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Details on Person Many signaling pathways rely on the activation of nuclear fa...
| Class:Id | Summation:5607899 |
|---|---|
| _displayName | Many signaling pathways rely on the activation of nuclear fa... |
| _timestamp | 2015-02-15 10:41:34 |
| created | [InstanceEdit:5607886] Shamovsky, Veronica, 2014-07-14 |
| literatureReference | [LiteratureReference:5607894] The pro- or anti-apoptotic function of NF-kappaB is determined by the nature of the apoptotic stimulus [LiteratureReference:5607879] Transcriptional regulation of endothelial cell adhesion molecules: NF-kappa B and cytokine-inducible enhancers [LiteratureReference:5607892] The nuclear factor NF-kappaB pathway in inflammation [LiteratureReference:5607847] IKK-gamma is an essential regulatory subunit of the IkappaB kinase complex [LiteratureReference:5607876] The complexity of NF-?B signaling in inflammation and cancer [LiteratureReference:5607889] The NF-kappaB family of transcription factors and its regulation [LiteratureReference:5607891] Molecular analysis of the genetic defect in a large cohort of IP patients and identification of novel NEMO mutations interfering with NF-kappaB activation [LiteratureReference:5262960] X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by impaired NF-kappaB signaling [LiteratureReference:5262899] A recurrent deletion in the ubiquitously expressed NEMO (IKK-gamma) gene accounts for the vast majority of incontinentia pigmenti mutations [LiteratureReference:5607887] Specific missense mutations in NEMO result in hyper-IgM syndrome with hypohydrotic ectodermal dysplasia [LiteratureReference:5607884] The zinc finger domain of IKK? (NEMO) protein in health and disease [LiteratureReference:5607796] A point mutation in NEMO associated with anhidrotic ectodermal dysplasia with immunodeficiency pathology results in destabilization of the oligomer and reduces lipopolysaccharide- and tumor necrosis factor-mediated NF-kappa B activation [LiteratureReference:5262892] Hypomorphic nuclear factor-kappaB essential modulator mutation database and reconstitution system identifies phenotypic and immunologic diversity [LiteratureReference:5607812] Alterations of the IKBKG locus and diseases: an update and a report of 13 novel mutations [LiteratureReference:5675070] Human nuclear factor kappa B essential modulator mutation can result in immunodeficiency without ectodermal dysplasia |
| modified | [InstanceEdit:5608047] Shamovsky, Veronica, 2014-07-15 [InstanceEdit:5625554] Shamovsky, Veronica, 2014-10-06 [InstanceEdit:5675066] Shamovsky, Veronica, 2015-02-15 |
| text | 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). |
| (summation) | [Pathway:5603027] IKBKG deficiency causes anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) (via TLR) [Homo sapiens] |
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