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Human nuclear factor kappa B essential modulator mutation can result in immunodeficiency without ectodermal dysplasia.

Orange J.S., Levy O., Brodeur S.R., Krzewski K., Roy R.M., Niemela J.E., Fleisher T.A., Bonilla F.A., Geha R.S.

BACKGROUND: Many receptors rely on the appropriate activation of nuclear factor (NF) kappa B to induce cellular function. This process depends critically on the phosphorylation of the inhibitor of NF-kappa B (I kappa B) by the I kappa B kinase. This targets I kappa B for ubiquitination and degradation, allowing NF-kappa B to translocate to the nucleus, where it can direct transcription. Hypomorphic human mutations affecting one I kappa B kinase component, the NF-kappa B 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-kappa B 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-kappa B activation. CONCLUSION: Mutation of the gene encoding NEMO can result in immunodeficiency without ectodermal dysplasia.

J. Allergy Clin. Immunol. 114:650-656(2004) [PubMed] [Europe PMC]

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