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 IKK gamma) is required for activation of the trans cription factor NF-kappaB. We describe mutations in the putative zinc-finge r domain of NEMO that result in an X-linked primary immunodeficiency charac terized by hyper-IgM syndrome and hypohydrotic ectodermal dysplasia (XHM-ED ). These mutations prevent CD40 ligand (CD40L)-mediated degradation of inhi bitor of NF-kappaB alpha (I kappaB-alpha) and account for the following obs ervations: B cells from XHM-ED patients are unable to undergo immunoglobuli n 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. Neverth eless, innate immunity is preserved in XHM-ED patients because APCs retain the capacity to respond to stimulation by lipopolysaccharide or Staphylococ cus aureus Cowan's antigen (SAC). Overall, the phenotype observed in XHM-ED patients shows that the putative zinc-finger domain of NEMO has a regulato ry function and demonstrates the definite requirement of CD40-mediated NF-k appaB activation for B cell immunoglobulin class-switching.