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Specific missense mutations in NEMO result in hyper-IgM syndrome with hypohydrotic ectodermal dysplasia

Nature Immunology volume 2, pages 223–228 (2001)Cite this article

Abstract

The gene that encodes nuclear factor κ (NF-κB) essential modulator (or NEMO, also known as IKKγ) is required for activation of the transcription factor NF-κB. We describe mutations in the puta-tive zinc-finger domain of NEMO that result in an X-linked primary immunodeficiency characterized by hyper-IgM syndrome and hypohydrotic ectodermal dysplasia (XHM-ED). These mutations prevent CD40 ligand (CD40L)-mediated degradation of inhibitor of NF-κB α (IκB-α) and account for the following observations: B cells from XHM-ED patients are unable to undergo immunoglobulin class-switch recombination and antigen-presenting cells (APCs) are unable to synthesize the NF-κB–regulated cytokines interleukin 12 (IL-12) or tumor necrosis factor α (TNF-α) when stimulated with CD40L. Nevertheless, innate immunity is preserved in XHM-ED patients because APCs retain the capacity to respond to stimulation by lipopolysaccharide or Staphylococcus aureus Cowan's antigen (SAC). Overall, the phenotype observed in XHM-ED patients shows that the putative zinc-finger domain of NEMO has a regulatory function and demonstrates the definite requirement of CD40-mediated NF-κB activation for B cell immunoglobulin class-switching.

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Figure 1: NEMO mutations.
Figure 2: Defective IκB-α activation XHM-ED patients.
Figure 3: B cells from XHM-ED patients have diminished expression of cell surface molecules when stimulated with CD40L.
Figure 4: XHM-ED patients fail to secrete IL-12 and TNF-α when stimulated with CD40L.
Figure 5: T cells from XHM-ED secrete normal concentrations of IFN-γ.

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Acknowledgements

We thank the families studied for their invaluable contribution to this project; R. Dhanasekaran for technical assistance; V. Dixit (Genentech), J. Derry and W. Fanslow (Immunex), P. Lipsky, A. Grammer and K. Brown for helpful discussions; and U. Seibenlist for critical review of the manuscript. Supported by the Immune Deficiency Foundation and the National Foundation of Ectodermal Dysplasia

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Authors and Affiliations

  1. Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, 20892, MD, USA

    Ashish Jain, Chi Adrian Ma, Jeffrey Cohen & Warren Strober

  2. Nursing Department, Clinical Center, NIH, Bethesda, 20892, MD, USA

    Shiyung Liu

  3. Department of Laboratory Medicine, Clinical Center, NIH, Bethesda, 20892, MD, USA

    Margaret Brown

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  1. Ashish Jain
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Correspondence to Warren Strober.

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Jain, A., Ma, C., Liu, S. et al. Specific missense mutations in NEMO result in hyper-IgM syndrome with hypohydrotic ectodermal dysplasia. Nat Immunol 2, 223–228 (2001). https://doi.org/10.1038/85277

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