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

BackgroundNuclear factor κB (NF-κB) is a master transcriptional regulator critical for ectodermal development and normal innate and adaptive immune function. Mutations in the IκB kinase γ/NF-κB essential modifier have been described in male subjects with the syndrome of X-linked ectodermal dysplasia with immune deficiency that results from impaired activation of NF-κB.ObjectivesWe sought to determine the genetic cause of ectodermal dysplasia with immune deficiency in a female patient.MethodsToll-like receptor–induced production of the NF-κB–dependent cytokines TNF-α and IFN-α was examined by means of ELISA, the patient's IκBα gene was sequenced, and NF-κB activation was evaluated by means of electrophoretic mobility shift assay and NF-κB–luciferase assays in transfectants.ResultsToll-like receptor function was impaired in the patient. Sequencing of the patient's IκBα gene revealed a novel heterozygous mutation at amino acid 11 (W11X). The mutant IκBαW11X protein did not undergo ligand-induced phosphorylation or degradation and retained NF-κB in the cytoplasm. This led to roughly a 50% decrease in NF-κB DNA-binding activity, leading to functional haploinsufficiency of NF-κB activation. Unlike the only other reported IκBα mutant associated with ectodermal dysplasia associated with immune deficiency (ED-ID), S32I, IκBαW11X exerted no dominant-negative effect.ConclusionsFunctional NF-κB haploinsufficiency was associated with ED-ID, and this strongly suggests that normal ectodermal development and immune function are stringently dependent on NF-κB in that they might require more than half of normal NF-κB activity.Clinical implicationsAlthough 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-κB pathway.