NF-KappaB1

NF-kappa (Nuclear Factor Kappa B) is a 105 kD protein that is encoded by the NFKB1 gene (NFKB1 stands for "Nuclear Factor Kappa B Subunit 1") located on chromosome 4q24. The 105 kD protein can be cotranslated into a 50 kD protein by the 26S proteasome. The 105 kD protein is a Rel protein-specific transcription inhibitor, the 50 kD protein is a DNA-binding subunit of the NF-kappa-B (NFKB) protein complex.

The protein complex NF-kappa-B, encoded by the NFKB1 gene, is a pleiotropic transcription factor present in almost all cell types and is the endpoint of a series of signal transduction events triggered by a variety of stimuli related to many biological processes such as inflammation, immunity, differentiation, cell growth, tumorigenesis and apoptosis.

NF-kappa-B is a homo- or heterodimeric complex. It is formed by proteins that contain Rel-like domains, such as RELA/p65 (see RELA gene below), RELB, NFKB1/p105, NFKB1/p50, REL and NFKB2/p52. The dimers bind to kappa B sites in the DNA of their target genes. The individual dimers have different preferences for different kappa B sites, which they can bind with different affinity and specificity.

The transcription factor NF-kappa-B (NFKB) is activated by various intra- and extracellular stimuli such as cytokines, oxidative free radicals, ultraviolet radiation and bacterial or viral products. Activated NF-kappa-B migrates into the cell nucleus and stimulates the expression of genes involved in a variety of biological functions.

Uncontrolled activation of NF-kappa-B (NFKB) has been associated with a number of inflammatory diseases, while prolonged inhibition of NFKB leads to defective immune cell development or delayed cell growth. NFKB is a key regulator of the immediate and early response to viral infection.

The NFKB1-associated autoinflammatory diseases (NFKB1-AD) comprise a group of three different autosomal dominant diseases caused by mutations in the NFKB1 gene. Alternative splicing results in multiple transcript variants encoding different isoforms, at least one of which is proteolytically processed. The mutations in NFKB1-AD affect the NK-κB subunits p50 and p105, which in some cases leads to increased expression of interleukin-1β and TNF-alpha and corresponding clinical symptoms (Kaustio M et al. 2019).

Initial descriptions of patients with NFKB1 gene mutations were associated with an immunodeficiency phenotype consisting of recurrent respiratory tract infections, chronic lung disease with bronchiectasis, diarrhea, lymphadenopathy lymphadenopathy, splenomegaly, recurrent autoimmune phenomena (hemolytic anemia, thrombocytopenia and leukopenia), hypogammaglobulinemia, deficient production of specific antibodies and a reduced number of class-specific and memory B cells (Kaustio M et al. 2019; Schipp C et al. 2016; Lorenzini T et al. (2020)

Two other autoinflammatory phenotypes associated with mutations in the NFKB1 gene have been described in two families (Kaustio M et al. 2017).

The first autoinflammatory phenotype is NFKB1-associated Behçet-like disease, which is associated with the non-truncating mutation H67R in the NFKB1 gene. It has been described in six individuals in the same family with clinical manifestations similar to those of Behçet's disease (aphthae, arthritis and abdominal pain) (Kaustio M et al. 2017). It is noteworthy that the mutations in NFKB1 affect the same signaling pathway as in HA20 (ubiquinopathy - Behcet's-like familial autoinflammatory syndrome). However, HA20 is associated with IgG hypogammaglobulinemia. The Behcet-like phenotype does not appear to cause overactivation of the canonical inflammasome in vitro, so that drug suppression of IL-1β and TNF may not seem appropriate. (Kaustio M et al. 2017).

The second autoinflammatory phenotype is NFKB1-associated sterile familial autoinflammatory necrotizing fasciitis (FANF), which is caused by a truncating mutation R157X in the NFKB1 gene. This was described in two brothers who suffered from localized, recurrent, sterile, necrotizing inflammation after a banal tissue trauma (e.g. after a minor surgical procedure) that spread to the muscle fascia (clinical picture of necrotizing fasciitis). The patients had neither other organ or systemic involvement nor any obvious manifestations of immunodeficiency (Kaustio M et al. 2017). In other casuistics, pyoderma gangraenosum is mentioned as an associated disease (Bergbreiter A et al.2021; Fang R et al. 2021). The mutations in the NFKB1 gene cause increased inflammasome activation in vitro. In this respect, it can be assumed that agents that inhibit IL-1β or TNF could be useful.

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2. Fang R et al. (2021) Case report: a novel mutation in associated with pyoderma gangrenosum. Front Genet 12:673453.
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