IKBKG deficiency causes anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) (via TLR)

Stable Identifier
R-HSA-5603027
Type
Pathway
Species
Homo sapiens
ReviewStatus
5/5
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IKBKG deficiency causes anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) (via TLR)
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Many signaling pathways rely on the activation of nuclear factor kappa B (NFkB), which is critical for the induction of the appropriate cellular function in response to various stimuli such as inflammatory cytokines, microbial products or various types of stress (Lawrence T 2009; Hoesel B and Schmid JA 2013). The NFkB family of transcription factors is kept inactive in the cytoplasm by inhibitor of kappa B (IkB) family members (Oeckinghaus A and Ghosh S 2009). Canonical NFkB activation depends on the phosphorylation of IkB by the I kappa B kinase (IKK) complex, which contains two catalytic subunits named IKK alpha, IKK beta and a regulatory subunit named NFkB essential modulator (NEMO or IKBKG) (Rothwarf DM et al. 1998). Phosphorylation of IkB leads to K48-linked ubiquitination and proteasomal degradation of IkB, allowing translocation of NFkB factor to the nucleus, where it can activate transcription of a variety of genes participating in the immune and inflammatory response, cell adhesion, growth control, and protection against apoptosis (Collins T et al. 1995; Kaltschmidt B et al. 2000; Lawrence T 2009).

IKBKG is encoded by an X-linked gene. Null alleles of the gene are lethal in hemizygous males, whereas hypomorphic alleles typically result in the impaired NFkB signaling in patients with a broad spectrum of clinical phenotypes in terms of both developmental defects and immunodeficiency (Döffinger R et al. 2001; Hanson EP et al. 2008). Several categories of mutations affecting IKBKG have been reported in humans (Döffinger R et al. 2001; Vinolo E et al. 2006; Fusko F et al. 2008). The first category of these mutations consists of hypomorphic mutations typically involving the zinc finger domain and nearby C-terminal regions and causing hypohidrotic ectodermal dysplasia with immune deficiency (HED-ID) in males (Jain A et al. 2001; Shifera AS 2010). The second category consists of amorphic mutations causing incontinentia pigmenti (IP) in females and, generally, prenatal death in males (Aradhya S et al. 2001; Fusco F et al. 2004). The third category is composed of hypomorphic mutations involving the stop codon causing anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID), osteopetrosis and lymphedema (OL-EDA-ID) in males (Döffinger R et al. 2001). Also some patients with a defective IKBKG gene can develop immunodeficiency without ectodermal dysplasia (Orange JS et al. 2004). This module describes several EDA-ID-associated hypomorphic IKBKG mutations that have been reported to affect inflammatory responses initiated by toll like receptors (TLR).

Literature References
PubMed ID Title Journal Year
18851874 Hypomorphic nuclear factor-kappaB essential modulator mutation database and reconstitution system identifies phenotypic and immunologic diversity

Hanson, EP, Monaco-Shawver, L, Solt, LA, Madge, LA, Banerjee, PP, May, MJ, Orange, JS

J. Allergy Clin. Immunol. 2008
15229184 Molecular analysis of the genetic defect in a large cohort of IP patients and identification of novel NEMO mutations interfering with NF-kappaB activation

Fusco, F, Bardaro, T, Fimiani, G, Mercadante, V, Miano, MG, Falco, G, Israel, A, Courtois, G, D'Urso, M, Ursini, MV

Hum. Mol. Genet. 2004
11242109 X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by impaired NF-kappaB signaling

Döffinger, R, Smahi, A, Bessia, C, Geissmann, F, Feinberg, J, Durandy, A, Bodemer, C, Kenwrick, S, Dupuis-Girod, S, Blanche, S, Wood, P, Rabia, SH, Headon, DJ, Overbeek, PA, Le Deist, F, Holland, SM, Belani, K, Kumararatne, DS, Fischer, A, Shapiro, R, Conley, ME, Reimund, E, Kalhoff, H, Abinun, M, Munnich, A, Israël, A, Courtois, G, Casanova, JL

Nat. Genet. 2001
Participants
Events
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as an event of
Disease
Name Identifier Synonyms
primary immunodeficiency disease DOID:612 immune deficiency disorder, immunodeficiency syndrome, hypoimmunity
Cross References
Mondo
BioModels Database
Authored
Shamovsky, V  (2014-05-21)
Reviewed
D'Eustachio, P  (2014-09-06)
McDonald, DR  (2015-02-15)
Created
Shamovsky, V  (2014-06-26)
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