Many receptors rely on the appropriate activation of nuclear factor (NF) κB to induce cellular function. This process depends critically on the phosphorylation of the inhibitor of NF-κB (IκB) by the IκB kinase. This targets IκB for ubiquitination and degradation, allowing NF-κB to translocate to the nucleus, where it can direct transcription. Hypomorphic human mutations affecting one IκB kinase component, the NF-κB 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.We sought to genetically and biochemically characterize a patient with a mutant NEMO molecule without ectodermal abnormalities.We evaluated NEMO in a patient who had immunodeficiency and atypical mycobacterial infection but normal ectoderm.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-κB 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-κB activation.Mutation of the gene encoding NEMO can result in immunodeficiency without ectodermal dysplasia.
- IκB kinase
- X-chromosome-linked genetic diseases
- immunologic deficiency syndromes
- innate immunity