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Lookup NU author(s): Dr Mario Abinun
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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.
Author(s): Abinun M; Doffinger R; Smahi A; Bessia C; Geissmann F; Feinberg J; Durandy A; Bodemer C; Kenwrick S; Dupuis-Girod S; Blanche S; Wood P; Rabia SH; Headon DJ; Overbeek PA; Le Deist F; Holland SM; Belani K; Kumararatne DS; Fischer A; Shapiro R; Conley ME; Reimund E; Kalhoff H; Munnich A; Israel A; Courtois G; Casanova JL
Publication type: Letter
Publication status: Published
Journal: Nature Genetics
Year: 2001
Volume: 27
Issue: 3
Pages: 277-285
ISSN (print): 1061-4036
ISSN (electronic): 1546-1718
URL: http://dx.doi.org/10.1038/85837
DOI: 10.1038/85837
