X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by impaired NF-kappaB signaling.
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.
Döffinger
R
R
Laboratoire de Génétique Humaine des Maladies Infectieuses, Faculté de Médecine Necker-Enfants Malades, Paris, France.
Smahi
A
A
Bessia
C
C
Geissmann
F
F
Feinberg
J
J
Durandy
A
A
Bodemer
C
C
Kenwrick
S
S
Dupuis-Girod
S
S
Blanche
S
S
Wood
P
P
Rabia
S H
SH
Headon
D J
DJ
Overbeek
P A
PA
Le Deist
F
F
Holland
S M
SM
Belani
K
K
Kumararatne
D S
DS
Fischer
A
A
Shapiro
R
R
Conley
M E
ME
Reimund
E
E
Kalhoff
H
H
Abinun
M
M
Munnich
A
A
Israël
A
A
Courtois
G
G
Casanova
J L
JL
D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D018388:Codon, Terminator / Q000235:genetics; D004476:Ectodermal Dysplasia / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D053331:Ectodysplasins; D008040:Genetic Linkage; D006801:Humans; D051550:I-kappa B Kinase; D007111:Immunity, Cellular; D007153:Immunologic Deficiency Syndromes / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D007223:Infant; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D013577:Syndrome; D014960:X Chromosome / Q000235:genetics
D018388:Codon, Terminator; C506018:EDA protein, human; D053331:Ectodysplasins; D008565:Membrane Proteins; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human