X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by impaired NF-kappa B signaling

The molecular basis of X-linked recessive anhidrotic ectodermal dysplasia w ith immunodeficiency (EDA-ID) has remained elusive. Here we report hypomorp hic mutations in the gene IKBKG in 12 males with EDA-ID from 8 kindreds. an d 2 patients with a related and hitherto unrecognized syndrome of EDA-ID wi th osteopetrosis and lymphoedema (OL-EDA-ID). Mutations in the coding regio n of IKBKG are associated with EDA-ID. and stop codon mutations, with OL-ED A-ID. IKBKG encodes NEMO, the regulatory subunit of the IKK (I kappaB kinas e) complex, which is essential for NF-kappaB signaling. Germline loss-of-fu nction mutations in IKBKG are lethal in male fetuses. We show that IKBKG mu tations causing OL-EDA-ID and EDA-ID impair but do not abolish NF-kappaB si gnaling. We also show that the ectodysplasin receptor, DL, triggers NF-kapp aB through the NEMO protein, indicating that EDA results from impaired NF-k appaB signaling. Finally. we show that abnormal immunity in OL-EDA-ID patie nts results from impaired cell responses to lipopolysaccharide, interleukin (IL)-1 beta, IL-18, TNF alpha and CD154. We thus report for the first time that impaired but not abolished NF-kappaB signaling in humans results in t wo related syndromes that associate specific developmental and immunologica l defects.