X-linked Anhidrotic Ectodermal Dysplasia With Immunodeficiency Is Caused by Impaired NF-kappaB Signaling

Nat Genet. 2001 Mar;27(3):277-85. doi: 10.1038/85837.

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 types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • Codon, Terminator
  • EDA protein, human
  • Ectodysplasins
  • Membrane Proteins
  • NF-kappa B
  • Protein-Serine-Threonine Kinases
  • CHUK protein, human
  • I-kappa B Kinase
  • IKBKB protein, human
  • IKBKE protein, human