Deficient natural killer cell cytotoxicity in patients with IKK-γ/NEMO mutations

Hypohidrotic ectodermal dysplasia (HED) is a rare syndrome associated with aberrant development of the hair, teeth, and eccrine sweat glands (1). The majority of cases of HED are X-linked and are due to mutations of the gene coding for ectodysplasin-A, a member of the TNF superfamily (2). A minority of cases are autosomal recessive and are due to mutations in the ectodysplasin-A receptor, which is the homologue of the murine downless gene (3), or a mutation in the Edar-associated death domain adapter protein, which is involved in downstream signaling from the ectodysplasin-A receptor (4). A small subset of X-linked cases of HED are associated with immunodeficiency, characterized by susceptibility to mycobacterial and streptococcal infections, dys-γ-globulinemia (with decreased IgG and decreased or elevated IgM and IgA), poor polysaccharide-specific antibody responses, and depressed antigen-specific lymphocyte proliferation (1, 5–9). Recent studies have demonstrated HED with immunodeficiency (HED-ID) to be associated with mutations in the gene coding for NF-κB essential modifier (NEMO), also known as I-κB kinase (IKK)-γ (7–9). The NEMO gene consists of ten exons and codes for a scaffold protein that binds IKK-α and IKK-β and is essential for forming a functional IKK complex (10). Signaling by a variety of cell surface receptors activates the IKK complex, rendering it capable of phosphorylating I-κBα, which allows translocation of NF-κB to the nucleus where it participates in transcriptional regulation (11). The