Human nuclear factor κB essential modulator mutation can result in immunodeficiency without ectodermal dysplasia

Background: Many receptors rely on the appropriate activation of nuclear factor (NF)kappaB to induce cellular function. This process depends critically on the phosphorylation of the inhibitor of NF-kappaB (IkappaB) by the IkappaB kinase. This targets IkappaB for ubiquitination and degradation, allowing NF-kappaB to translocate to the nucleus, where it can direct transcription. Hypomorphic human mutations affecting one IkappaB kinase component, the NF-kappaB essential modulator (NEMO), result in impaired signaling from receptors required for ectodermal development and immune function. Male subjects with these mutant NEMO molecules have an X-linked syndrome known as ectodermal dysplasia with immunodeficiency, which is characterized by severe infections, with herpesviruses, bacteria, and mycobacterial susceptibility. Objective: We sought to genetically and biochemically characterize a patient with a mutant NEMO molecule without ectodermal abnormalities. Methods: We evaluated NEMO in a patient who had immunodeficiency and atypical mycobacterial infection but normal ectoderm. Results: We identified a novel NEMO mutant causing immunodeficiency without ectodermal dysplasia. The mutation, which altered the exon 9 splice site, was present in cells of ectodermal and hematopoetic origin and resulted in a heterogeneous mixture of mutant and wild-type cDNA species. Immunologic function was variably impaired, with reduced CD40-induced B-cell proliferation, partially reduced NF-kappaB p65 nuclear translocation, and variable Toll-like receptor-induced TNF production. This variability might be explained by an inconsistent ratio of mutant to wild-type NEMO. The lack of any ectodermal phenotype, however, suggested a separation in the hematopoetic and ectodermal function of NEMO that leads to NF-kappaB activation. Conclusion: Mutation of the gene encoding NEMO can result in immunodeficiency without ectodermal dysplasia.