A novel mutation in NFKBIA/IKBA results in a degradation-resistant N-truncated protein and is associated with ectodermal dysplasia with immunodeficiency

Abstract

Alterations in nuclear factor kappa B (NF-κB) essential modulator (NEMO; HUGO-approved symbol IKBKG) underlie most cases of ectodermal dysplasia with immune deficiency (EDI), a human disorder characterized by anhidrosis with diminished immunity. EDI has also been associated with a single heterozygous mutation at position Ser32 of the NF-κB inhibitor IκBα, one of two phosphorylation sites that are essential for targeting IκBα for proteasomal degradation and hence for activation of NF-κB. We report a novel heterozygous nonsense mutation in the IKBA (HUGO-approved symbol, NFKBIA) gene of a 1-year-old male child with EDI that introduces a premature termination codon at position Glu14. An in-frame methionine downstream of the nonsense mutation allows for reinitiation of translation. The resulting N-terminally truncated protein lacks both serine phosphorylation sites and inhibits NF-κB signaling by functioning as a dominant negative on NF-κB activity in lymphocytes and monocytes. These findings support the scanning model for translation initiation in eukaryotes and confirm the critical role of the NF-κB in the human immune response.

Infectious Diseases in Patients with IRAK-4, MyD88, NEMO, or IκBα Deficiency

“…NEMO is a regulatory subunit of the IKK complex (59). Up to 100 male patients with hypomorphic mutations of NEMO have been reported, and about 43 different mutations leading to impaired NF-B acti- (12,19,29,39,42). The patients originated from three countries on two continents: North America (United States) and Europe (Italy and the Netherlands).…”

“…All five IB␣-deficient patients have developed recurrent bacterial infections, with pneumonia in five cases, sepsis or meningitis in three cases, and arthritis in one case (Table 3) (19,29,39,42). They are also prone to opportunistic infections, with three of them having had pulmonary pneumocystosis and chronic mucocutaneous candidiasis (Table 4).…”

Hematopoietic stem cell transplantations for primary immune deficiencies associated with NFκB mutations: A review of the literature

“…Between the years 2003 and 2015, reports of 7 patients with AD-EDA-ID who underwent HSCT were published (Courtois et al 2003;Janssen et al 2004;Dupuis-Girod et al 2006;Lopez-Granados et al 2008;Fish et al 2009;Wu et al 2010;Schimke et al 2013;Yoshioka et al 2013;Scarselli et al 2015). A summary of patient characteristics can be found in Table 3.…”

Integrity of IKK/NF‐κB Shields Thymic Stroma That Suppresses Susceptibility to Autoimmunity, Fungal Infection, and Carcinogenesis

“…The enforced interaction among inflammation, damaged epithelial cells, and fungi in the epithelial tissues may promote GI tumorigenesis in CMC patients. [96][97][98][99][100][101][102][103][104] Embyonic lethality LOF CHUK, severe encasement malformation [50] CHUK deletions and somatic [79,80] suggesting that type I IFN-mediated pathways regulate mTEC development. Stat1 À/À mice are sensitive to infection by microbial pathogens and viruses.…”

“…[99][100][101][102][103][104] These GOF mutations, including S32I, W11X, E14X, Q9X, M37K, E14X, and E40X at the N-terminal region of IkBα, are heterozygous and generate a dominant-negative IkBα mutant (mIkBα) that is resistant to cytokine-induced degradation. Thus, mIkBα increases its inhibitory activity for NF-kB.…”