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

J Allergy Clin Immunol. 2004 Sep;114(3):650-6. doi: 10.1016/j.jaci.2004.06.052.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adolescent
  • Carrier Proteins*
  • Ectodermal Dysplasia / genetics
  • Ectodermal Dysplasia / immunology*
  • Genetic Diseases, X-Linked / genetics
  • Genetic Diseases, X-Linked / immunology
  • Humans
  • I-kappa B Kinase
  • Immunity, Innate
  • Immunologic Deficiency Syndromes / genetics*
  • Immunologic Deficiency Syndromes / immunology
  • Male
  • Mutation*
  • Proteins / genetics*
  • Proteins / metabolism


  • Carrier Proteins
  • IKBKG protein, human
  • Proteins
  • I-kappa B Kinase