A Novel Gain-of-Function IKBA Mutation Underlies Ectodermal Dysplasia with Immunodeficiency and Polyendocrinopathy

Purpose This study reports the identification of a novel heterozygous IKBA missense mutation ( p.M37K) in a boy presenting with ectodermal dysplasia with immunodeficiency (EDA-ID) who had wild type IKBKG gene encoding NEMO. Our aim was to characterize the clinical course of this I kappa B-alpha gain-of-function mutant and to investigate if the p.M37K substitution affects NF-kappa B activation by interfering with I kappa B-alpha degradation, thus impairing NF-kappa B signaling and causing the EDA-ID phenotype. Methods NF-kappa B signaling was evaluated by measuring I kappa B-alpha degradation in patient fibroblasts. In addition, transientlytransfected HeLa cells expressing either the M37K-mutant I kappa B-alpha allele, the previously characterized S36A-mutant I kappa B-alpha allele, or wild type I kappa B-alpha were evaluated for I kappa B-alpha degradation and NF-kappa B nuclear translocation following stimulation with TNF-alpha. Results Clinical findings revealed a classical ectodermal dysplasia phenotype complicated by recurrent mucocutaneous candidiasis, hypothyroidism, hypopituitarism, and profound combined immunodeficiency with decreased numbers of IL-17 T cells. I kappa B-alpha degradation after TNF-alpha and TLR agonist stimulation was abolished in patient fibroblasts as well as in HeLa cells expressing M37K-I kappa B-alpha similar to cells expressing S36A-I kappa B-alpha resulting in impaired nuclear translocation of NF-kappa B and reduced NF-kappa B dependent luciferase activity compared to cells expressing wild type I kappa B-alpha. Patient whole blood cells failed to secrete IL-6 in response to IL-1 beta, Pam(2)CSK(4), showed reduced responses to LPS and PMA/Ionomycin, and lacked IL-10 production in response to TNF-alpha. Conclusion The novel heterozygous mutation p.M37K in I kappa B-alpha impairs NF-kappa B activation causing autosomal dominant EDA-ID with an expanded clinical phenotype.