Heterozygous N-terminal deletion of IκBα results in functional nuclear factor κB haploinsufficiency, ectodermal dysplasia, and immune deficiency

Background: Nuclear factor kappa B (NF-kappa B) is a master transcriptional regulator critical for ectodermal development and normal innate and adaptive immune function. Mutations in the I kappa B kinase gamma/NF-kappa B essential modifier have been described in male subjects with the syndrome of X-finked ectodermal dysplasia with immune deficiency that results from impaired activation of NF-kappa B. Objectives: We sought to determine the genetic cause of ectodermal dysplasia with immune deficiency in a female patient. Methods: Toll-like receptor-induced production of the NF-kappa B-dependent cytokines TNF-alpha and IFN-alpha. was examined by means of ELISA, the patient's I kappa B alpha gene was sequenced, and NF-kappa B activation was evaluated by means of electrophoretic mobility shift assay and NF-kappa B-luciferase assays in transfectants. Results: Toll-like receptor function was impaired in the patient. Sequencing of the patient's I kappa B alpha gene revealed a novel heterozygous mutation at amino acid 11 (W11X). The mutant I kappa B alpha W11X protein did not undergo ligand-induced phosphorylation or degradation and retained NF-kappa B in the cytoplasm. This led to roughly a 50% decrease in NF-kappa B DNA-binding activity, leading to functional haploinsufficiency of NF-kappa B activation. Unlike the only other reported I kappa B alpha mutant associated with ectodermal dysplasia associated with immune deficiency (ED-ID), S32I, I kappa B alpha W11X exerted no dominant-negative effect. Conclusions: Functional NF-kappa B haploinsufficiency was associated with ED-ID, and this strongly suggests that normal ectodermal development and immune function are stringently dependent on NF-kappa B in that they might require more than half of normal NF-KB activity. Clinical implications: Although ED-ID is well described in male subjects, female subjects can present with a similar syndrome of ectodermal dysplasia with immune deficiency resulting from mutations in autosomal genes within the NF-kappa B pathway.