received: 3 January 2025; Revised: 11 February 2025; Accepted: 25 February 2025; Published: 11 March 2025 Abstract: Hypohidrotic Ectodermal Dysplasia (HED) is a rare genetic disorder characterized by hypodontia, hypohidrosis, and hypotrichosis. The study aims to identify a novel mutation in the EDA2R gene in a 20-year-old female with HED and investigate its impact on the NF-κB signaling pathway. Whole genome sequencing confirmed the mutation, and bioinformatic tools predicted it to be pathogenic by destabilizing the EDA2R structure and weakening its interaction with EDA-A2. Molecular dynamics simulation and binding free energy calculations further revealed reduced hydrogen bond formation in the mutant EDA2R/EDA-A2 complex, while molecular docking and AlphaFold analyses indicated decreased binding to TRAF3 and TRAF6. In vitro experiments demonstrated that cells expressing the mutant EDA2R had significantly reduced proliferation and NF-κB activity, along with impaired nuclear translocation of NF-κB p65. However, Western blot analysis showed that the JNK signaling pathway remained unaffected. This study identifies a novel missense mutation in EDA2R and introduces a new pathogenic mechanism of HED, emphasizing the crucial role of EDA2R in regulating NF-κB signaling.