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

Stable Identifier
Homo sapiens
Locations in the PathwayBrowser
SVG |   | PPTX  | SBGN
Click the image above or here to open this pathway in the Pathway Browser
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

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

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

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

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

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

Nat. Genet. 2001
Name Identifier Synonyms
primary immunodeficiency disease DOID:612 immune deficiency disorder, immunodeficiency syndrome, hypoimmunity
Cross References
Cite Us!