X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by impaired NF-kappaB signaling

R Döffinger, A Smahi, C Bessia, F Geissmann, J Feinberg, A Durandy, C Bodemer, S Kenwrick, S Dupuis-Girod, S Blanche, P Wood, S H Rabia, D J Headon, P A Overbeek, F Le Deist, S M Holland, K Belani, D S Kumararatne, A Fischer, R ShapiroM E Conley, E Reimund, H Kalhoff, M Abinun, A Munnich, A Israël, G Courtois, J L Casanova

Research output: Contribution to journalArticlepeer-review


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.
Original languageEnglish
Pages (from-to)277-85
Number of pages9
JournalNature Genetics
Issue number3
Publication statusPublished - Mar 2001


  • Adolescent
  • Child
  • Child, Preschool
  • Codon, Terminator
  • Ectodermal Dysplasia
  • Ectodysplasins
  • Genetic Linkage
  • Humans
  • I-kappa B Kinase
  • Immunity, Cellular
  • Immunologic Deficiency Syndromes
  • Infant
  • Male
  • Membrane Proteins
  • Mutation
  • NF-kappa B
  • Protein-Serine-Threonine Kinases
  • Signal Transduction
  • Syndrome
  • X Chromosome


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