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 (IκB kinase) complex, which is essential for NF-κB 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-κB signaling. We also show that the ectodysplasin receptor, DL, triggers NF-κB through the NEMO protein, indicating that EDA results from impaired NF-κB signaling. Finally, we show that abnormal immunity in OL-EDA-ID patients results from impaired cell responses to lipopolysaccharide, interleukin (IL)-1β, IL-18, TNFα and CD154. We thus report for the first time that impaired but not abolished NF-κB signaling in humans results in two related syndromes that associate specific developmental and immunological defects.
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Acknowledgements
We thank P. Darocca, G. Barcenas-Döffinger, M. Feinberg, P. Revy, G. de Saint Basile, P. Darbyshire, C. Moss and J. Clarke. J.-L.C. thanks J.-C. Weill for encouragement and support. This work was supported by grants from Faculté Necker, Université de Paris René Descartes, Fondation Schlumberger, Fondation Jean Valade, Legs Poix, FRM, Fondation BNP-Parisbas, PNRFMMIP, Institut Universitaire de France, National Incontinentia Pigmenti Foundation, Action Incitative Blanche and INSERM U550 to J.-L.C.
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Döffinger, R., Smahi, A., Bessia, C. et al. X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by impaired NF-κB signaling. Nat Genet 27, 277–285 (2001). https://doi.org/10.1038/85837
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DOI: https://doi.org/10.1038/85837
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