X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by impaired NF-kappaB signaling |
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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 |
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Institution: | Laboratoire de Génétique Humaine des Maladies Infectieuses, Faculté de Médecine Necker-Enfants Malades, Paris, France. |
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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. |
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