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created	[InstanceEdit:9630925] Shamovsky, Veronica, 2018-12-03
dbId	9630941
displayName	Under normal conditions, stimuli-induced nuclear factor kapp...
literatureReference	[LiteratureReference:5228832] A novel mutation in NFKBIA/IKBA results in a degradation-resistant N-truncated protein and is associated with ectodermal dysplasia with immunodeficiency [LiteratureReference:5228855] A hypermorphic IkappaBalpha mutation is associated with autosomal dominant anhidrotic ectodermal dysplasia and T cell immunodeficiency [LiteratureReference:5228879] A novel gain-of-function IKBA mutation underlies ectodermal dysplasia with immunodeficiency and polyendocrinopathy [LiteratureReference:5228779] Heterozygous N-terminal deletion of IkappaBalpha results in functional nuclear factor kappaB haploinsufficiency, ectodermal dysplasia, and immune deficiency [LiteratureReference:5228775] A rapid screening method to detect autosomal-dominant ectodermal dysplasia with immune deficiency syndrome [LiteratureReference:9630947] Regulation of NF-?B by ubiquitination and degradation of the I?Bs [LiteratureReference:2685476] Phosphorylation meets ubiquitination: the control of NF-[kappa]B activity [LiteratureReference:9630934] 30 Years of NF-?B: A Blossoming of Relevance to Human Pathobiology
schemaClass	Summation
text	Under normal conditions, stimuli-induced nuclear factor kappa B (NFkB) signaling induces IkB kinase (IKK)-mediated phosphorylation of the inhibitor of NFkB alpha (IKBA or NFKBIA) protein at two critical residues, Ser32 and Ser36 (Karin M & Ben-Neriah 2000). This triggers polyubiquitination of NFKBIA at Lys21 and Lys22 and subsequent proteasomal degradation thus allowing nuclear translocation of NFkB dimers (Karin M & Ben-Neriah Y 2000; Kanarek N & Ben-Neriah Y 2012). Several patients with ectodermal dysplasia with immunodeficiency (EDA-ID) were found to carry mutations in NFKBIA gene (Courtois G et al. 2003; MacDonald DR et al. 2007; Lopes-Granados E et al. 2008; Schimke LF et al. 2013; Ohnidi H et al. 2012). All human NFKBIA mutations are heterozygous gain-of-function (GoF) mutations that augment NF-kB inhibition, causing autosomal dominant disease (Courtois G et al. 2003; Schimke LF et al. 2013; Zhang Q et al. 2016). NFKBIA mutations are either substitutions (S32I or M37K) affecting the phosphorylation of residues Ser32 and Ser36 or nonsense mutations (W11TER or E14TER) (Courtois G et al. 2003; Lopes-Granados E et al. 2008; Schimke LF et al. 2013; Zhang Q et al. 2016). The nonsense mutations in NFKBIA gene causing premature termination codons at positions 9 (Q9TER), 11 (W11TER), or 14 (E14TER) lead to translation reinitiation at an in-frame M37 downstream of the nonsense mutations resulting in the N-terminally truncated variant (NFKBIA F2_M37del) that lacks the critical phosphorylation sites at Ser32 or Ser36 (Lopes-Granados E et al. 2008; Schimke LF et al. 2013; Ohnishi H et al. 2012).The NFKBIA (IkBa) protein variants are expressed but cannot undergo phosphorylation-driven degradation. Disregarding induction signals, they remain constitutively bound to NFkB dimer and freeze the pathway sequestering NFkB dimers in the cytoplasm (Courtois G et al. 2003; Lopes-Granados E et al. 2008; Schimke LF et al. 2013). This has been verified by overexpressing mutant NFKBIA proteins encoded by patient alleles and showing that they override the wild-type protein and block NFkB-induced gene expression (Courtois G et al., 2003). NFkB signaling can be variably impaired in patients with IKBA-deficiency ranging from severe dominant-negative effect of NFKBIA S32I variant comparing to NFKBIA W11TER which results in functional NFkB haploinsufficiency (Lopes-Granados E et al. 2008; McDonald DR et al, 2007).

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[Reaction:R-HSA-9630921] NFKBIA variant binds NFkB complex

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