D÷ffinger,R., Smahi,A., Bessia,C., Geissmann,F., Feinberg,J., Durandy,A., Bodemer,C., Kenwrick,S., Dupuis-Girod,S., Blanche,S., Wood,P., Rabia,S.H., Headon,D.J., Overbeek,P.A., Le Deist,F., Holland,S.M., Belani,K., Kumararatne,D.S., Fischer,A., Shapiro,R., Conley,M.E., Reimund,E., Kalhoff,H., Abinun,M., Munnich,A., and, Casanova,J.L.
X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by impaired NF- kappa B signaling.
Nature Genetics 27(3):277-285 (2001).
The molecular basis of X-linked recessive anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) has remained elusive. Here we report hypomorphic mutations in the gene IKBKG in 12 males with EDA-ID from 8 kindreds. and 2 patients with a related and hitherto unrecognized syndrome of EDA-ID with osteopetrosis and lymphoedema (OL-EDA-ID). Mutations in the coding region of IKBKG are associated with EDA-ID. and stop codon mutations, with OL-EDA-ID. IKBKG encodes NEMO, the regulatory subunit of the IKK (I kappaB kinase) complex, which is essential for NF- kappaB signaling. Germline loss-of-function mutations in IKBKG are lethal in male fetuses. We show that IKBKG mutations causing OL-EDA-ID and EDA-ID impair but do not abolish NF-kappaB signaling. We also show that the ectodysplasin receptor, DL, triggers NF-kappaB through the NEMO protein, indicating that EDA results from impaired NF-kappaB signaling. Finally. we show that abnormal immunity in OL-EDA-ID patients 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 two related syndromes that associate specific developmental and immunological defects. [References: 50].

Last edited 10.12.2004 by P.N.