Entry - *164011 - NUCLEAR FACTOR KAPPA-B, SUBUNIT 1; NFKB1

NFKB has been detected in numerous cell types that express cytokines, chemokines, growth factors, cell adhesion molecules, and some acute phase proteins in health and in various disease states. NFKB is activated by a wide variety of stimuli such as cytokines, oxidant-free radicals, inhaled particles, ultraviolet irradiation, and bacterial or viral products. Inappropriate activation of NF-kappa-B has been linked to inflammatory events associated with autoimmune arthritis, asthma, septic shock, lung fibrosis, glomerulonephritis, atherosclerosis, and AIDS. In contrast, complete and persistent inhibition of NF-kappa-B has been linked directly to apoptosis, inappropriate immune cell development, and delayed cell growth. For reviews, see Chen et al. (1999) and Baldwin (1996).

NFKB1 or NFKB2 (164012) is bound to REL (164910), RELA (164014), or RELB (604758) to form the NFKB complex. The NFKB complex is inhibited by I-kappa-B proteins (NFKBIA, 164008 or NFKBIB, 604495), which inactivate NF-kappa-B by trapping it in the cytoplasm. Phosphorylation of serine residues on the I-kappa-B proteins by kinases (IKBKA, 600664, or IKBKB, 603258) marks them for destruction via the ubiquitination pathway (see 603482), thereby allowing activation of the NF-kappa-B complex. Activated NFKB complex translocates into the nucleus and binds DNA at kappa-B-binding motifs such as 5-prime GGGRNNYYCC 3-prime or 5-prime HGGARNYYCC 3-prime (where H is A, C, or T; R is an A or G purine; and Y is a C or T pyrimidine).

▼ Cloning and Expression

NFKB1 was first described as interacting with an 11-bp cis-acting sequence in the immunoglobulin light-chain enhancer (Sen and Baltimore, 1986). The NFKB complex has 2 alternative DNA binding subunits, p105 and p52/p100 (164012). Meyer et al. (1991) isolated and sequenced cDNA clones for the DNA binding subunit of nuclear factor kappa-B (NF-kappa-B). The encoded open reading frame of about 105 kD contains at its N-terminal half all 6 tryptic peptide sequences, suggesting that the 51-kD NF-kappa-B protein is processed from a 105-kD precursor. This region shows high homology to a domain shared by the Drosophila 'dorsal' gene and the avian and mammalian REL oncogene products. The level of 3.8-kb mRNA was strongly increased after stimulation with tumor necrosis factor-alpha (TNF; 191160) or phorbol ester.

▼ Gene Structure

Heron et al. (1995) showed that NFKB1 has 24 exons spanning 156 kb.

▼ Mapping

By Southern blot analysis of panels of human/Chinese hamster cell hybrids, Liptay et al. (1992) assigned the p105 gene to 4q21.1-q24. The localization was confirmed and more precisely determined as 4q23 by fluorescence in situ hybridization (FISH). By FISH, Mathew et al. (1993) mapped the NFKB1 gene, referred to by them as NF-kappa-Bp50, to 4q24. Le Beau et al. (1992) likewise mapped the gene, which they probably mistakenly referred to as NFKB2, to 4q24.

▼ Gene Function

Processing

Lin et al. (1998) demonstrated that the p50 protein product of NFKB1 is generated by a unique cotranslational processing event involving the 26S proteasome (see 602706), whereas cotranslational folding of sequences near the C terminus of p50 abrogates proteasome processing and leads to production of p105, the other protein product of NFKB1. According to Lin et al. (1998), these results indicated that p105 is not the precursor of p50 and revealed a novel mechanism of gene regulation that ensures the balanced production and independent function of the p50 and p105 proteins.

Role in Immune Function and Inflammation

Barnes and Karin (1997) reviewed the role of NF-kappa-B in chronic inflammatory diseases. They tabulated the stimuli that activate NF-kappa-B and the proteins regulated by this transcription factor. They also discussed the effects of glucocorticoids on NF-kappa-B and the therapeutic implications.

Yamamoto and Gaynor (2001) reviewed the therapeutic potential of inhibition of the NF-kappa-B pathway in the treatment of inflammation and cancer.

Hiscott et al. (2001) reviewed the many ways in which viruses interact with the NF-kappa-B pathway. The wide functional implications of NFKB1 are reflected in the reviews on the relationship to cancer by Baldwin (2001), on the relationship to neuronal plasticity and treatment of neurologic disorders by Mattson and Camandola (2001), and on the possible relationship to atherogenesis by Collins and Cybulsky (2001).

Expression of HLA-DR antigen (see 142860) and intracellular adhesion molecule-1 (ICAM1; 147840) in human conjunctival epithelium is upregulated in patients with dry eyes associated with Sjogren syndrome (270150). Tsubota et al. (1999) reported that this upregulation in Sjogren syndrome patients may be controlled by interferon-gamma (147570) through the activation of NF-kappa-B.

Aljada et al. (2001) investigated whether insulin inhibits the proinflammatory chemokine monocyte chemoattractant protein-1 (MCP1; 158105), which attracts leukocytes to inflamed sites and is regulated by NF-kappa-B. Insulin was incubated with cultured human aortic endothelial cells at 0, 100, and 1000 microU/mL. Intranuclear NF-kappa-B binding activity was suppressed by approximately 45% at 100 microU/mL and by 60% at 1000 microU/mL. MCP1 mRNA expression was also suppressed by 47% at 100 microU/mL and by 79% at 1000 microU/mL. The authors concluded that insulin at physiologically relevant concentrations exerts an inhibitory effect on the cardinal proinflammatory transcription factor NF-kappa-B and the proinflammatory chemokine MCP1; these effects suggest an antiinflammatory and potential antiatherogenic effect of insulin.

Nitric oxide (NO) generated from inducible NO synthase (NOS2A; 163730) participates in inflammatory responses and has been implicated in migraine (157300) based on pharmacologic evidence in animals and humans. In a rat model, Reuter et al. (2002) showed that the NO donor glyceryl trinitrate (GTN) caused NOS2A expression in macrophages, mediated by increased activity of NFKB1, resulting in generation of NO within rodent dura mater 6 hours later. Parthenolide, a lactone found in the medical herb 'feverfew' which has been used successfully in the treatment of inflammatory conditions and migraine, blocked NOS2A expression in dura mater by inhibiting NFKB1. Reuter et al. (2002) concluded that NFKB1 plays a major role in the expression of proinflammatory proteins that lead to increased blood vessel permeability, tissue edema, and pain sensitization that underlie the pathogenesis of migraine, and that blockade of NFKB1 could be a transcriptional target of antimigraine drugs.

To test the hypothesis that activation of NFKB, which is frequently detected in tumors, may constitute a missing link between inflammation and cancer, Pikarsky et al. (2004) studied the Mdr2 (171060) knockout mouse, which spontaneously develops cholestatic hepatitis followed by hepatocellular carcinoma, a prototype of inflammation-associated cancer. Pikarsky et al. (2004) monitored hepatitis and cancer progression in Mdr2 knockout mice and showed that the inflammatory process triggers hepatocyte Nfkb through upregulation of TNF-alpha (191160) in adjacent endothelial and inflammatory cells. Switching off Nfkb in mice from birth to 7 months of age, using a hepatocyte-specific inducible I-kappa-B (see 164008) superrepressor transgene, had no effect on the course of hepatitis, nor did it affect early phases of hepatocyte transformation. By contrast, suppressing Nfkb inhibition through anti-TNF-alpha treatment or induction of I-kappa-B superrepressor in later stages of tumor development resulted in apoptosis of transformed hepatocytes and failure to progress to hepatocellular carcinoma. Pikarsky et al. (2004) concluded that NFKB is essential for promoting inflammation-associated cancer and is therefore a potential target for cancer prevention in chronic inflammatory diseases.

Lawrence et al. (2005) described a role for IKK-alpha (600664) in the negative regulation of macrophage activation and inflammation. IKK-alpha contributes to suppression of NF-kappa-B activity by accelerating both the turnover of the NF-kappa-B subunits Rela (164014) and c-Rel (REL; 164910) and their removal from proinflammatory gene promoters. Inactivation of IKK-alpha in mice enhanced inflammation and bacterial clearance. Lawrence et al. (2005) concluded that the 2 IKK catalytic subunits have evolved opposing but complementary roles needed for the intricate control of inflammation and innate immunity.

Nenci et al. (2007) demonstrated that the transcription factor NFKB, a master regulator of proinflammatory responses, functions in gut epithelial cells to control epithelial integrity and the interaction between the mucosal immune system and gut microflora. Intestinal epithelial cell-specific inhibition of NFKB through conditional ablation of NEMO (300248) or both IKBKA (600664) and IKBKB (603258), IKK subunits essential for NFKB activation, spontaneously caused severe chronic intestinal inflammation in mice. NFKB deficiency led to apoptosis of colonic epithelial cells, impaired expression of antimicrobial peptides, and translocation of bacteria into the mucosa. Concurrently, this epithelial defect triggered a chronic inflammatory response in the colon, initially dominated by innate immune cells but later also involving T lymphocytes. Deficiency of the gene encoding the adaptor protein MyD88 (602170) prevented the development of intestinal inflammation, demonstrating that Toll-like receptor (TLR) activation by intestinal bacteria is essential for disease pathogenesis in this mouse model. Furthermore, NEMO deficiency sensitized epithelial cells to TNF (191160)-induced apoptosis, whereas TNFR1 (191190) inactivation inhibited intestinal inflammation, demonstrating that TNFR1 signaling is crucial for disease induction. Nenci et al. (2007) concluded that a primary NFKB signaling defect in intestinal epithelial cells disrupts immune homeostasis in the gastrointestinal tract, causing an inflammatory bowel disease-like phenotype. Their results further identified NFKB signaling in the gut epithelium as a critical regulator of epithelial integrity and intestinal immune homeostasis and have important implications for understanding the mechanisms controlling the pathogenesis of human inflammatory bowel disease.

Carmody et al. (2007) reported the identification of B-cell leukemia-3 (BCL3; 109560) as an essential negative regulator of TLR signaling. By blocking ubiquitination of p50, Bcl3 stabilizes a p50 complex that inhibits gene transcription. As a consequence, Bcl3-deficient mice and cells were found to be hypersensitive to TLR activation and unable to control responses to lipopolysaccharides. Carmody et al. (2007) concluded that thus, p50 ubiquitination blockade by BCL3 limits the strength of TLR responses and maintains innate immune homeostasis.

Kravchenko et al. (2008) showed that a bacterial small molecule, N-(3-oxo-dodecanoyl) homoserine lactone (C12), selectively impairs the regulation of NFKB functions in activated mammalian cells. The consequence is specific repression of stimulus-mediated induction of NFKB-responsive genes encoding inflammatory cytokines and other immune regulators. Kravchenko et al. (2008) concluded that their findings uncovered a strategy by which C12-producing opportunistic pathogens, such as P. aeruginosa, attenuate the innate immune system to establish and maintain local persistent infection in humans, for example, in cystic fibrosis patients.

Zhang et al. (2013) showed that the hypothalamus is important for the development of whole-body aging in mice, and that the underlying basis involves hypothalamic immunity mediated by IKK-beta, NF-kappa-B, and related microglia-neuron immune crosstalk. Several interventional models were developed showing that aging retardation and life span extension were achieved in mice by preventing aging-related hypothalamic or brain IKK-beta and NF-kappa-B activation. Mechanistic studies further revealed that IKK-beta and NF-kappa B inhibit gonadotropin-releasing hormone (GNRH; 152760) to mediate aging-related hypothalamic GNRH decline, and GNRH treatment amends aging-impaired neurogenesis and decelerates aging. Zhang et al. (2013) concluded that the hypothalamus plays a programmatic role in aging development via immune-neuroendocrine integration.

Dying cells initiate adaptive immunity by providing antigens and apoptotic stimuli for dendritic cells, which in turn activate CD8-positive T cells through antigen cross-priming. Yatim et al. (2015) established models of apoptosis and necroptosis in which dying cells were generated through dimerization of RIPK3 (603453) and CASP8 (601763), respectively. They found that release of inflammatory mediators, such as damage-associated molecular patterns, was not sufficient for CD8-positive T-cell cross-priming. Instead, robust cross-priming required RIPK1 signaling and NFKB-induced transcription within the dying cells. Lack of NFKB signaling in necroptosis or inflammatory apoptosis reduced priming efficiency and tumor immunity. Yatim et al. (2015) proposed that coordinated inflammatory and cell death signaling pathways within dying cells are required for adaptive immunity.

NFKB Signaling Pathway

Ozes et al. (1999) showed that AKT1 (164730) is involved in the activation of NFKB1 by TNF, following the activation of phosphatidylinositol 3-kinase (PIK3; see 171834). Constitutively active AKT1 induces NFKB1 activity, mediated by phosphorylation of IKBKA (600664) at threonine-23, which can be blocked by dominant-negative NIK (604655). Conversely, NIK activation of NFKB1, mediated by phosphorylation of IKBKA at serine-176, is blocked by an AKT1 mutant lacking kinase activity (i.e., kinase-dead AKT), indicating that both AKT1 and NIK are necessary for TNF activation of NFKB1 through the phosphorylation of IKBKA. IKBKB (603258) is not phosphorylated by either NIK or AKT1 and is apparently differentially regulated.

Most proliferating cells are programmed to undergo apoptosis unless specific survival signals are provided. Platelet-derived growth factor (PDGF; 190040) promotes cellular proliferation and inhibits apoptosis. Romashkova and Makarov (1999) showed that PDGF activates the RAS (see 190020)/PIK3 (see 171834)/AKT1/IKK/NFKB1 pathway. In this pathway, NFKB1 does not induce c-myc (190080) and apoptosis, but instead induces putative antiapoptotic genes. In response to PDGF, AKT1 transiently associates with IKK (see 600664) and induces IKK activation. The authors suggested that under certain conditions PIK3 may activate NFKB1 without the involvement of NFKBIA or NFKBIB degradation.

Aliprantis et al. (1999) demonstrated that bacterial lipoproteins stimulated NF-kappa-B and activated the respiratory burst through TLR2 (603028). Thus, TLR2 is a molecular link between microbial products, apoptosis, and host defense mechanisms.

The tumor suppressor p53 (191170) inhibits cell growth through activation of cell cycle arrest and apoptosis. Most cancers lack active p53, suggesting a therapeutic intervention. The NFKB transcription factor can protect from or contribute to apoptosis. Ryan et al. (2000) examined in detail the effect of p53 induction on activation of NFKB. In cells without NFKB activity, p53-induced apoptosis is abrogated. P53 activates NFKB through the RAF (164760)/MEK1 (176872)/p90(rsk) (see 601684) pathway rather than the TNFR1 (191190)/TRAF2 (601895)/IKK pathway used by TNF. Ryan et al. (2000) showed that inhibition of MEK1 blocks p53-induced NFKB activation and apoptosis but not cell cycle arrest.

In addition to its role as a kidney cytokine regulating hematopoiesis, erythropoietin (133170) is also produced in the brain after oxidative or nitrosative stress. The transcription factor HIF1 (603348) upregulates erythropoietin following hypoxic stimuli. Digicaylioglu and Lipton (2001) demonstrated that preconditioning with erythropoietin protects neurons in models of ischemic and degenerative damage due to excitotoxins and consequent generation of free radicals, including nitric oxide. Activation of neuronal erythropoietin receptors (133171) prevents apoptosis induced by NMDA or nitric oxide by triggering crosstalk between the signaling pathways JAK2 (147796) and NFKB. Digicaylioglu and Lipton (2001) demonstrated that erythropoietin receptor-mediated activation of JAK2 leads to phosphorylation of the inhibitor of NFKB (I-kappa-B), subsequent nuclear translocation of the transcription factor NFKB, and NFKB-dependent transcription of neuroprotective genes. Transfection of cerebrocortical neurons with a dominant interfering form of JAK2 or an I-kappa-B-alpha superrepressor blocks erythropoietin-mediated prevention of neuronal apoptosis. Thus, neuronal erythropoietin receptors activate a neuroprotective pathway that is distinct from previously well characterized JAK and NFKB functions. Moreover, this erythropoietin effect may underlie neuroprotection mediated by hypoxic-ischemic preconditioning.

Baek et al. (2002) demonstrated that interleukin-1-beta (IL1B; 147720) causes nuclear export of a specific NCOR (600849) corepressor complex, resulting in derepression of a specific subset of NFKB-regulated genes. These genes are exemplified by the tetraspanin KAI1 (600623), which regulates membrane receptor function. Nuclear export of the NCOR/TAB2 (605101)/HDAC3 (605166) complex by IL1B is temporally linked to selective recruitment of a TIP60 (601409) coactivator complex. KAI1 is also directly activated by a ternary complex, dependent on the acetyltransferase activity of TIP60, that consists of the presenilin-dependent C-terminal cleavage product of the beta amyloid precursor protein (APP; 104760), FE65 (602709), and TIP60, identifying a specific in vivo gene target of an APP-dependent transcription complex in the brain.

Zhong et al. (2002) demonstrated that transcriptionally inactive nuclear NFKB in resting cells consists of homodimers of either p65 or p50 complexed with the histone deacetylase HDAC1 (601241). Only the p50-HDAC1 complexes bound to DNA and suppressed NFKB-dependent gene expression in unstimulated cells. Appropriate stimulation caused nuclear localization of NFKB complexes containing phosphorylated p65 that associated with CBP (600140) and displaced the p50-HDAC1 complexes. These results demonstrated that phosphorylation of p65 determines whether it associates with either CBP or HDAC1, ensuring that only p65 entering the nucleus from cytoplasmic NFKB-IKB complexes can activate transcription.

Waterfield et al. (2003) demonstrated that the Nfkb1 gene product p105 regulates MAPK signaling triggered by the bacterial component lipopolysaccharide in mice. P105 exerted this signaling function by controlling the stability and function of an upstream kinase, Tpl2 (191195). In mouse macrophages, Tpl2 formed a stable and inactive complex with p105, and activation of Tpl2 involved its dissociation from p105 and subsequent degradation. The authors concluded that p105 functions as a physiologic partner and inhibitor of TPL2, providing an example of how a transcription factor component regulates upstream signaling events.

By affinity purification in HeLa cells, Lang et al. (2004) identified ABIN2 (TNIP2; 610669) as a protein associated with p105. Cotransfection studies in HeLa cells showed that ABIN2 also interacted with TPL2 and preferentially formed a ternary complex with both proteins. In bone marrow-derived macrophages, a substantial fraction of endogenous ABIN2 was associated with both p105 and TPL2. Mutation and binding analysis showed that ABIN2 interacted with the death domain and PEST region of p105 and with the C terminus of TPL2. Depletion of ABIN2 by RNA interference in HeLa cells and human embryonic kidney cells dramatically reduced TPL2 protein levels, but did not alter TPL2 mRNA or p105 protein levels. ABIN2 increased the half-life of cotransfected TPL2 in human embryonic kidney cells. Lang et al. (2004) concluded that optimal TPL2 stability requires interaction with both ABIN2 and p105.

Anest et al. (2003) demonstrated nuclear accumulation of IKKA (600664) after cytokine exposure, suggesting a nuclear function for this protein. Consistent with this, chromatin immunoprecipitation assays revealed that IKKA was recruited to the promoter regions of NF-kappa-B-regulated genes on stimulation with tumor necrosis factor-alpha (191160). Notably, NF-kappa-B-regulated gene expression was suppressed by the loss of IKKA, and this correlated with a complete loss of gene-specific phosphorylation of histone H3 (see 602810) on serine-10, a modification previously associated with positive gene expression. Furthermore, Anest et al. (2003) showed that IKKA can directly phosphorylate histone H3 in vitro, suggesting a new substrate for this kinase. Anest et al. (2003) proposed that IKKA is an essential regulator of NFKB-dependent gene expression through control of promoter-associated histone phosphorylation after cytokine exposure.

Yamamoto et al. (2003) independently demonstrated that IKKA functions in the nucleus to activate the expression of NF-kappa-B-responsive genes after stimulation with cytokines. IKKA interactions with CREB-binding protein (600140) and in conjunction with RELA (164014) is recruited to NF-kappa-B-responsive promoters and mediates the cytokine-induced phosphorylation and subsequent acetylation of specific residues in histone H3. Yamamoto et al. (2003) concluded that their results defined a new nuclear role of IKKA in modifying histone function that is critical for the activation of NF-kappa-B-directed gene expression.

Brummelkamp et al. (2003) designed a collection of RNA interference vectors to suppress 50 human deubiquitinating enzymes and used these vectors to identify deubiquitinating enzymes in cancer-relevant pathways. They demonstrated that inhibition of CYLD (605018) enhances activation of the transcription factor NF-kappa-B. They showed that CYLD binds to the NEMO (IKBKG; 300248) component of the IKK complex (see 600664), and appears to regulate its activity through deubiquitination of TRAF2 (601895), as TRAF2 ubiquitination can be modulated by CYLD. Inhibition of CYLD increased resistance to apoptosis, suggesting a mechanism through which loss of CYLD contributes to oncogenesis. Brummelkamp et al. (2003) further demonstrated that this effect can be relieved by aspirin derivatives that inhibit NF-kappa-B activity.

Trompouki et al. (2003) identified CYLD as a deubiquitinating enzyme that negatively regulates activation of NF-kappa-B by specific tumor necrosis factor receptors (TNFRs). Loss of the deubiquitinating activity of CYLD correlated with tumorigenesis. CYLD inhibits activation of NF-kappa-B by the TNFR family members CD40 (109535), XEDAR (300276), and EDAR (604095) in a manner that depends on deubiquitinating activity of CYLD. Downregulation of CYLD by RNA-mediated interference augments both basal and CD40-mediated activation of NF-kappa-B. The inhibition of NF-kappa-B activation by CYLD is mediated, at least in part, by the deubiquitination and inactivation of TRAF2 and, to a lesser extent, TRAF6 (602355). Trompouki et al. (2003) concluded that CYLD is a negative regulator of the cytokine-mediated activation of NF-kappa-B that is required for appropriate cellular homeostasis of skin appendages.

Smahi et al. (2002) reviewed the NFKB signaling pathway, with emphasis on its dysregulation in the genetic disorders incontinentia pigmenti (308300), hypohidrotic/anhidrotic ectodermal dysplasia (see 305100), anhidrotic ectodermal dysplasia with immunodeficiency (EDAID; 300291), and EDAID with osteopetrosis and lymphedema (see 300291).

Using an integrated approach comprising tandem affinity purification, liquid chromatography tandem mass spectrometry, network analysis, and directed functional perturbation studies using RNA interference or loss-of-function analysis, Bouwmeester et al. (2004) identified 221 molecular associations and 80 previously unknown interactors, including 10 novel functional modulators, of the TNFA/NFKB signal transduction pathway.

Ducut Sigala et al. (2004) identified ELKS (607127) as an essential regulatory subunit of the IKK complex. Silencing ELKS expression by RNA interference blocked induced expression of NF-kappa-B target genes, including the NF-kappa-B inhibitor IKBA (164008) and proinflammatory genes such as cyclooxygenase-2 (COX2; 600262) and interleukin-8 (IL8; 146930). These cells were also not protected from apoptosis in response to cytokines. Ducut Sigala et al. (2004) concluded that ELKS likely functions by recruiting IKBA to the IKK complex and thus serves a regulatory function in IKK activation.

Wertz et al. (2004) demonstrated that A20 (191163) downregulates NF-kappa-B signaling through the cooperative activity of its 2 ubiquitin-editing domains. The N-terminal domain of A20, which is a deubiquitinating enzyme of the OTU (ovarian tumor) family, removes lysine-63-linked ubiquitin chains from receptor-interacting protein (RIPK1; 603453), an essential mediator of the proximal TNF receptor-1 (TNFR1; 191190) signaling complex. The C-terminal domain of A20, composed of 7 C2/C2 zinc fingers, then functions as a ubiquitin ligase by polyubiquitinating RIPK1 with lysine-48-linked ubiquitin chains, thereby targeting RIPK1 for proteasomal degradation. Wertz et al. (2004) defined a novel ubiquitin ligase domain and identified 2 sequential mechanisms by which A20 downregulates NF-kappa-B signaling. They also provided an example of a protein containing separate ubiquitin ligase and deubiquitinating domains, both of which participate in mediating a distinct regulatory effect.

Covert et al. (2005) showed that whereas the activation dynamics of NF-kappa-B exhibit damped oscillatory behavior when cells are stimulated by TNFA, they show stable behavior when stimulated by lipopolysaccharide. Lipopolysaccharide binding to Toll-like receptor-4 (TLR4; 603030) causes activation of NF-kappa-B that requires 2 downstream pathways, each of which when isolated exhibits damped oscillatory behavior. Computational modeling of the 2 TLR4-dependent signaling pathways suggests that 1 pathway requires a time delay to establish early antiphase activation of NF-kappa-B by the 2 pathways. The MyD88 (602170)-independent pathway required interferon regulatory factor-3 (IRF3; 603734)-dependent expression of TNFA to activate NF-kappa-B, and the time required for TNFA synthesis established the delay.

Activation of the NF-kappa-B pathway by the TNF receptor EDAR (604095) and its downstream adaptor EDARADD (606603) is essential for the development of hair follicles, teeth, exocrine glands, and other ectodermal derivatives. Morlon et al. (2005) performed a yeast 2-hybrid screen and isolated TAB2 (MAP3K7IP2; 605101) as a binding partner of EDARADD. TAB2 is an adaptor protein that bridges TNF receptor-associated factor-6 (TRAF6; 602355) to TAK1 (NR2C2; 601426), allowing TAK1 activation and subsequent IKK activation. Endogenous and overexpressed TAB2, TRAF6, and TAK1 coimmunoprecipitated with EDARADD in HEK293 cells. Moreover, dominant-negative forms of TAB2, TRAF6, and TAK1 blocked the NF-kappa-B activation induced by EDARADD. Morlon et al. (2005) concluded that the TAB2/TRAF6/TAK1 signaling complex is involved in the EDAR signal transduction pathway.

Wu et al. (2006) demonstrated that regulated nuclear shuttling of NEMO (300248) links 2 signaling kinases, ATM (607585) and IKK, to activate NF-kappa-B by genotoxic signals. NEMO associates with activated ATM after the induction of DNA double-strand breaks. ATM phosphorylates serine-85 of NEMO to promote its ubiquitin-dependent nuclear export. ATM is also exported in a NEMO-dependent manner to the cytoplasm, where it associates with and causes the activation of IKK in a manner dependent on another IKK regulator, a protein rich in glutamate, leucine, lysine, and serine (ELKS; 607127).

Medeiros et al. (2007) presented evidence for a previously unrecognized function for ADAP (602731) in regulating T-cell receptor (TCR)-mediated activation of the transcription factor NF-kappa-B. Stimulation of ADAP-deficient mouse T cells with antibodies to CD3 (see 186740) and CD28 (186760) resulted in impaired nuclear translocation of NF-kappa-B, a reduced DNA binding, and delayed degradation and decreased phosphorylation of I-kappa-B (see 164008). TCR-stimulated assembly of the CARMA1-BCL10 (603517)-MALT1 (604860) complex was substantially impaired in the absence of ADAP. Medeiros et al. (2007) further identified a region of ADAP that is required for association with the CARMA1 adaptor and NF-kappa-B activation but is not required for ADAP-dependent regulation of adhesion.

Using mice lacking Ikbkb in different cell types, Rius et al. (2008) showed that NF-kappa-B was a critical transcriptional activator of Hif1a (603348) and that basal NF-kappa-B activity was required for Hif1a protein accumulation under hypoxia in cultured cells and in the liver and brain of hypoxic animals. IKBKB deficiency resulted in defective induction of Hif1a target genes including vascular endothelial growth factor (VEGF; 192240). Ikbkb was essential for Hif1a accumulation in macrophages experiencing a bacterial infection.

Ashall et al. (2009) showed that pulsatile stimulation with TNF-alpha determines timing and specificity of NF-kappa-B-dependent transcription.

Tay et al. (2010) used high-throughput microfluidic cell culture and fluorescence microscopy, quantitative gene expression analysis, and mathematical modeling to investigate how single mammalian cells respond to different concentrations of TNF-alpha and relay information to the gene expression programs by means of NF-kappa-B. Tay et al. (2010) measured NF-kappa-B activity in thousands of live cells under TNF-alpha doses covering 4 orders of magnitude. They found that, in contrast to population-level studies with bulk assays, the activation was heterogeneous and was a digital process at the single-cell level with fewer cells responding at lower doses. Cells also encoded a subtle set of analog parameters, including NF-kappa-B peak intensity, response time, and number of oscillations, to modulate the outcome. Tay et al. (2010) developed a stochastic mathematical model that reproduced both the digital and analog dynamics, as well as most gene expression profiles, at all measured conditions, constituting a broadly applicable model for TNA-alpha-induced NF-kappa-B signaling in various types of cells.

Bivona et al. (2011) used a pooled RNAi screen to show that knockdown of FAS (134637) and several components of the NF-kappa-B pathway specifically enhanced cell death induced by the EGFR (131550) tyrosine kinase inhibitor (TKI) erlotinib in EGFR-mutant lung cancer cells. Activation of NF-kappa-B through overexpression of c-FLIP (603599) or IKK-beta (603258), or silencing of I-kappa-B (see 164008), rescued EGFR-mutant lung cancer cells from EGFR TKI treatment. Genetic or pharmacologic inhibition of NF-kappa-B enhanced erlotinib-induced apoptosis in erlotinib-sensitive and erlotinib-resistant EGFR-mutant lung cancer models. Increased expression of the NF-kappa-B inhibitor I-kappa-B predicted improved response and survival in EGFR-mutant lung cancer patients treated with EGFR TKI. Bivona et al. (2011) concluded that their data identified NF-kappa-B as a potential companion drug target, together with EGFR, in EGFR-mutant lung cancers and provided insight into the mechanisms by which tumor cells escape from oncogene dependence.

Using proteomic analysis, Toubiana et al. (2011) found that stimulation of a human monocyte cell line with TLR2 agonists resulted in rapidly increased expression of posttranslationally modified IMPDHII (IMPDH2; 146691) in lipid rafts. Mass spectrometric and immunoprecipitation analyses determined that the IMPDHII modification involved tyrosine phosphorylation. Luciferase analysis showed that IMPDHII inhibited NFKB activity and reduced TNF production, but IMPDHII did not modify MAP kinase activation or prevent degradation of IKB. IMPDHII inhibited phosphorylation of p65 (RELA) and modulated PI3K (see 601232) activation upstream of AKT. IMPDHII inhibition of NFKB activation involved dephosphorylation of the p85-alpha subunit (PIK3R1; 171833) of PI3K through increased SHP1 (PTPN6; 176883) activity.

Role in Differentiation

MYOD (159970) regulates skeletal muscle differentiation and is essential for repair of damaged tissue. NFKB is activated by the cytokine tumor necrosis factor (TNF; 191160), a mediator of skeletal muscle wasting in cachexia. Guttridge et al. (2000) explored the role of NFKB in cytokine-induced muscle degeneration. In differentiating C2C12 myocytes, TNF-induced activation of NFKB inhibited smooth skeletal muscle differentiation by suppressing MYOD mRNA at the posttranscriptional level. In contrast, in differentiated myotubes, TNF plus interferon-gamma signaling was required for NFKB-dependent downregulation of MYOD and dysfunction of skeletal myofibers. MYOD mRNA was also downregulated by TNF and interferon-gamma expression in mouse muscle in vivo. Guttridge et al. (2000) concluded that their data elucidate a possible mechanism that may underlie the skeletal muscle decay in cachexia.

Role in Cancer

In studies using a highly bone-metastatic human breast cancer cell line, Park et al. (2007) found that constitutive NFKB activity in breast cancer cells initiated the bone resorption characteristic of osteolytic bone metastasis. A key target of NFKB was CSF2 (138960), which mediated osteolytic bone metastasis of breast cancer by stimulating osteoclast development. Immunostaining of human bone-metastatic breast tumor tissue revealed that expression of CSF2 correlated with NFKB activation. Park et al. (2007) concluded that NFKB in breast cancer cells promotes osteolytic bone metastasis by inducing osteoclastogenesis via CSF2.

In studies involving bone marrow progenitor cells and T-cell acute lymphoblastic leukemia (T-ALL) cell lines, Vilimas et al. (2007) found that constitutively active NOTCH1 (190198) activated the NFKB pathway transcriptionally and via the IKK complex, thereby causing increased expression of NFKB target genes. The NFKB pathway was highly active in establishing human T-ALL, and inhibition of the pathway efficiently restricted tumor growth both in vitro and in vivo. Vilimas et al. (2007) concluded that NFKB is one of the major mediators of NOTCH1-induced transformation.

Meylan et al. (2009) showed that the NF-kappa-B pathway is required for the development of tumors in a mouse model of lung adenocarcinoma. Concomitant loss of p53 (191170) and expression of oncogenic Kras containing the G12D mutation (190070.0003) resulted in NF-kappa-B activation in primary mouse embryonic fibroblasts. Conversely, in lung tumor cell lines expressing Kras(G12D) and lacking p53, p53 restoration led to NF-kappa-B inhibition. Furthermore, the inhibition of NF-kappa-B signaling induced apoptosis in p53-null lung cancer cell lines. Inhibition of the pathway in lung tumors in vivo, from the time of tumor initiation or after tumor progression, resulted in significantly reduced tumor development. Meylan et al. (2009) concluded that, together, their results indicate a critical function for NF-kappa-B signaling in lung tumor development and, further, that this requirement depends on p53 status.

Barbie et al. (2009) used systematic RNA interference to detect synthetic lethal partners of oncogenic KRAS and found that the noncanonical I-kappa-B kinase TBK1 (604834) was selectively essential in cells that contain mutant KRAS. Suppression of TBK1 induced apoptosis specifically in human cancer cell lines that depend on oncogenic KRAS expression. In these cells, TBK1 activated NF-kappa-B antiapoptotic signals involving c-REL (164910) and BCLXL (BCL2L1; 600039) that were essential for survival, providing mechanistic insights into this synthetic lethal interaction. Barbie et al. (2009) concluded that TBK1 and NF-kappa-B signaling are essential in KRAS mutant tumors, and that their findings established a general approach for the rational identification of codependent pathways in cancer.

Role in Brain Function

Meffert et al. (2003) found that the p65/p50 NFKB form is selectively localized at synapses in isolated hippocampal neuronal cultures, and that it is activated by increases in calcium, likely via the calcium/calmodulin-dependent kinase CaMKII (114078). Activated NFKB moved to the nucleus, where it could bind DNA. P65-deficient mice had no detectable synaptic NFKB and showed a selective spatial learning deficit. Meffert et al. (2003) suggested that long-term changes to adult neuronal function caused by synaptic stimulation may be regulated by NFKB nuclear translocation and gene activation.

▼ Evolution

Kasowski et al. (2010) examined genomewide differences in transcription factor binding in several humans and a single chimpanzee by using chromatin immunoprecipitation followed by sequencing. They mapped the binding sites of RNA polymerase II (see 180660) and NF-kappa-B in 10 lymphoblastoid cell lines and found that 25% and 7.5% of the respective binding regions differed between individuals. Binding differences were frequently associated with SNPs and genomic structural variants, and these differences were often correlated with differences in gene expression, suggesting functional consequences of binding variation. Furthermore, the results of comparing PollII binding between humans and chimpanzee suggested extensive divergence in transcription factor binding.

▼ Biochemical Features

Crystal Structure

The inhibitory protein, NFKBIA, sequesters the transcription factor, NFKB, as an inactive complex in the cytoplasm (Jacobs and Harrison, 1998). Jacobs and Harrison (1998) and Huxford et al. (1998) determined the structure of the NFKBIA ankyrin repeat domain, bound to a partially truncated NFKB heterodimer (p50/p65), by x-ray crystallography at 2.7- and 2.3-angstrom resolution, respectively. It shows a stack of 6 NFKBIA ankyrin repeats facing the C-terminal domains of the NFKB rel homology regions. Contacts occur in discontinuous patches, suggesting a combinatorial quality for ankyrin repeat specificity. The first 2 repeats cover an alpha helically ordered segment containing the p65 nuclear localization signal. The position of the sixth ankyrin repeat shows that full-length NFKBIA will occlude the NFKB DNA-binding cleft. The orientation of NFKBIA in the complex places its N- and C-terminal regions in appropriate locations for their known regulatory functions. Baeuerle (1998) discussed the model of interactions between NFKBIA and NFKB.

▼ Molecular Genetics

Common Variable Immunodeficiency 12 with Autoimmunity

In affected members of 3 unrelated families with autosomal dominant common variable immunodeficiency-12 with autoimmunity (CVID12; 616576), Fliegauf et al. (2015) identified 3 different heterozygous mutations in the NFKB1 gene (164011.0001-164011.0003). The mutations in 2 families were found by whole-exome sequencing; the mutation in the third family was found by targeted sequencing of a cohort of families with CVID. Studies of patient cells and in vitro studies of cells transfected with the mutations showed that all mutations resulted in functional haploinsufficiency of the NFKB1 p50 protein.

In 2 unrelated women with CVID12, Schipp et al. (2016) identified heterozygous loss-of-function mutations in the NFKB1 gene (164011.0004 and 164011.0005). The frameshift and nonsense mutations both occurred in the RHD domain. The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing; one occurred de novo and the other was inherited from an unaffected parent, consistent with incomplete penetrance. Studies of patient cells showed showed decreased RNA and protein levels of both the p50 and p105 isoforms, decreased NFKB1 transcriptional activity, and decreased expression of NFKB-related genes. The findings were consistent with a loss-of-function effect and haploinsufficiency.

In 16 probands of European descent with CVID12, Tuijnenburg et al. (2018) identified heterozygous mutations in the NFKB1 gene (see, e.g., 164011.0006-164011.0008). The mutations, which were found by whole-genome sequencing and confirmed by Sanger sequencing, were absent from the gnomAD database. Twelve patients had truncating variants, 3 had missense variants, and 1 had a gene deletion. All point mutations were located in the N-terminal p50 part of the protein in the RHD domain. Analysis of patient cells showed decreased NFKB1 protein levels (about 50%) compared to controls. Functional studies were not performed, but the findings were consistent with haploinsufficiency as a pathogenetic mechanism.

Through worldwide collaborative efforts, Lorenzini et al. (2020) identified 157 individuals with CVID12 from 68 unrelated families, mostly of European descent, with 56 distinct heterozygous variants in the NFKB1 gene that were classified as pathogenic through in silico analysis and/or in vitro functional expression studies (see, e.g., 164011.0008-164011.0010). This set of patients came from a larger cohort of 231 patients from 129 unrelated families with 105 heterozygous NFKB1 variants. The variants were identified by next-generation, whole-exome, or whole-genome sequencing. Half of the pathogenic variants had previously been reported, whereas half were novel. Most were located in the N-terminal Rel homology domain (RHD). The authors categorized the mutations into 3 groups by postulated effect: haploinsufficiency due to nonsense, frameshift, or splice site mutations; 'precursor-skipping mutations' causing a lack of p105 with expression of a p50-like protein that localizes normally to the nucleus; and missense variants. In vitro functional expression studies, performed on some of the mutations, showed aberrant protein localization, decreased protein stability, and/or reduced NFKB1 promoter activation, consistent with haploinsufficiency as a disease mechanism. However, detailed functional studies showed that most of the missense variants had normal cellular localization and normal NFKB activation. The authors suggested that these variants may have subtle effects.

Associations Pending Confirmation

Karban et al. (2004) identified 6 nucleotide variants in NFKB1, including a common insertion/deletion promoter polymorphism (-94ins/delATTG). Using the family-based association test and the pedigree disequilibrium test, they observed modest evidence for linkage disequilibrium between the -94delATTG allele and ulcerative colitis (see 266600) in 131 IBD pedigrees with ulcerative colitis offspring (p = 0.047 and p = 0.052, respectively). The -94delATTG association with ulcerative colitis was replicated in a second set of 258 unrelated, non-Jewish ulcerative colitis patients and 653 non-Jewish controls (p = 0.021). Nuclear proteins from normal human colon tissue and colonic cell lines showed significant binding to -94insATTG-containing but not to -94delATTG-containing oligonucleotides. Cells transfected with reporter plasmid constructs containing the -94delATTG allele showed less promoter activity than comparable constructs containing the -94insATTG allele. Borm et al. (2005) confirmed the association in Dutch patients with ulcerative colitis; however, Oliver et al. (2005) and Mirza et al. (2005) found no association between the -94delATTG allele and ulcerative colitis in Spanish and British ulcerative colitis patients, respectively.

▼ Animal Model

Sha et al. (1995) found that transgenic mice lacking the p50 subunit of NFKB show no developmental abnormalities but exhibit multifocal defects in immune responses involving B lymphocytes and nonspecific responses to infection.

Iotsova et al. (1997) generated Nfkb1/Nfkb2-null double-knockout mice and observed the development of osteopetrosis due to a defect in osteoclast differentiation. The osteopetrotic phenotype was rescued by bone marrow transplantation, indicating that the hematopoietic component was impaired. Iotsova et al. (1997) concluded that the Nfkb1/Nfkb2 double-knockout mouse can serve as an osteopetrotic model and that NFKB1 and NFKB2 are involved in bone development.

Yang et al. (2004) observed that after hyperoxic exposure, neonatal mice showed increased Nfkb binding, whereas adult mice did not. Neonatal Nfkb/luciferase transgenic mice demonstrated enhanced in vivo Nfkb activation after hyperoxia. Inhibition of Nfkbia (164008) resulted in decreased Bcl2 (151430) protein levels in neonatal lung homogenates and decreased cell viability in lung primary cultures after hyperoxic exposure. In addition, neonatal Nfkb1-null mice showed increased lung DNA degradation and decreased survival in hyperoxia compared with wildtype mice. Yang et al. (2004) concluded that there are maturational differences in lung NFKB activation and that enhanced NFKB may serve to protect the neonatal lung from acute hyperoxic injury via inhibition of apoptosis.

Atherosclerosis is a chronic inflammatory condition in which macrophages play a central role. In transgenic mice deficient for the LDL receptor (Ldlr; 606945) and with a macrophage-restricted deletion of Ikbkb, an activator of NFKB, Kanters et al. (2003) found an increase in atherosclerosis, as characterized by increased lesion size, more lesions, and necrosis. In vitro studies showed that Ikbkb deletion in macrophages resulted in a reduction of TNF and the antiinflammatory cytokine Il10 (124092). The findings suggested that inhibition of the NFKB pathway affects the pro- and antiinflammatory balance that controls the development of atherosclerosis.

In mice subjected to aortic banding, Cook et al. (2003) detected greater than 4-fold A20 upregulation (p less than 0.05) at 3 hours, coinciding with peak NFKB activation. A20 was also upregulated in cultured neonatal cardiomyocytes stimulated with phenylephrine or endothelin-1 (EDN1; 131240) (2.8-fold and 4-fold, respectively; p less than 0.05), again paralleling NFKB activation. Cardiomyocytes infected with an adenoviral vector (Ad) encoding A20 inhibited TNF-stimulated NFKB signaling with an efficacy comparable to dominant-negative inhibitor of kappa-B kinase-beta (IKBKB; 603258). Ad-IKBKB-infected cardiomyocytes exhibited increased apoptosis when serum-starved or subjected to hypoxia-reoxygenation, whereas Ad-A20-infected cardiomyocytes did not. Expression of Ad-A20 inhibited the hypertrophic response in cardiomyocytes stimulated with phenylephrine or endothelin-1. Cook et al. (2003) concluded that A20 is dynamically regulated during acute biomechanical stress in the heart and functions to attenuate cardiac hypertrophy through the inhibition of NFKB signaling without sensitizing cardiomyocytes to apoptosis.

Misra et al. (2003) found that transgenic mice with a defect in Nfkb activation showed increased susceptibility to tissue injury after acute left anterior descending coronary artery occlusion. The cytoprotective effect of Nfkb was mediated, at least in part, by Bcl2 or Ciap1 (BIRC2; 601712).

In both Nfkb1 and Bcl3 (109560)-null mice subjected to hindlimb unloading, Hunter and Kandarian (2004) observed reduced muscle fiber atrophy and abolition of NF-kappa-B reporter activity compared to wildtype mice. Hunter and Kandarian (2004) concluded that both the NFKB1 and BCL3 genes are necessary for unloading-induced skeletal muscle atrophy.

Cai et al. (2004) created transgenic mice with Nfkb either activated or inhibited selectively in skeletal muscle through expression of constitutively active IKKB or a dominant inhibitory form of IKBA, respectively. They referred to these mice as MIKK (muscle-specific expression of IKKB) or MISR (muscle-specific expression of IKBA superrepressor), respectively. MIKK mice showed profound muscle wasting that resembled clinical cachexia, whereas MISR mice showed no overt phenotype. Muscle loss in MIKK mice was due to accelerated protein breakdown through ubiquitin-dependent proteolysis. Expression of the E3 ligase Murf1 (RNF28; 606131), a mediator of muscle atrophy, was increased in MIKK mice. Pharmacologic or genetic inhibition of the Ikkb/Nfkb/Murf1 pathway in MIKK mice reversed the muscle atrophy. The Nfkb inhibition in MISR mice substantially reduced denervation- and tumor-induced muscle loss and improved survival rates. The results were consistent with a critical role for NFKB in the pathology of muscle wasting and established NFKB as an important clinical target for the treatment of muscle atrophy.

In mouse livers, Cai et al. (2005) demonstrated that Nfkb and transcriptional targets were activated by obesity and high-fat diet. They generated transgenic mice with a similar state of chronic, subacute inflammation due to low-level constitutive activation of Ikbkb in the liver; the mice exhibited a type II diabetes phenotype characterized by hyperglycemia, profound hepatic insulin resistance, and moderate systemic insulin resistance, including effects in muscle. Hepatic production of proinflammatory cytokines in these mice was increased to an extent similar to that induced by a high-fat diet in wildtype mice, and parallel increases were observed in cytokine signaling in liver and muscle. Insulin resistance was improved by systemic neutralization of Il6 (147620) or salicylate inhibition of Ikbkb. Cai et al. (2005) concluded that lipid accumulation in the liver leads to subacute hepatic inflammation through NFKB activation and downstream cytokine production, causing both local and systemic insulin resistance.

Adler et al. (2007) showed that an inducible block of Nfkb1 expression for 2 weeks in the epidermis of aged mice reverted the tissue characteristics and global gene expression programs to those of younger mice. Nfkb1 controlled cell cycle exit and gene expression during aging in parallel pathways and was continually required to enforce features of aging in a tissue-specific manner.

Chang et al. (2009) generated mice with a dominant-negative Ikbkg mutation (300248) targeted to mature osteoblasts and demonstrated that time- and stage-specific inhibition of Nfkb in differentiated murine osteoblasts substantially increased trabecular bone mass and bone mineral density without affecting osteoclast activities in postnatal mice. Inhibition of Ikbkg-Nfkb in differentiated osteoblasts prevented osteoporotic bone loss induced by ovariectomy in adult mice by maintaining bone formation. Ikbkg-Nfkb inhibition also enhanced the expression of Fos-related antigen (FOSL1; 136515), an essential transcription factor involved in bone matrix formation in vitro and in vivo. Chang et al. (2009) concluded that NFKB is a crucial factor responsible for impaired bone formation in osteoporosis.

Dissanayake et al. (2011) found that transfer of TLR-stimulated bone marrow-derived dendritic cells (BMDCs) from Nfkb1 -/- mice to transgenic mice expressing lymphocytic choriomeningitis virus glycoprotein on pancreatic islet beta cells (RIP-gp mice) resulted in induction of diabetes with infiltration of Cd8 (see 186910) cells into pancreas, as shown by blood glucose levels and immunohistochemistry, respectively. Lack of Nfkb1 in resting DCs was associated with impaired induction of T-cell tolerance. Flow cytometric analysis demonstrated a lack of upregulation of maturation markers, such as Cd40, Cd80 (112203), Cd86 (601020), and MHC class I and class II, in stimulated Nfkb1 -/- BMDCs; however, stimulated Nfkb1 -/- could produce increased Tnfa. Stimulated BMDCs from Nfkb1 -/- Tnfa -/- mice were unable to induce diabetes and Cd8-positive T-cell autoimmunity upon transfer to RIP-gp mice, indicating that induction of diabetes depended on Tnfa production by transferred DCs. Dissanayake et al. (2011) concluded that NFKB1 negatively regulates TNFA production in resting DCs and prevents the subsequent induction of CD8-positive effector activity. They proposed that their findings may explain the association between a Tnfa promoter polymorphism (191160.0006) that results in reduced p50 homodimer binding (Udalova et al., 2000) with human autoimmune disease.

▼ ALLELIC VARIANTS ( 10 Selected Examples):

Table View ClinVar

.0001 IMMUNODEFICIENCY, COMMON VARIABLE, 12, WITH AUTOIMMUNITY

NFKB1, IVS8DS, A-G, +4

RCV000192693

In affected members of a large multigenerational Dutch-Australian family (FamNL1) with autosomal dominant common variable immunodeficiency-12 with autoimmunity (CVID12; 616576), Fliegauf et al. (2015) identified a heterozygous c.730+4A-G transition (c.730+4A-G, NM_003998.3) in intron 8 of the NFKB1 gene, resulting in the skipping of exon 8 in variant 1 of the precursor protein. The mutation was predicted to delete an internal fragment from the N-terminal RHD domain (Asp191_Lys244delinsGlu). Western blot analysis of patient cells showed about 50% reduced levels of the p105 and p50 proteins, and only marginal presence of the mutant p105 protein; mutant p50 was not detected. These findings suggested that the mutant p105 protein was not processed to a corresponding truncated p50 protein, resulting in functional haploinsufficiency of NFKB1 subunit p50. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family, and was not found in the dbSNP, 1000 Genomes Project, or ExAC databases. In vitro functional expression assays in transfected cells showed almost undetectable levels of mutant NFKB1 p105 and p50, suggesting that they are highly unstable and probably nonfunctional. The mutation was found in 10 family members with CVID and in 3 with hypogammaglobulinemia; it was not found in several additional family members who had hypogammaglobulinemia, suggesting that the latter individuals had a phenocopy. The family had previously been reported by Nijenhuis et al. (2001) and Finck et al. (2006).

.0002 IMMUNODEFICIENCY, COMMON VARIABLE, 12, WITH AUTOIMMUNITY

NFKB1, IVS9DS, T-G, +2

RCV000194108

In affected members of a German family (Fam089) with autosomal dominant common variable immunodeficiency-12 with autoimmunity (CVID12; 616576), Fliegauf et al. (2015) identified a heterozygous c.835+2T-G transversion (c.835+2T-G, NM_003998.3) in intron 9 of the NFKB1 gene, resulting in the in-frame skipping of exon 9 (Lys244_Asp279delinsAsn), partial deletion of the N-terminal RHD domain, and functional haploinsufficiency of p50.

.0003 IMMUNODEFICIENCY, COMMON VARIABLE, 12, WITH AUTOIMMUNITY

NFKB1, 1-BP DUP, 465A

RCV000195130

In affected members of a family from New Zealand of European descent (FamNZ) with autosomal dominant common variable immunodeficiency-12 with autoimmunity (CVID12; 616576), Fliegauf et al. (2015) identified a heterozygous 1-bp duplication (c.465dupA, NM_003998.3) in exon 7 of the NFKB1 gene, resulting in a frameshift and premature termination (Ala156SerfsTer12). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not found in the ExAC database. Patient cells showed severely reduced p105 and p50 levels, consistent with functional p50 haploinsufficiency.

.0004 IMMUNODEFICIENCY, COMMON VARIABLE, 12, WITH AUTOIMMUNITY

NFKB1, 1-BP DEL, 137A

RCV001374703

In a 26-year-old woman (patient 1) with common variable immunodeficiency-12 with autoimmunity (CVID12; 616576), Schipp et al. (2016) identified a de novo heterozygous 1-bp deletion (c.137delA) in exon 4 of the NFKB1 gene, resulting in a frameshift and premature termination (Ile47TyrfsTer2) in the RHD domain. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. Patient cells showed decreased RNA and protein levels of both the p50 and p105 isoforms, as well as decreased expression of NFKB-related genes. al.

.0005 IMMUNODEFICIENCY, COMMON VARIABLE, 12, WITH AUTOIMMUNITY

NFKB1, ARG157TER

RCV001374705...

In a 19-year-old woman (patient 2) with common variable immunodeficiency-12 with autoimmunity (CVID12; 616576), Schipp et al. (2016) identified a heterozygous c.469C-T transition in exon 7 of the NFKB1 gene, resulting in an arg157-to-ter (R157X) substitution in the RHD domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was present in several unaffected family members, consistent with incomplete penetrance. Patient cells showed low mRNA levels and decreased p50/p105 expression, suggesting that the mutation caused nonsense-mediated mRNA decay. In vitro functional expression studies showed that the mutation caused a lack of measurable NFKB1 transcriptional responses, as well as decreased basal expression of target genes.

.0006 IMMUNODEFICIENCY, COMMON VARIABLE, 12, WITH AUTOIMMUNITY

NFKB1, ARG284TER

RCV001027598...

In 3 affected members of a family of European descent (family A) with common variable immunodeficiency-12 with autoimmunity (CVID12; 616576), Tuijnenburg et al. (2018) identified a heterozygous c.850C-T transition (c.850C-T, NM_003998.3) in the NFKB1 gene, resulting in an arg284-to-ter (R284X) substitution in the N-terminal p50 part of the protein in the RHD domain. The mutation, which was found by whole-genome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. Three mutation carriers in the family were unaffected, consistent with incomplete penetrance. Analysis of patient cells showed about a 50% decrease in NFKB1 protein levels compared to controls. Although functional studies were not performed, the findings were consistent with a loss-of-function effect and haploinsufficiency.

.0007 IMMUNODEFICIENCY, COMMON VARIABLE, 12, WITH AUTOIMMUNITY

NFKB1, 5-BP DEL, 1539CATGC

RCV001027596...

In a father and daughter of European descent (family B) with common variable immunodeficiency-12 with autoimmunity (CVID12; 616576), Tuijnenburg et al. (2018) identified a heterozygous 5-bp deletion (c.1539delCATGC, NM_003998.3) in the NFKB1 gene, resulting in a frameshift and premature termination (His513GlnfsTer28) in the N-terminal p50 part of the protein in the RHD domain. The mutation, which was found by whole-genome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. Analysis of patient cells showed about a 50% decrease in NFKB1 protein levels compared to controls. Although functional studies were not performed, the findings were consistent with a loss-of-function effect and haploinsufficiency.

.0008 IMMUNODEFICIENCY, COMMON VARIABLE, 12, WITH AUTOIMMUNITY

NFKB1, ILE87SER

RCV001027589...

In a patient of European descent (family G) with sporadic occurrence of common variable immunodeficiency-12 with autoimmunity (CVID12; 616576), Tuijnenburg et al. (2018) identified a heterozygous c.260T-G transversion (c.260T-G, NM_003998.3) in the NFKB1 gene, resulting in an ile87-to-ser (I87S) substitution in the N-terminal p50 part of the protein in the RHD domain. The mutation, which was found by whole-genome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. Analysis of patient cells showed about a 50% decrease in NFKB1 protein levels compared to controls. Although functional studies were not performed, the findings were consistent with a loss-of-function effect and haploinsufficiency.

Lorenzini et al. (2020) showed that the I87S mutant protein formed abnormal cytoplasmic clumps upon stimulation, suggesting accelerated decay. Western blot analysis revealed decreased expression of mutant I87S, and luciferase reporter assays showed reduced NFKB promoter activation compared to controls.

.0009 IMMUNODEFICIENCY, COMMON VARIABLE, 12, WITH AUTOIMMUNITY

NFKB1, ARG57CYS

RCV001368038...

In a 17-year-old boy (family BK) with common variable immunodeficiency-12 with autoimmunity (CVID12; 616576), Lorenzini et al. (2020) identified a heterozygous c.169C-T transition in the NFKB1 gene, resulting in an arg57-to-cys (R57C) substitution in the RHD domain. The patient's father was reportedly affected, although his mutation status was inferred. In vitro functional expression assays showed that the R57C mutant caused reduced NFKB activation compared to controls.

.0010 IMMUNODEFICIENCY, COMMON VARIABLE, 12, WITH AUTOIMMUNITY

NFKB1, 1-BP DEL, 1012T

RCV001374708

In 3 male members of a family (family AT) with common variable immunodeficiency-12 with autoimmunity (CVID12; 616576), Lorenzini et al. (2020) identified a heterozygous 1-bp deletion (c.1012delT) in the NFKB1 gene, resulting in a frameshift and premature termination (Ser338LeufsTer94) in the N-terminal region. There was 1 asymptomatic family member who carried the mutation, consistent with incomplete penetrance. Studies of HEK293 cells transfected with the mutation showed reduced levels of both p105 and p50, as well as aberrant protein localization compared to controls. The findings were consistent with haploinsufficiency.

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Contributors:

Cassandra L. Kniffin - updated : 04/12/2021

Paul J. Converse - updated : 10/29/2015
Cassandra L. Kniffin - updated : 9/28/2015
Paul J. Converse - updated : 12/2/2013
Ada Hamosh - updated : 5/22/2013
Paul J. Converse - updated : 2/28/2012
Ada Hamosh - updated : 5/12/2011
Ada Hamosh - updated : 8/24/2010
Ada Hamosh - updated : 5/25/2010
Ada Hamosh - updated : 12/29/2009
Marla J. F. O'Neill - updated : 8/4/2009
Ada Hamosh - updated : 6/16/2009
George E. Tiller - updated : 4/23/2009
Ada Hamosh - updated : 7/25/2008
Ada Hamosh - updated : 7/9/2008
Patricia A. Hartz - updated : 1/14/2008
Ada Hamosh - updated : 8/20/2007
Ada Hamosh - updated : 5/30/2007
Ada Hamosh - updated : 4/12/2007
Marla J. F. O'Neill - updated : 2/26/2007
Paul J. Converse - updated : 12/21/2006
Ada Hamosh - updated : 4/19/2006
George E. Tiller - updated : 2/17/2006
Patricia A. Hartz - updated : 12/19/2005
Ada Hamosh - updated : 11/14/2005
Marla J. F. O'Neill - updated : 11/11/2005
Ada Hamosh - updated : 5/25/2005
Stylianos E. Antonarakis - updated : 3/30/2005
Marla J. F. O'Neill - updated : 3/29/2005
Marla J. F. O'Neill - updated : 1/19/2005
Ada Hamosh - updated : 11/29/2004
Marla J. F. O'Neill - updated : 11/19/2004
Marla J. F. O'Neill - updated : 10/22/2004
Ada Hamosh - updated : 9/13/2004
Ada Hamosh - updated : 7/22/2004
Paul J. Converse - updated : 1/30/2004
George E. Tiller - updated : 12/3/2003
Cassandra L. Kniffin - updated : 11/5/2003
Cassandra L. Kniffin - updated : 9/4/2003
Ada Hamosh - updated : 8/26/2003
Ada Hamosh - updated : 6/17/2003
Victor A. McKusick - updated : 5/30/2003
Victor A. McKusick - updated : 5/28/2003
Stylianos E. Antonarakis - updated : 4/15/2003
Stylianos E. Antonarakis - updated : 9/23/2002
Stylianos E. Antonarakis - updated : 7/29/2002
Ada Hamosh - updated : 8/15/2001
John A. Phillips, III - updated : 7/10/2001
Ada Hamosh - updated : 10/20/2000
Paul J. Converse - updated : 4/19/2000
Paul J. Converse - updated : 3/7/2000
Paul J. Converse - updated : 2/15/2000
Jane Kelly - updated : 8/26/1999
Ada Hamosh - updated : 7/28/1999
Stylianos E. Antonarakis - updated : 12/22/1998
Stylianos E. Antonarakis - updated : 5/20/1998
Victor A. McKusick - updated : 5/28/1997
Alan F. Scott - updated : 2/27/1996
Alan F. Scott - updated : 1/5/1996

Creation Date:

Victor A. McKusick : 3/6/1992

Edit History:

alopez : 04/25/2024

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terry : 11/29/2004
tkritzer : 11/23/2004
tkritzer : 11/19/2004
carol : 10/22/2004
terry : 10/22/2004
alopez : 9/15/2004
terry : 9/13/2004
alopez : 7/26/2004
terry : 7/22/2004
alopez : 2/17/2004
mgross : 1/30/2004
mgross : 1/30/2004
mgross : 12/3/2003
mgross : 12/3/2003
tkritzer : 11/14/2003
ckniffin : 11/5/2003
alopez : 10/16/2003
tkritzer : 9/9/2003
ckniffin : 9/4/2003
alopez : 8/27/2003
terry : 8/26/2003
alopez : 6/19/2003
alopez : 6/19/2003
terry : 6/17/2003
carol : 6/2/2003
terry : 5/30/2003
terry : 5/28/2003
mgross : 4/15/2003
carol : 3/28/2003
carol : 2/14/2003
ckniffin : 1/31/2003
mgross : 9/23/2002
mgross : 7/29/2002
terry : 11/15/2001
alopez : 8/17/2001
terry : 8/15/2001
alopez : 7/10/2001
carol : 1/24/2001
terry : 1/18/2001
alopez : 10/23/2000
alopez : 10/20/2000
mgross : 9/19/2000
alopez : 4/19/2000
alopez : 4/14/2000
alopez : 4/14/2000
carol : 3/7/2000
carol : 2/15/2000
carol : 2/15/2000
carol : 8/26/1999
alopez : 7/30/1999
carol : 7/28/1999
carol : 12/22/1998
carol : 5/20/1998
mark : 6/10/1997
terry : 5/28/1997
mark : 3/11/1997
terry : 4/17/1996
mark : 2/27/1996
mark : 1/5/1996
terry : 12/13/1995
carol : 10/4/1993
carol : 4/27/1993
carol : 4/7/1993
carol : 8/10/1992
carol : 5/29/1992
carol : 5/11/1992

* 164011

NUCLEAR FACTOR KAPPA-B, SUBUNIT 1; NFKB1

Alternative titles; symbols

TRANSCRIPTION FACTOR NFKB1
NUCLEAR FACTOR OF KAPPA LIGHT CHAIN GENE ENHANCER IN B CELLS 1

Other entities represented in this entry:

NFKB p105, INCLUDED

NFKB p50, INCLUDED

HGNC Approved Gene Symbol: NFKB1

Cytogenetic location: 4q24 Genomic coordinates (GRCh38): 4:102,501,359-102,617,302 (from NCBI)

Gene-Phenotype Relationships

Location	Phenotype	Phenotype MIM number	Inheritance	Phenotype mapping key
4q24	Immunodeficiency, common variable, 12	616576	Autosomal dominant	3

TEXT

Description

Cloning and Expression

Gene Structure

Heron et al. (1995) showed that NFKB1 has 24 exons spanning 156 kb.

Mapping

Gene Function

Processing

Role in Immune Function and Inflammation

Yamamoto and Gaynor (2001) reviewed the therapeutic potential of inhibition of the NF-kappa-B pathway in the treatment of inflammation and cancer.

NFKB Signaling Pathway

Ashall et al. (2009) showed that pulsatile stimulation with TNF-alpha determines timing and specificity of NF-kappa-B-dependent transcription.

Role in Differentiation

Role in Cancer

Role in Brain Function

Evolution

Biochemical Features

Crystal Structure

Molecular Genetics

Common Variable Immunodeficiency 12 with Autoimmunity

Associations Pending Confirmation

Animal Model

ALLELIC VARIANTS 10 Selected Examples):

.0001 IMMUNODEFICIENCY, COMMON VARIABLE, 12, WITH AUTOIMMUNITY

NFKB1, IVS8DS, A-G, +4
SNP: rs869320688, ClinVar: RCV000192693

.0002 IMMUNODEFICIENCY, COMMON VARIABLE, 12, WITH AUTOIMMUNITY

NFKB1, IVS9DS, T-G, +2
SNP: rs869320689, ClinVar: RCV000194108

.0003 IMMUNODEFICIENCY, COMMON VARIABLE, 12, WITH AUTOIMMUNITY

NFKB1, 1-BP DUP, 465A
SNP: rs869320754, ClinVar: RCV000195130

.0004 IMMUNODEFICIENCY, COMMON VARIABLE, 12, WITH AUTOIMMUNITY

NFKB1, 1-BP DEL, 137A
SNP: rs2149123423, ClinVar: RCV001374703

.0005 IMMUNODEFICIENCY, COMMON VARIABLE, 12, WITH AUTOIMMUNITY

NFKB1, ARG157TER
SNP: rs2149181831, ClinVar: RCV001374705, RCV002550945

.0006 IMMUNODEFICIENCY, COMMON VARIABLE, 12, WITH AUTOIMMUNITY

NFKB1, ARG284TER
SNP: rs1578793312, ClinVar: RCV001027598, RCV001027604, RCV001262753, RCV002552007

.0007 IMMUNODEFICIENCY, COMMON VARIABLE, 12, WITH AUTOIMMUNITY

NFKB1, 5-BP DEL, 1539CATGC
SNP: rs1578811073, ClinVar: RCV001027596, RCV001374706

.0008 IMMUNODEFICIENCY, COMMON VARIABLE, 12, WITH AUTOIMMUNITY

NFKB1, ILE87SER
SNP: rs1578771120, ClinVar: RCV001027589, RCV001374707

.0009 IMMUNODEFICIENCY, COMMON VARIABLE, 12, WITH AUTOIMMUNITY

NFKB1, ARG57CYS
SNP: rs1040399901, ClinVar: RCV001368038, RCV001374704

.0010 IMMUNODEFICIENCY, COMMON VARIABLE, 12, WITH AUTOIMMUNITY

NFKB1, 1-BP DEL, 1012T
SNP: rs2149192665, ClinVar: RCV001374708

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Contributors:

Cassandra L. Kniffin - updated : 04/12/2021
Paul J. Converse - updated : 10/29/2015
Cassandra L. Kniffin - updated : 9/28/2015
Paul J. Converse - updated : 12/2/2013
Ada Hamosh - updated : 5/22/2013
Paul J. Converse - updated : 2/28/2012
Ada Hamosh - updated : 5/12/2011
Ada Hamosh - updated : 8/24/2010
Ada Hamosh - updated : 5/25/2010
Ada Hamosh - updated : 12/29/2009
Marla J. F. O'Neill - updated : 8/4/2009
Ada Hamosh - updated : 6/16/2009
George E. Tiller - updated : 4/23/2009
Ada Hamosh - updated : 7/25/2008
Ada Hamosh - updated : 7/9/2008
Patricia A. Hartz - updated : 1/14/2008
Ada Hamosh - updated : 8/20/2007
Ada Hamosh - updated : 5/30/2007
Ada Hamosh - updated : 4/12/2007
Marla J. F. O'Neill - updated : 2/26/2007
Paul J. Converse - updated : 12/21/2006
Ada Hamosh - updated : 4/19/2006
George E. Tiller - updated : 2/17/2006
Patricia A. Hartz - updated : 12/19/2005
Ada Hamosh - updated : 11/14/2005
Marla J. F. O'Neill - updated : 11/11/2005
Ada Hamosh - updated : 5/25/2005
Stylianos E. Antonarakis - updated : 3/30/2005
Marla J. F. O'Neill - updated : 3/29/2005
Marla J. F. O'Neill - updated : 1/19/2005
Ada Hamosh - updated : 11/29/2004
Marla J. F. O'Neill - updated : 11/19/2004
Marla J. F. O'Neill - updated : 10/22/2004
Ada Hamosh - updated : 9/13/2004
Ada Hamosh - updated : 7/22/2004
Paul J. Converse - updated : 1/30/2004
George E. Tiller - updated : 12/3/2003
Cassandra L. Kniffin - updated : 11/5/2003
Cassandra L. Kniffin - updated : 9/4/2003
Ada Hamosh - updated : 8/26/2003
Ada Hamosh - updated : 6/17/2003
Victor A. McKusick - updated : 5/30/2003
Victor A. McKusick - updated : 5/28/2003
Stylianos E. Antonarakis - updated : 4/15/2003
Stylianos E. Antonarakis - updated : 9/23/2002
Stylianos E. Antonarakis - updated : 7/29/2002
Ada Hamosh - updated : 8/15/2001
John A. Phillips, III - updated : 7/10/2001
Ada Hamosh - updated : 10/20/2000
Paul J. Converse - updated : 4/19/2000
Paul J. Converse - updated : 3/7/2000
Paul J. Converse - updated : 2/15/2000
Jane Kelly - updated : 8/26/1999
Ada Hamosh - updated : 7/28/1999
Stylianos E. Antonarakis - updated : 12/22/1998
Stylianos E. Antonarakis - updated : 5/20/1998
Victor A. McKusick - updated : 5/28/1997
Alan F. Scott - updated : 2/27/1996
Alan F. Scott - updated : 1/5/1996

Creation Date:

Victor A. McKusick : 3/6/1992

Edit History:

alopez : 04/25/2024
carol : 02/14/2022
carol : 04/22/2021
carol : 04/21/2021
alopez : 04/20/2021
ckniffin : 04/12/2021
carol : 06/16/2020
carol : 08/22/2016
mgross : 10/29/2015
alopez : 9/30/2015
alopez : 9/30/2015
ckniffin : 9/28/2015
alopez : 10/10/2014
mgross : 12/2/2013
mcolton : 11/8/2013
alopez : 5/28/2013
alopez : 5/22/2013
carol : 4/11/2013
carol : 4/1/2013
mgross : 2/5/2013
mgross : 2/28/2012
terry : 2/28/2012
alopez : 5/12/2011
mgross : 5/11/2011
terry : 5/5/2011
mgross : 8/31/2010
terry : 8/24/2010
alopez : 7/16/2010
alopez : 5/26/2010
terry : 5/25/2010
alopez : 1/6/2010
terry : 12/29/2009
wwang : 8/10/2009
terry : 8/4/2009
alopez : 6/22/2009
terry : 6/16/2009
wwang : 6/16/2009
terry : 4/23/2009
terry : 4/23/2009
wwang : 4/20/2009
carol : 8/14/2008
alopez : 7/30/2008
terry : 7/25/2008
wwang : 7/16/2008
terry : 7/9/2008
mgross : 1/15/2008
terry : 1/14/2008
alopez : 8/28/2007
terry : 8/20/2007
alopez : 5/30/2007
terry : 5/30/2007
alopez : 4/12/2007
wwang : 2/26/2007
mgross : 12/21/2006
alopez : 4/20/2006
terry : 4/19/2006
wwang : 3/6/2006
terry : 2/17/2006
wwang : 12/19/2005
alopez : 11/16/2005
terry : 11/14/2005
wwang : 11/11/2005
terry : 11/11/2005
tkritzer : 5/26/2005
terry : 5/25/2005
mgross : 3/30/2005
tkritzer : 3/29/2005
terry : 3/16/2005
carol : 1/31/2005
terry : 1/19/2005
tkritzer : 11/29/2004
terry : 11/29/2004
tkritzer : 11/23/2004
tkritzer : 11/19/2004
carol : 10/22/2004
terry : 10/22/2004
alopez : 9/15/2004
terry : 9/13/2004
alopez : 7/26/2004
terry : 7/22/2004
alopez : 2/17/2004
mgross : 1/30/2004
mgross : 1/30/2004
mgross : 12/3/2003
mgross : 12/3/2003
tkritzer : 11/14/2003
ckniffin : 11/5/2003
alopez : 10/16/2003
tkritzer : 9/9/2003
ckniffin : 9/4/2003
alopez : 8/27/2003
terry : 8/26/2003
alopez : 6/19/2003
alopez : 6/19/2003
terry : 6/17/2003
carol : 6/2/2003
terry : 5/30/2003
terry : 5/28/2003
mgross : 4/15/2003
carol : 3/28/2003
carol : 2/14/2003
ckniffin : 1/31/2003
mgross : 9/23/2002
mgross : 7/29/2002
terry : 11/15/2001
alopez : 8/17/2001
terry : 8/15/2001
alopez : 7/10/2001
carol : 1/24/2001
terry : 1/18/2001
alopez : 10/23/2000
alopez : 10/20/2000
mgross : 9/19/2000
alopez : 4/19/2000
alopez : 4/14/2000
alopez : 4/14/2000
carol : 3/7/2000
carol : 2/15/2000
carol : 2/15/2000
carol : 8/26/1999
alopez : 7/30/1999
carol : 7/28/1999
carol : 12/22/1998
carol : 5/20/1998
mark : 6/10/1997
terry : 5/28/1997
mark : 3/11/1997
terry : 4/17/1996
mark : 2/27/1996
mark : 1/5/1996
terry : 12/13/1995
carol : 10/4/1993
carol : 4/27/1993
carol : 4/7/1993
carol : 8/10/1992
carol : 5/29/1992
carol : 5/11/1992

NOTE: OMIM is intended for use primarily by physicians and other professionals concerned with genetic disorders, by genetics researchers, and by advanced students in science and medicine. While the OMIM database is open to the public, users seeking information about a personal medical or genetic condition are urged to consult with a qualified physician for diagnosis and for answers to personal questions.
OMIM^® and Online Mendelian Inheritance in Man^® are registered trademarks of the Johns Hopkins University.
Copyright^® 1966-2024 Johns Hopkins University.
Printed: April 29, 2024

▼ External Links

NUCLEAR FACTOR KAPPA-B, SUBUNIT 1; NFKB1

TRANSCRIPTION FACTOR NFKB1 NUCLEAR FACTOR OF KAPPA LIGHT CHAIN GENE ENHANCER IN B CELLS 1

TEXT

▼ Description

▼ Cloning and Expression

▼ Gene Structure

▼ Mapping

▼ Gene Function

▼ Evolution

▼ Biochemical Features

▼ Molecular Genetics

▼ Animal Model

▼ ALLELIC VARIANTS ( 10 Selected Examples):

.0001 IMMUNODEFICIENCY, COMMON VARIABLE, 12, WITH AUTOIMMUNITY

.0002 IMMUNODEFICIENCY, COMMON VARIABLE, 12, WITH AUTOIMMUNITY

.0003 IMMUNODEFICIENCY, COMMON VARIABLE, 12, WITH AUTOIMMUNITY

.0004 IMMUNODEFICIENCY, COMMON VARIABLE, 12, WITH AUTOIMMUNITY

.0005 IMMUNODEFICIENCY, COMMON VARIABLE, 12, WITH AUTOIMMUNITY

.0006 IMMUNODEFICIENCY, COMMON VARIABLE, 12, WITH AUTOIMMUNITY

.0007 IMMUNODEFICIENCY, COMMON VARIABLE, 12, WITH AUTOIMMUNITY

.0008 IMMUNODEFICIENCY, COMMON VARIABLE, 12, WITH AUTOIMMUNITY

.0009 IMMUNODEFICIENCY, COMMON VARIABLE, 12, WITH AUTOIMMUNITY

.0010 IMMUNODEFICIENCY, COMMON VARIABLE, 12, WITH AUTOIMMUNITY

▼ REFERENCES

* 164011

NUCLEAR FACTOR KAPPA-B, SUBUNIT 1; NFKB1

TRANSCRIPTION FACTOR NFKB1 NUCLEAR FACTOR OF KAPPA LIGHT CHAIN GENE ENHANCER IN B CELLS 1

Gene-Phenotype Relationships

TEXT

Description

Cloning and Expression

Gene Structure

Mapping

Gene Function

Evolution

Biochemical Features

Molecular Genetics

Animal Model

ALLELIC VARIANTS 10 Selected Examples):

.0001 IMMUNODEFICIENCY, COMMON VARIABLE, 12, WITH AUTOIMMUNITY

.0002 IMMUNODEFICIENCY, COMMON VARIABLE, 12, WITH AUTOIMMUNITY

.0003 IMMUNODEFICIENCY, COMMON VARIABLE, 12, WITH AUTOIMMUNITY

.0004 IMMUNODEFICIENCY, COMMON VARIABLE, 12, WITH AUTOIMMUNITY

.0005 IMMUNODEFICIENCY, COMMON VARIABLE, 12, WITH AUTOIMMUNITY

.0006 IMMUNODEFICIENCY, COMMON VARIABLE, 12, WITH AUTOIMMUNITY

.0007 IMMUNODEFICIENCY, COMMON VARIABLE, 12, WITH AUTOIMMUNITY

.0008 IMMUNODEFICIENCY, COMMON VARIABLE, 12, WITH AUTOIMMUNITY

.0009 IMMUNODEFICIENCY, COMMON VARIABLE, 12, WITH AUTOIMMUNITY

.0010 IMMUNODEFICIENCY, COMMON VARIABLE, 12, WITH AUTOIMMUNITY

REFERENCES

▼

External Links

TRANSCRIPTION FACTOR NFKB1
NUCLEAR FACTOR OF KAPPA LIGHT CHAIN GENE ENHANCER IN B CELLS 1

TRANSCRIPTION FACTOR NFKB1
NUCLEAR FACTOR OF KAPPA LIGHT CHAIN GENE ENHANCER IN B CELLS 1