X-Linked Hypohidrotic Ectodermal Dysplasia: The Pathogenic Role of the EDA Gene

The term ectodermal dysplasia (ED) describes a large group of clinically heterogeneous disorders caused by a developmental failure in two or more ectodermal structures. ED is characterized by a triad of typical signs: hypotrichosis, hypohidrosis, and hypodontia. The most common form is X-linked hypohidrotic ectodermal dysplasia (XLHED), with a frequency of one per 17,000 in the general population. The gene associated with XLHED is ectodysplasin A (EDA), which encodes for components of the tumor necrosis factor (TNF) superfamily. The two isoforms, EDA-A1 and EDA-A2, are the two longest transcripts known to be biologically active. They are involved in multiple molecular signaling pathways, particularly shared with organs with ectodermal dysplasias and developing as ectodermal appendages. The EDA mutations identified in XLHED patients mainly affect three different regions of the protein: the collagen-like domain, the furin protease recognition sequence, and the C-terminal TNF homology domain (THD). Overall, mutations that involve and/or disrupt the binding interface between EDA and its receptor EDAR determine more severe phenotypes of XLHED compared to mutations that result in only partial weakening of the interaction that determines mild and non-syndromic manifestation.