NFKBIA variant is not phosphorylated within IkBA:NF-kappaB

Stable Identifier
Reaction [transition]
Homo sapiens
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Several patients with ectodermal dysplasia with immunodeficiency (EDA-ID) were found to carry mutations in NFKBIA gene, which encodes inhibitor of NFkB alpha (IKBA, IkB alpha or NFKBIA) (Courtois G et al. 2003; MacDonald DR et al. 2007; Lopes-Granados E et al. 2008; Schimke LF et al. 2013; Ohnidi). All human NFKBIA mutations are heterozygous gain-of-function (GoF) mutations that augment NFkB 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).
Literature References
PubMed ID Title Journal Year
18412279 A novel mutation in NFKBIA/IKBA results in a degradation-resistant N-truncated protein and is associated with ectodermal dysplasia with immunodeficiency

Kinney, MC, Leo, H, Keenan, JE, Jain, A, Lopez-Granados, E, Jain, N, Gelfand, EW, Ma, CA, Quinones, R

Hum. Mutat. 2008
22078572 A rapid screening method to detect autosomal-dominant ectodermal dysplasia with immune deficiency syndrome

Kondo, N, Miyata, R, Ohnishi, H, Kato, Z, Kaneko, H, Kubota, K, Suzuki, T, Nose, T

J. Allergy Clin. Immunol. 2012
14523047 A hypermorphic IkappaBalpha mutation is associated with autosomal dominant anhidrotic ectodermal dysplasia and T cell immunodeficiency

Döffinger, R, Courtois, G, Munnich, A, Chable-Bessia, C, Fischer, A, Dupuis-Girod, S, Yamaoka, S, Le Deist, F, Livadiotti, S, Puel, A, Bonnet, M, Novelli, F, Reichenbach, J, Israel, A, Cancrini, C, Rossi, P, Bodemer, C, Casanova, JL, Feinberg, J, Smahi, A

J. Clin. Invest. 2003
15337789 The same IkappaBalpha mutation in two related individuals leads to completely different clinical syndromes

van Dissel, JT, ten Dam, M, van der Burg, M, Janssen, R, Hoeve, MA, Ottenhoff, TH, Weemaes, C, van de Vosse, E, van Dongen, J, van Wengen, A, Lankester, A, van Tol, M, Bredius, R

J. Exp. Med. 2004
23708964 A novel gain-of-function IKBA mutation underlies ectodermal dysplasia with immunodeficiency and polyendocrinopathy

Hubbard, N, Notheis, G, Rylaarsdam, S, Repp, R, Hökfelt, T, Schwarz, HP, Albert, MH, Belohradsky, BH, Rieber, N, Torgerson, TR, Puel, A, Picard, C, Cabral-Marques, O, Sombke, SA, Schimke, LF, Renner, ED, Kallmann, L, Kammer, B, Ochs, HD, Casanova, JL

J. Clin. Immunol. 2013
Catalyst Activity

protein serine/threonine kinase activity of CHUK:p-S177,S181-IKBKB:IKBKG [cytosol]

Normal reaction
Functional status

Loss of function of NFKBIA variants:NFkB complex [cytosol]

Name Identifier Synonyms
primary immunodeficiency disease DOID:612 immune deficiency disorder, immunodeficiency syndrome, hypoimmunity
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