Alternative titles; symbols
HGNC Approved Gene Symbol: NFKBIA
Cytogenetic location: 14q13.2 Genomic coordinates (GRCh38): 14:35,401,513-35,404,749 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 14q13.2 | Ectodermal dysplasia and immunodeficiency 2 | 612132 | Autosomal dominant | 3 |
NFKB1 (164011) 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 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, 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).
Haskill et al. (1991) cloned 1 form of I-kappa-B (referred to as I-kappa-B-alpha by them) and showed that it is a protein with multiple ankyrin (612641) repeats.
Cells from patients with ataxia-telangiectasia (208900) are hypersensitive to ionizing radiation and are defective in the regulation of DNA synthesis. By expression cloning, Jung et al. (1995) isolated a cDNA that corrected the radiation sensitivity in DNA synthesis defects in fibroblasts from an ataxia-telangiectasia group D patient. They showed that the cDNA encoded a truncated form of I-kappa-B-alpha. The parental AT1 fibroblast expressed large amounts of the I-kappa-B-alpha transcript and showed constitutive activation of NF-kappa-B. AT1 fibroblasts transfected with the truncated NFKBI gene expressed normal amounts of the NFKBI transcript and showed regulated activation of NF-kappa-B. These results suggested that aberrant regulation of these 2 genes contribute to the cellular defect in ataxia-telangiectasia since the NFKBI gene is localized to chromosome 14. Whereas genetic linkage analysis has mapped the putative AT1 gene to 11q, Jung et al. (1995) hypothesized that the contribution of the NFKB and inhibitor complex to the ataxia-telangiectasia phenotype must act downstream of the gene representing the primary defect.
Rupec et al. (1999) cloned the mouse Ikba gene and determined its structure.
Glucocorticoids are among the most potent antiinflammatory and immunosuppressive agents known. They inhibit synthesis of almost all cytokines and of several cell-surface molecules required for immune function. Scheinman et al. (1995) and Auphan et al. (1995) showed that the synthetic glucocorticoid dexamethasone induces transcription of the I-kappa-B-alpha gene, which results in an increased rate of synthesis of the inhibitor protein. The inhibitory protein traps activated NF-kappa-B in inactive cytoplasmic complexes. Because NF-kappa-B activates many immunoregulatory genes in response to proinflammatory stimuli, the inhibition of its activity can be a major component of the antiinflammatory activity of glucocorticoids.
The mucosal lining of the intestine coexists with diverse luminal prokaryotic microflora by maintaining a state of tolerance or inflammatory hyporesponsiveness. However, enteropathogens that cause acute inflammatory colitis do activate the NFKB pathway, resulting in the secretion of chemokines such as IL8 (146930). Using a model system of intestinal epithelia and live nonpathogenic Salmonella bacteria, Neish et al. (2000) found that IL8 secretion and mRNA expression, as well as IKBA expression, was attenuated compared to the response elicited by proinflammatory Salmonella strains and proinflammatory stimuli such as TNFA (191160), calcium-mobilizing carbachol, and phorbol ester. Attenuation of IL8 secretion and IKBA expression also occurred if the model epithelia were colonized with the nonvirulent Salmonella before proinflammatory stimulation. Immunofluorescence analysis revealed that the NFKB complex did not translocate to the nucleus in epithelial cells colonized with the antiinflammatory organisms. Western blot analysis confirmed that in epithelial cells exposed to the avirulent Salmonella, IKBA, in spite of becoming phosphorylated via the JNK (see 601158) pathway, was stabilized; challenge with virulent organisms or TNFA alone resulted in degradation of IKBA. The same results were not achieved with monocytic or endothelial cells. Immunoblot analysis further showed that the antiinflammatory strains block the ubiquitination of phosphorylated IKBA, induced by the inflammatory Salmonella strains or inflammatory stimuli. Neish et al. (2000) also observed abrogation of ubiquitination of beta-catenin (CTNNB1; 116806) but not of other proteins in this model, suggesting that the effect of the nonpathogenic bacteria is specific to the SCF complex (see BTRC, 603482) substrates CTNNB1 and IKBA. Neish et al. (2000) noted that their model may help to explain the beneficial effects of treatment of inflammatory bowel disease with nonpathogenic probiotic enteric organisms.
Using electrophoretic mobility shift analysis (EMSA), Hoffmann et al. (2002) showed that persistent stimulation of T cells, monocytes, or fibroblasts with TNFA resulted in the coordinated degradation, synthesis, and localization of IKBA, IKBB, and IKBE (604548) necessary to generate the characteristic NFKB activation profile.
Because therapeutics inhibiting RAS (190020) and NFKB pathways are used to treat human cancer, experiments assessing the effects of altering these regulators have been performed in mice. The medical relevance of murine studies is limited, however, by differences between mouse and human skin, and by the greater ease of transforming murine cells. To study RAS and NFKB in a setting more relevant to human tumorigenesis, Dajee et al. (2003) expressed the active HRAS gly12-to-val mutation (190020.0001), NFKB p65 (164014), and a stable NFKB repressor mutant of IKBA in human skin tissue. Primary human keratinocytes were retrovirally transduced and used to regenerate human skin on immune-deficient mice. Tissue expressing IKBA alone showed mild hyperplasia, whereas expression of oncogenic RAS induced growth arrest with graft failure. Although implicated in promoting features of neoplasia in other settings, the coexpression of oncogenic RAS with NFKB subunits failed to support proliferation. Coexpression of RAS and IKBA produced large neoplasms with deep invasion through fat into underlying muscle and fascia, similar to human squamous cell carcinomas (SCC), in 3 weeks. These tumors showed more than 10-fold increase in mitotic index, preserved telomeres, and increased amounts of TERT (187270) protein. Human keratinocytes lacking laminin-5 (LAMB3; 150310) and ITGB4 (147557) failed to form tumors on coexpression with RAS and IKBA; however, introduction of wildtype LAMB3 and ITGB4 restored tumor-forming capacity, suggesting that these 2 proteins are required for SCC tumorigenesis. Dajee et al. (2003) demonstrated that growth arrest triggered by oncogenic RAS can be bypassed by IKBA-mediated blockade of NFKB and that RAS opposed the increased susceptibility to apoptosis caused by NFKB blockade. Thus, IKBA circumvents restraints on growth promotion induced by oncogenic RAS and can act with RAS to induce invasive human tissue neoplasia.
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 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.
Carbia-Nagashima et al. (2007) found that human RSUME (RWDD3; 615875) enhanced sumoylation of I-kappa-B, leading to inhibition of NF-kappa-B transcriptional activity and reduced expression of NF-kappa-B target genes. In contrast, knockdown of RSUME via small interfering RNA in human 1321 glial cells stimulated NF-kappa-B transcriptional activity.
Crystal Structure
Jacobs and Harrison (1998) and Huxford et al. (1998) determined the structure of the IKBA 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 IKBA 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 IKBA will occlude the NFKB DNA-binding cleft. The orientation of IKBA in the complex places its N- and C-terminal regions in appropriate locations for their known regulatory functions.
Baeuerle (1998) discussed the crystallographic models of interactions between IKBA and NFKB.
The IKBA gene was shown by Ito et al. (1995) to have 6 exons spanning about 3.5-kb of genomic DNA. The organization of the gene is similar to that of other members of the ankyrin family including BCL3 (109560) and NFKB2.
Le Beau et al. (1992) mapped the NFKBI gene to 14q13 by fluorescence in situ hybridization. Rupec et al. (1999) mapped the Nfkbi gene to mouse chromosome 12 in a region of conserved synteny with human chromosome 14.
Ectodermal Dysplasia and Immunodeficiency 2
X-linked anhidrotic ectodermal dysplasia with immunodeficiency (EDAID1; 300291) is caused by hypomorphic mutations in the gene encoding IKK-gamma (IKBKG; 300248), the regulatory subunit of the IKK complex. IKK normally phosphorylates the I-kappa-B inhibitors of NF-kappa-B at specific serine residues, thereby promoting their ubiquitination and degradation by the proteasome. This in turn allows NF-kappa-B complexes to translocate into the nucleus where they activate their target genes. In patients with X-linked EDAID, impaired immunity and EDA result from impaired NF-kappa-B activation. Courtois et al. (2003) described a patient with an autosomal dominant form of EDAID (EDAID2; 612132) associated with a heterozygous mutation in the NFKBIA gene (S32I; 164008.0001). This gain-of-function mutation enhanced the inhibitory capacity of I-kappa-B-alpha by preventing its phosphorylation and degradation, and resulted in impaired NF-kappa-B activation. Developmental, immunologic, and infectious phenotypes associated with hypomorphic IKBKG mutations and hypermorphic IKBA mutations largely overlap; however, autosomal dominant EDAID2, but not X-linked EDAID1, was associated with a severe and unique T-cell immunodeficiency. Despite marked blood lymphocytosis, there were no detectable memory T cells in vivo, and naive T cells did not respond to CD3-TCR activation in vitro. The report highlighted both the diversity of genotypes associated with EDAID and the diversity of immunologic phenotypes associated with mutations in different components of the NF-kappa-B signaling pathway.
McDonald et al. (2007) identified a heterozygous nonsense mutation in the NFKBIA gene (W11X; 164008.0002) in a girl with anhidrotic ectodermal dysplasia and immunodeficiency.
In a male infant with anhidrotic ectodermal dysplasia and T-cell immunodeficiency, Lopez-Granados et al. (2008) identified a nonsense mutation in the NFKBIA gene (D14X; 164008.0003). In vitro studies indicated a gain-of-function mutation resulting in impaired NFKB1 activity.
In a female infant with autosomal dominant anhidrotic ectodermal dysplasia with immunodeficiency, Giancane et al. (2013) identified a de novo heterozygous mutation in the NFKBIA gene (M37R; 164008.0004).
In a boy with anhidrotic ectodermal dysplasia with immunodeficiency and polyendocrinopathy, Schimke et al. (2013) identified a heterozygous missense mutation in the NFKBIA gene (M37K; 164008.0005). Functional studies showed that the mutation interfered with degradation of I-kappa-B-alpha proteins, resulting in a gain-of-function protein that impairs NFKB activation.
In a boy with mild ectodermal dysplasia (sparse hair and hypohidrosis, but normal teeth) and noninfectious systemic inflammation, Yoshioka et al. (2013) identified a de novo heterozygous missense mutation in the NFKBIA gene (S36Y; 164008.0006). Lee et al. (2016) identified heterozygosity for the S36Y mutation in a girl with severe mycobacterial disease and no signs of ectodermal dysplasia.
In a 6-year-old girl with immunodeficiency and pointed teeth, but no other features of ectodermal dysplasia, Staples et al. (2017) identified a de novo heterozygous mutation in the NFKBIA gene (S32G; 164008.0007). In 2 patients with ectodermal dysplasia and immune dysregulation presenting as severe noninfectious systemic inflammation, partially or fully responsive to steroids, Moriya et al. (2018) reported different heterozygous mutations at the same codon in the NFKBIA gene (S32R, 164008.0008 and S32N, 164008.0009).
Boisson et al. (2017) reviewed 14 unrelated patients with autosomal dominant anhidrotic ectodermal dysplasia with immunodeficiency and germline mutations in the NFKBIA gene. All mutations enhanced the inhibitory activity of NFKBIA by preventing its phosphorylation at Ser32 or Ser36 and its subsequent degradation. The mutation was thought to be de novo in 13 patients and inherited from a parent with somatic mosaicism in 1 patient. Mutations could be divided into 2 groups: (1) 8 mutations in 11 patients were missense involving Ser32, Ser36 or neighboring residues; and (2) 3 mutations in 3 patients were nonsense mutations upstream from Ser32 associated with reinitiation of translation downstream from Ser36. Patients with missense mutations were more severely affected, which was thought to be due to higher levels of gain of function.
In a female infant with EDAID2, Tan et al. (2020) identified a de novo heterozygous missense mutation in the NFKBIA gene (L34P; 164008.0010). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. In vitro studies showed defective phosphorylation and degradation of NFKBIA, resulting in a severe reduction in NFKB activation, nuclear translocation, and cytokine production with a dominant-negative gain-of-function effect. These findings were consistent with the patient's recurrent invasive infections. Although production of certain cytokines was decreased, the patient showed hypersecretion of IL1B (147720) from myeloid cells. In addition, stimulation of patient blood with IL1B increased the secretion of cytokines associated with eosinophilic, neutrophilic, and monocytic inflammation. In addition to immunodeficiency and recurrent infections due to impaired NFKB activation, she developed autoinflammatory-based liver disease and neutrophilia due to increased IL1B secretion. The findings indicated that inhibition of NFKB signaling through the prevention of NFKBIA degradation in macrophages increased IL1B secretion. Hematopoietic bone marrow transplant restored abnormal immune features and liver function initially, but she later relapsed. Treatment with an IL1B antagonist (anakinra) resulted in some improvement and a decrease in IL1B levels. However, anakinra was stopped due to a rash and she again developed recurrent infections, sepsis, and an inflammatory disease with liver and renal failure resulting in death at 27.5 months of age. Of note, she had poor hair growth, delayed tooth eruption, and absence of sweat glands on skin biopsy.
Somatic Mutations in Glioblastoma
Bredel et al. (2011) analyzed 790 human glioblastomas (see 137800) for deletions, mutations, or expression of NFKBIA and EGFR (131550). They further studied the tumor suppressor activity of NFKBIA in tumor cell culture and compared the molecular results with the outcome of glioblastoma in 570 affected individuals. Bredel et al. (2011) found that NFKBIA is often deleted but not mutated in glioblastomas; most deletions occur in nonclassical subtypes of the disease. Deletion of NFKBIA and amplification of EGFR show a pattern of mutual exclusivity. Restoration of the expression of NFKBIA attenuated the malignant phenotype and increased the vulnerability to chemotherapy of cells cultured from tumors with NFKBIA deletion; it also reduced the viability of cells with EGFR amplification but not of cells with normal gene dosages of both NFKBIA and EGFR. Deletion and low expression of NFKBIA were associated with unfavorable outcomes. Patients who had tumors with NFKBIA deletion had outcomes that were similar to those in patients with tumors harboring EGFR amplification. These outcomes were poor as compared with the outcomes in patients with tumors that had normal gene dosages of NFKBIA and EGFR. Bredel et al. (2011) suggested a 2-gene model that was based on expression of NFKBIA and O(6)-methylguanine DNA methyltransferase (156569) being strongly associated with the clinical course of the disease, and concluded that deletion of NFKBIA has an effect that is similar to the effect of EGFR amplification in the pathogenesis of glioblastoma and is associated with comparatively short survival.
Polymorphisms
Ali et al. (2013) evaluated the impact of 3 NFKBIA promoter SNPs, rs3138053, rs2233406, and rs2233409, on NFKBIA mRNA expression, NFKBIA protein expression, and TLR (see 603030) responsiveness. They detected enhanced NFKBIA mRNA and protein expression in individuals homozygous for the haplotype comprising the common promoter variants (ACC) compared with those heterozygous for the haplotype comprising the minor promoter variants (GTT). Cord blood from ACC/GTT heterozygous neonates had higher production of TNF in response to lipopolysaccharide. Systems biology and functional analyses identified NFKBIA as a candidate gene in asthma, respiratory syncytial virus infection, and bronchopulmonary dysplasia. Ali et al. (2013) concluded that negative innate immune regulators are important in pediatric lung disease.
Hoffmann et al. (2002) generated mice deficient in Ikbb and Ikbe by homologous recombination and intercrossed them with Ikba-deficient mice to yield embryonic fibroblasts containing only 1 Ikb isoform. TNFA stimulation of the Ikba fibroblasts resulted in a highly oscillatory Nfkb response, whereas in Ikbb and Ikbe fibroblasts nuclear Nfkb increased monotonically. Hoffmann et al. (2002) concluded that IKBA mediates rapid NFKB activation and strong negative feedback regulation, while IKBB and IKBE respond more slowly to IKK activation and act to dampen long-term oscillations of the NFKB response. Computational and EMSA analyses revealed bimodal signal-processing characteristics with respect to the duration of the stimulus, enabling the generation of specificity in gene expression of IP10 (CXCL10; 147310) and RANTES (CCL5; 187011). In a commentary, Ting and Endy (2002) compared the duration of signaling to the creation of an audible tone by pressing a piano key, which causes a hammer to hit a string. How hard the string is hit, and whether or not string vibration is sustained after the key is released, can be modified by depressing a foot pedal, much as signal transduction pathways are activated and modified by information in the environment.
Cai et al. (2004) created transgenic mice with Nfkb either activated or inhibited selectively in skeletal muscle through expression of constitutively active IKKB (603258) 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.
Mooster et al. (2015) found that mice heterozygous for the Ikba S32I mutation exhibited typical features of EDAID. Mutant mice had a lack of lymph nodes, Peyer patches, splenic marginal zones, and follicular dendritic cells, and contact hypersensitivity and germinal center formation failed to develop. Induction of chemokine and adhesion molecule expression through Ltbr (600979) interaction, mediated by NFKB pathways, was also impaired. Creation of mutant Ikba bone marrow chimeras in Rag2 -/- mice, but not wildtype to Ikba -/- chimeras, resulted in proper lymphoid organ development, contact hypersensitivity, and germinal center formation. Mooster et al. (2015) proposed that immunodeficiency and poor outcome after hemopoietic stem cell transplantation in patients with IKBA deficiency is explained by defective architectural cell function.
In a 7-year-old boy with autosomal dominant anhidrotic ectodermal dysplasia and immune deficiency (EDAID2; 612132), Courtois et al. (2003) identified a de novo heterozygous c.94G-T transversion in the NFKBIA gene, resulting in a ser32-to-ile (S32I) change. Ser32 is a key phospho-acceptor site of I-kappa-B-alpha, and is conserved in the other 2 I-kappa-B proteins. The patient was born to unrelated parents. Since 2 months of age he had chronic diarrhea, recurrent bronchopneumonitis, hepatosplenomegaly, and failure to thrive. Bone marrow transplantation was performed at 1 year of age. A diagnosis of ectodermal dysplasia with immunodeficiency was made at the age of 3 years on the basis of a dry, rough skin, moderately sparse scalp hair, and conical teeth. The patient had no other overt developmental defects.
Janssen et al. (2004) identified heterozygosity for the S32I mutation in a boy with anhidrotic ectodermal dysplasia and T-cell immunodeficiency. The father had a less severe phenotype and was found to be mosaic for the mutation. Monocytes from both father and son showed impaired function, but T cells from the father showed relatively normal function and displayed the wildtype allele. Ser32 is 1 of the 2 serines that is phosphorylated on NFKBIA, leading to ubiquitin-related degradation of NFKBIA and allowing NFKB1 to be translocated to the nucleus for activation of downstream targets.
In a girl with anhidrotic ectodermal dysplasia with T-cell immunodeficiency (EDAID2; 612132), McDonald et al. (2007) identified a heterozygous 32G-A transition in exon 1 of the NFKBIA gene, resulting in a trp11-to-ter (W11X) substitution. Studies of patient fibroblasts showed that a downstream initiation sequence resulted in the translation of an N-terminally truncated protein. The mutant protein did not undergo ligand-induced phosphorylation or degradation, and retained NFKB in the cytoplasm. This led to roughly a 50% decrease in NFKB DNA-binding activity and functional haploinsufficiency of NFKB activation. Unlike S32I NFKBIA mutant also associated with ectodermal dysplasia with immune deficiency (164008.0001), the W11X mutation did not exert a dominant-negative effect but rather a 'persistence-of-function' mutant, resulting in functional NFKB haploinsufficiency.
In a male infant with anhidrotic ectodermal dysplasia and T-cell immunodeficiency (EDAID2; 612132), Lopez-Granados et al. (2008) identified a de novo heterozygous 40G-T transversion in exon 1 of the NFKBIA gene, resulting in a glu14-to-ter (E14X) substitution. He had failure to thrive, developed multiple infections including gastrointestinal and respiratory infections, and died from complications of a cord blood transplant. Skin biopsy showed absence of sweat glands, and laboratory studies showed normal serum immunoglobulin levels but impaired production of NFKB1-regulated cytokines. In vitro studies showed that an in-frame methionine downstream of the G14X mutation allowed for reinitiation of translation. The resulting N-terminally truncated protein lacked both serine phosphorylation sites and inhibited NFKB1 signaling by functioning as a dominant negative on NFKB1 activity in lymphocytes and monocytes. These findings supported the scanning model for translation initiation in eukaryotes and confirmed the critical role of NFKB1 in human immune response.
In a female infant with anhidrotic ectodermal dysplasia and immunodeficiency (EDAID2; 612132), Giancane et al. (2013) identified a de novo heterozygous c.110T-G transversion (c.110T-G, NM_020529) in exon 1 of the NFKBIA gene, resulting in a met37-to-arg (M37R) substitution. This substitution occurs at a conserved residue adjacent to Ser36, 1 of the 2 phosphorylation sites essential for targeting I-kappa-B-alpha for proteasomal degradation and activation of NFKB. The mutation was not found in 1000 Genomes Project or the Exome Variant Server databases or in 192 control chromosomes.
In a boy with anhidrotic ectodermal dysplasia with immunodeficiency (EDAID2; 612132) and polyendocrinopathy, Schimke et al. (2013) identified a heterozygous c.110T-A transversion (c.110T-A, NM_020529.2) in the NFKBIA gene, resulting in a met37-to-lys (M37K) substitution at a highly conserved residue. The mother did not have the mutation and the father was not available for testing. Functional studies showed that the mutation led to defective NFKBIA degradation impairing NFKB activation as demonstrated by reduced NFKB nuclear translocation and NFKB dependent gene transcription.
In a boy with mild ectodermal dysplasia (sparse hair and hypohidrosis, with normal teeth) and noninfectious systemic inflammation (EDAID2; 612132), Yoshioka et al. (2013) identified a de novo heterozygous c.107C-A mutation in the NFKBIA gene, resulting in a ser36-to-tyr (S36Y) substitution. The mutation resulted in defective NFKBIA degradation and impaired NFKB activation. Because the phenotype was less severe than that in previously published patients, genetic analysis was performed on various cell lineages, but no evidence of somatic mosaicism was found.
Lee et al. (2016) identified the S36Y mutation in a patient with immunodeficiency resulting in severe mycobacterial disease but with no signs of ectodermal dysplasia.
In a girl with pointed teeth, but no other signs of ectodermal dysplasia, and immunodeficiency (EDAID2; 612132), Staples et al. (2017) identified a de novo heterozygous c.94A-G mutation in the NFKBIA gene, resulting in a ser32-to-gly (S32G) substitution. Fibroblasts from the patient showed increased IKB-alpha and reduced phospho-IKB-alpha compared to controls following TNF-alpha stimulation in vitro, confirming gain of function.
In a Japanese patient (P1) with ectodermal dysplasia and immunodeficiency (EDAID2; 612132), Moriya et al. (2018) identified a de novo heterozygous c.96C-G mutation in the NFKBIA gene, resulting in a ser32arg (S32R) substitution. In vitro studies demonstrated that the mutation had significantly more inhibitory effects on NFKB signalling compared to controls.
In a Japanese patient with ectodermal dysplasia and immunodeficiency (EDAID2; 612132), Moriya et al. (2018) identified a de novo heterozygous c.95G-A transition in the NFKBIA gene, resulting in a ser32-to-asn (S32N) substitution. In vitro studies demonstrated that the mutation had significantly more inhibitory effects on NFKB signaling compared to wildtype.
In a female infant with ectodermal dysplasia and immunodeficiency (EDAID2; 612132), Tan et al. (2020) identified a de novo heterozygous c.101T-C transition in the NFKBIA gene, resulting in a leu34-to-pro (L34P) substitution at a conserved residue between 2 phosphorylation sites (Ser32 and Ser36) that are critical for NFKBIA degradation and NFKB activation. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. In vitro studies showed defective phosphorylation and degradation of NFKBIA, resulting in a severe reduction in NFKB activation, nuclear translocation, and cytokine production with a dominant-negative gain-of-function effect. These findings were consistent with the patient's recurrent invasive infections. Although production of certain cytokines was decreased, the patient showed hypersecretion of IL1B (147720) from myeloid cells. In addition, stimulation of patient blood with IL1B increased the secretion of cytokines associated with eosinophilic, neutrophilic, and monocytic inflammation. In addition to immunodeficiency and recurrent infections due to impaired NFKB activation, she developed autoinflammatory-based liver disease and neutrophilia due to increased IL1B secretion. The findings indicated that inhibition of NFKB signaling through the prevention of NFKBIA degradation in macrophages increased IL1B secretion. Hematopoietic bone marrow transplant restored abnormal immune features and liver function initially, but she later relapsed. Treatment with an IL1B antagonist (anakinra) resulted in some improvement and a decrease in IL1B levels. However, anakinra was stopped due to a rash and she again developed recurrent infections, sepsis, and an inflammatory disease with liver and renal failure resulting in death at 27.5 months of age. Of note, she had poor hair growth, delayed tooth eruption, and absence of sweat glands on skin biopsy.
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