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

Jordan S. Orange, Ofer Levy, Scott R. Brodeur, Konrad Krzewski, Rene M. Roy, Julie E. Niemela, Thomas A. Fleisher, Francisco A. Bonilla, Raif S. Geha

Research output: Contribution to journalArticlepeer-review

101 Scopus citations


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.

Original languageEnglish
Pages (from-to)650-656
Number of pages7
JournalJournal of Allergy and Clinical Immunology
Issue number3
StatePublished - Sep 2004


  • IκB kinase
  • NF-κB
  • X-chromosome-linked genetic diseases
  • immunologic deficiency syndromes
  • innate immunity


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