Defective nuclear IKKα function in patients with ectodermal dysplasia with immune deficiency.

Ectodermal dysplasia with immune deficiency (EDI) is an immunological and developmental disorder caused by alterations in the gene encoding NF-kappa B essential modulator (NEMO; also known as I kappa B kinase gamma subunit [IKK gamma]). Missense mutations in the gene encoding NEMO are associated with reduced signal-induced nuclear translocation of NF-kappa B proteins, resulting in defective expression of NF-kappa B target genes. Here, we report 2 unrelated male patients with EDI, both of whom have normal NEMO coding sequences, but exhibit a marked reduction in expression of full-length NEMO protein. TLR4 stimulation of APCs from these patients induced normal cytoplasmic activation and nuclear translocation of NF-kappa B. However, cells deficient in full-length NEMO were defective in expression of NF-kappa B-regulated cytokines, such as IL-12, suggesting a downstream defect in chromatin accessibility for NF-kappa B transcription factors. TLR4-stimulated APCs from the patients were defective in IKK alpha-dependent H3 histone phosphorylation at the IL-12 promoter and recruitment of NF-kappa B heterodimers RelA and cRel to the promoter. Expression of a super-active form of IKK alpha restored IL-12 production in a NEMO knockdown human monocytic cell line following LPS treatment. Our findings suggest that NEMO regulates the nuclear function of IKK alpha and offer new insights into the mechanisms underlying diminished NF-kappa B signaling in patients with EDI.