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

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.

• Authors: 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 Shapiro, M E Conley, E Reimund, H Kalhoff, M Abinun, A Munnich, A Israël, G Courtois, J L Casanova
• Journal: Nature genetics (Nat Genet) Vol. 27 Issue 3 Pg. 277-85 (Mar 2001) ISSN: 1061-4036 [Print] United States
• PMID: 11242109 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

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