Specific missense mutations in NEMO result in hyper-IgM syndrome with hypohydrotic ectodermal dysplasia.
The gene that encodes nuclear factor kappaB (NF-kappaB) essential modulator (or NEMO, also known as IKKgamma) is required for activation of the transcription factor NF-kappaB. We describe mutations in the putative 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-kappaB alpha (IkappaB-alpha) 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-kappaB-regulated cytokines interleukin 12 (IL-12) or tumor necrosis factor alpha (TNF-alpha) 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-kappaB activation for B cell immunoglobulin class-switching.
Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA.
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A
Jain
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CA
Ma
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Liu
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Brown
J
J
Cohen
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W
Strober
D000293:Adolescent; D000938:Antigen-Presenting Cells / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology; D002648:Child; D016207:Cytokines / Q000096:biosynthesis; D004476:Ectodermal Dysplasia / Q000150:complications / Q000235:genetics* / Q000276:immunology; D008040:Genetic Linkage; D006801:Humans; D006942:Hypergammaglobulinemia / Q000150:complications / Q000235:genetics* / Q000276:immunology; D051550:I-kappa B Kinase; D007075:Immunoglobulin M / Q000096:biosynthesis*; D007136:Immunoglobulins / Q000096:biosynthesis; D008297:Male; D020125:Mutation, Missense; D016328:NF-kappa B / Q000378:metabolism; D010375:Pedigree; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D013601:T-Lymphocytes / Q000276:immunology; D014960:X Chromosome
D016207:Cytokines; D007075:Immunoglobulin M; D007136:Immunoglobulins; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human