Anhidrotic Ectodermal Dysplasia with Immunodeficiency (EDA-ID), Autosomal-Dominant

Synonyms

Human IkB-alpha gain of function

Definition

Autosomal-dominant EDA-ID (OMIM # 612132) is an immune deficiency with ectodermal dysplasia caused by germline heterozygous gain-of-function mutations in NFKBIA which encodes IkB-alpha.

Introduction

The NF-kB signaling cascade is comprised of transcription factors that are normally sequestered in an inactive state in the cytoplasm through an association with inhibitory proteins such as IkB-alpha. Signaling through a variety of cell surface receptors involved in innate (TLRs, IL-1Rs, TNFRs) and adaptive (TCR and BCR) immunity triggers the phosphorylation of two key serine residues (S32 and S36) leading to its dissociation and subsequent proteasomal degradation. Once free from inhibition, NF-kB transcription factors are free to translocate to the nucleus and initiate cell-specific gene expression programs. Autosomal-dominant EDA-ID is associated with gain of function mutations in NFKBIAthat reduce the degradation of IkB-alpha, thus...