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- Title
X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by impaired NF-kappaB signaling.
- Authors
Döffinger, 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; Israël, A; Courtois, G; Casanova, J L
- Abstract
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 (IkappaB 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)-1beta, IL-18, TNFalpha 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.
- Publication
Nature genetics, 2001, Vol 27, Issue 3, p277
- ISSN
1061-4036
- Publication type
Journal Article
- DOI
10.1038/85837