Alternative titles; symbols
HGNC Approved Gene Symbol: IKBKG
SNOMEDCT: 367520004; ICD10CM: Q82.3;
Cytogenetic location: Xq28 Genomic coordinates (GRCh38): X:154,541,238-154,565,046 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xq28 | Autoinflammatory disease, systemic, X-linked | 301081 | X-linked | 3 |
| Ectodermal dysplasia and immunodeficiency 1 | 300291 | X-linked recessive | 3 | |
| Immunodeficiency 33 | 300636 | X-linked recessive | 3 | |
| Incontinentia pigmenti | 308300 | X-linked dominant | 3 |
The IKBKG gene, also known as NEMO, encodes the regulatory gamma subunit of the IKB kinase (IKK) complex. Along with the other 2 subunits, IKBKA (CHUK; 600664) and IKBKB (603258), this IKK complex leads to the proteolytic degradation of the NFKB (see, e.g., 164011) inhibitor NFKBIA (164008), thus enabling NFKB to translocate to the nucleus and activate the transcription of cytokine-associated genes (summary by Heller et al., 2020).
IKBKG, or NEMO, is the founding member of an evolutionarily conserved family of NEMO-like kinases that function in numerous cell signaling pathways. NEMO-like kinases specifically phosphorylate serine or threonine residues that are followed by a proline residue (Chiu et al., 2011).
Yamaoka et al. (1998) characterized a mutant cell line, 5R, originally isolated as a cellular flat variant of Rat-1 fibroblasts transformed by the Tax protein of human T-cell leukemia virus type 1 (HTLV-1). The 5R cell line was unresponsive to all tested NF-kappa-B (NFKB; see 164011)-activating stimuli. Using a genetic complementation approach, Yamaoka et al. (1998) cloned a component of the I-kappa-B kinase complex that they termed NEMO for 'NF-kappa-B essential modulator' from 5R cells. The 2.8-kb NEMO cDNA encodes a 412-amino acid protein that is acidic, rich in glutamic acid and glutamine residues (each 13%), and contains a leucine zipper motif at amino acids 315-342. Yamaoka et al. (1998) determined that the defective phenotype of 5R cells resulted from the absence of the NEMO protein. NEMO also complemented the 1.3E2 mutant cell line, in which NFKB is not activated in response to a large set of stimuli.
By using a monoclonal antibody against IKK-alpha, Rothwarf et al. (1998) purified the IKK complex to homogeneity from human cell lines. They determined that the IKK complex is composed of IKK-alpha, IKK-beta, and 2 other polypeptides of 50 and 52 kD which are differentially processed forms of a third subunit, IKK-gamma. Rothwarf et al. (1998) cloned IKK-gamma and identified it as the human homolog of mouse NEMO. The 419-amino acid IKK-gamma protein is composed of several potential coiled-coil motifs and a leucine zipper motif.
Using a yeast 2-hybrid assay to search for proteins that could interact with adenovirus protein E3-14.7K, known to prevent TNF-alpha (TNFA; 191160)-induced cytolysis, Li et al. (1999) cloned IKK-gamma, which they called FIP3 (14.7K-interacting protein). FIP3 contains leucine zippers and a zinc finger domain.
Using Western blot analysis and transfection studies in embryonic kidney cells, Puel et al. (2006) demonstrated that the IKBKG gene encodes a predominant 48-kD protein and an N-terminally truncated protein of 45 kD produced in smaller amounts and translated from methionine-38.
Yamaoka et al. (1998) found that NEMO interacted with IKK2 (IKK-beta; 603258), but not with IKK1 (IKK-alpha; 600664).
Rothwarf et al. (1998) determined that IKK-gamma forms dimers and trimers and interacts preferentially with IKK-beta. IKK-gamma was required for activation of the IKK complex. An IKK-gamma carboxy-terminal truncation mutant that binds IKK-beta blocked the activation of IKK and NF-kappa-B.
Li et al. (1999) determined that FIP3 inhibits both basal and induced transcriptional activity of NFKB and causes a late-appearing apoptosis with unique morphologic manifestations. E3-14.7K partially reversed apoptotic death induced by FIP3. FIP3 bound RIP (603453) and NIK (604655), which had been described as essential components of TNF-alpha-induced NFKB activation. FIP3 inhibited activation of NFKB induced by TNF-alpha, TNFR1 (191190), RIP, NIK, and IKK-beta, as well as basal levels of endogenous NFKB in 293 cells. FIP3 appeared both to activate a cell death pathway and to inhibit an NFKB-dependent survival mechanism.
Although in vitro studies had suggested that NEMO associates preferentially with IKK2 and not IKK1, Li et al. (1999) found that IKK1 immunoprecipitated with NEMO, suggesting that in vivo, IKK1 associates with NEMO through a component other than IKK2 in the IKK complex.
May et al. (2000) determined that an N-terminal alpha-helical region of NEMO associates with a region of IKKA and IKKB that they termed the NBD for 'NEMO-binding domain.' The NBD is a 6-amino acid C-terminal segment within the region denoted alpha-2 of IKKA and IKKB. A cell-permeable wildtype NBD peptide, but not a mutant, blocked the association of NEMO with the IKK complex and inhibited cytokine-induced NFKB activation and the expression of an NFKB-dependent gene, E-selectin (SELE; 131210), in endothelial cells in vitro. Wildtype NBD peptide also ameliorated acute inflammation, namely ear edema and peritonitis, in 2 experimental mouse models as effectively as dexamethasone. May et al. (2000) proposed that an NBD-type drug targeting the interaction of NEMO and the IKK complex might control inflammation yet maintain basal NFKB activity, thus avoiding toxic side effects.
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 (164011). They showed that CYLD binds to the NEMO component of the IKK complex, 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.
Kovalenko et al. (2003) showed that CYLD interacts with NEMO and TRAF2. CYLD has a deubiquitinating activity that is directed toward the non-lys48-linked polyubiquitin chains and negatively modulates TRAF-mediated activation of IKK, strengthening the notion that ubiquitination is involved in IKK activation by TRAFs and suggesting that CYLD functions in this process.
Wu et al. (2006) demonstrated that NEMO associates with activated ATM (607585) 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). Thus, Wu et al. (2006) concluded that regulated nuclear shuttling of NEMO links 2 signaling kinases, ATM and IKK, to activate NF-kappa-B by genotoxic signals.
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-specific inhibition of NFKB through conditional ablation of NEMO or both IKK1 and IKK2, 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 activation by intestinal bacteria is essential for disease pathogenesis in this mouse model. Furthermore, NEMO deficiency sensitized epithelial cells to TNF-induced apoptosis, whereas TNF receptor-1 (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.
Cytokine signaling is thought to require assembly of multicomponent signaling complexes at cytoplasmic segments of membrane-embedded receptors, in which receptor-proximal protein kinases are activated. Matsuzawa et al. (2008) reported that, upon ligation, CD40 (109535) formed a complex containing adaptor molecules TRAF2 and TRAF3 (601896), ubiquitin-conjugating enzyme UBC13 (UBE2N; 603679), cellular inhibitor of apoptosis protein-1 (CIAP1, or BIRC2; 601712) and -2 (CIAP2, or BIRC3; 601721), IKK-gamma, and MEKK1 (MAP3K1; 600982). TRAF2, UBC13, and IKK-gamma were required for complex assembly and activation of MEKK1 and MAP kinase cascades. However, the kinases were not activated unless the complex was translocated from the membrane to the cytosol upon CIAP1/CIAP2-induced degradation of TRAF3. Matsuzawa et al. (2008) proposed that this 2-stage signaling mechanism may apply to other innate immune receptors and may account for spatial and temporal separation of MAPK and IKK signaling.
By studying responses to the TLR4 (603030) ligand lipopolysaccharide (LPS) and to the bacterial chemoattractant fMLP in polymorphonuclear neutrophils (PMNs) from 1 patient with IRAK4 deficiency (607676) and 3 patients with NEMO deficiency causing X-linked hyper-IgM immunodeficiency with ectodermal dysplasia (300291), Singh et al. (2009) demonstrated reduced or absent superoxide production after impaired priming and activation of the oligomeric neutrophil NADPH oxidase (NOX; see 300481). The response was particularly weak or absent in IRAK4-deficient PMNs. NEMO-deficient PMNs had a phenotype intermediate between IRAK4-deficient PMNs and normal PMNs. Decreased LPS- and fMLP-induced phosphorylation of p38 (MAPK14; 600289) was observed in both deficiencies. Singh et al. (2009) proposed that decreased activation of NOX may contribute to increased risk of infection in patients with IRAK4 deficiency or NEMO deficiency.
One of the E3 ligases responsible for K63-linked NEMO polyubiquitination is TRAF6 (602355) which participates in several signaling pathways controlling immunity, osteoclastogenesis, skin development, and brain function. Gautheron et al. (2010) determined that a site at the N terminus of NEMO binds the coiled-coil domain of TRAF6 and apparently works in concert with NEMO's ubiquitin-binding domain to provide a dual mode of TRAF6 recognition. The E57K NEMO mutation, found in a mild form of incontinentia pigmenti (IP; 308300), resulted in impaired TRAF6 binding and IL1-beta (147720) signaling. In contrast, activation of NF-kappa-B (see 164011) by TNF-alpha (191160) was not affected. The authors concluded that the NEMO-TRAF6 interaction has physiologic relevance.
Gerlach et al. (2011) identified SHARPIN (611885) as a third component of the linear ubiquitin chain assembly complex (LUBAC), recruited to the CD40 and TNF receptor (see 191190) signaling complexes together with its other constituents, HOIL1 (RBCK1; 610924) and HOIP (RNF31; 612487). Mass spectrometry of TNFA signaling complexes revealed RIP1, also known as RIPK1 (603453), and NEMO to be linearly ubiquitinated. Tokunaga et al. (2011) also identified SHARPIN as a component of LUBAC, and showed that SHARPIN-containing complexes can linearly ubiquitinate NEMO and activate NK-kappa-B (see 164011). Ikeda et al. (2011) reported that SHARPIN functions as a novel component of LUBAC and that the absence of SHARPIN causes dysregulation of NF-kappa-B and apoptotic signaling pathways, explaining the severe phenotypes displayed by cpdm in Sharpin-deficient mice. Upon binding to the LUBAC subunit HOIP, SHARPIN stimulates the formation of linear ubiquitin chains in vitro and in vivo. Coexpression of SHARPIN and HOIP promotes linear ubiquitination of NEMO, an adaptor of the I-kappa-B kinases (IKKs; see 600664) and subsequent activation of NK-kappa-B signaling, whereas SHARPIN deficiency in mice causes an impaired activation of the IKK complex and NF-kappa-B in B cells, macrophages, and mouse embryonic fibroblasts. This effect is further enhanced upon concurrent downregulation of HOIL1L, another HOIP-binding component of LUBAC.
PER1 (602260) is a master regulator of circadian rhythm and functions in the nucleus to repress expression of central circadian clock genes. The periodicity of PER1 abundance, nuclear translocation, and transcriptional repression is regulated by PER1 phosphorylation, ubiquitination, and proteasomal degradation. Using Drosophila cells and various Per mutants, Chiu et al. (2011) found that Per was progressively phosphorylated by Nemo and doubletime (CSNK1E; 600863) during the circadian cycle. This progressive phosphorylation defined the length of the circadian cycle and the timing of proteasome-mediated Per degradation.
The International Incontinentia Pigmenti Consortium (2000) sequenced the complete NEMO locus. NEMO is a 23-kb gene composed of 10 exons with 3 alternative noncoding first exons, 1a, 1b, and 1c (Jin and Jeang, 1999; Rothwarf et al., 1998; Li et al., 1999). The NEMO gene partially overlaps the G6PD (305900) gene, and it is transcribed in the opposite direction (Jin and Jeang, 1999).
Fusco et al. (2012) stated that the IKBKG gene has 9 coding exons (exons 2 through 10), 4 alternative noncoding first exons (exons 1A through 1D), and 2 promoters. Promoter A drives expression of IKBKG from exons 1D and 1A and is located within intron 2 of the more centromeric G6PD gene, which lies on the opposite strand. Promoter B is a bidirectional housekeeping promoter that drives expression of IKBKG from exons 1B and 1C, as well as G6PD. Fusco et al. (2012) determined that the region containing the G6PD gene and the 5-prime end of the IKBKG gene contains Alu elements.
By sequence alignment, Jin and Jeang (1999) mapped the human NEMO gene to chromosome Xq28.
IKBKG Segmental Duplication
Aradhya et al. (2001) identified a truncated copy of NEMO (delta-NEMO), which maps 22 kb distal to NEMO and contains only exons 3 through 10. A sequence of 26 kb 3-prime of the NEMO coding sequence is also present in the same position relative to the delta-NEMO locus, bringing the total length of the duplication to 35.5 kb. The LAGE2 gene (CTAG1B; 300156) is also located within this duplicated region, and a similar but unique LAGE1 gene (CTAG2; 300396) is located just distal to the duplicated loci. Mapping and sequence information indicated that the duplicated regions are in opposite orientation. Analysis of the great apes suggested that the 35.5-kb NEMO/LAGE2 duplication occurred after divergence of the lineage leading to present day humans, chimpanzees, and gorillas, 10 to 15 million years ago. Despite this substantial evolutionary history, only 22 single-nucleotide differences exist between the 2 copies over the entire 35.5 kb, making the duplications more than 99% identical. This high sequence identity and the inverted orientations of the 2 copies, along with duplications of smaller internal sections within each copy, predispose this region to various genomic alterations. Aradhya et al. (2001) detected 4 rearrangements that involved NEMO, delta-NEMO, or LAGE1 and LAGE2. The authors hypothesized that the susceptibility of this complex genomic region to various types of pathogenic and polymorphic rearrangements may underlie the recurrent lethal deletion associated with incontinentia pigmenti (see MOLECULAR GENETICS).
Fusco et al. (2012) stated that the IKBKG gene and the more telomeric CTAG1A gene (300657) were involved in an inverted 35.7-kb segmental duplication on chromosome Xq28 that produced the CTAG1B gene and an IKBKG pseudogene, IKBKGP1, copied from IKBKG exons 3 through 10. Fusco et al. (2012) found that the duplicated regions and the regions between and near them contain a high number of short and long interspersed elements and long terminal repeats.
X-Linked Dominant Incontinentia Pigmenti
The International Incontinentia Pigmenti Consortium (2000) demonstrated that heterozygous mutations in the IKBKG gene cause X-linked dominant incontinentia pigmenti (IP; 308300). The most common mutation in IP is a genomic rearrangement resulting in deletion of part of the NEMO gene (300248.0001). An 870-bp region of identity corresponding to an MER67B repeat exists both in intron 3 and 3-prime to exon 10; recombinations between the regions of identity delete exons 4 though 10 of NEMO. The International Incontinentia Pigmenti Consortium (2000) stated that this rearrangement, which occurs during paternal meiosis, causes 80% of new mutations. It was demonstrated that this mutation results in a lack of NF-kappa-B (see 164011) activation resulting in extreme susceptibility to apoptosis, leading to embryonic death in males and explaining the extremely skewed X inactivation seen in females with IP.
Aradhya et al. (2001) reported 2 families with IP with duplications in a 7-cytosine tract in exon 10 of the IKBKG gene (300248.0008 and 300248.0012). Aradhya et al. (2001) found that the duplication mutations of the IKBKG gene allowed males to survive and affected females to have random or slightly skewed X inactivation, whereas virtually all other mutations eliminate the production of NEMO, causing lethality in males and the typical skewing of X inactivation in females.
The International IP Consortium (2001) investigated 4 male patients with clinical hallmarks of IP. All 4 were found to carry the deletion in the NEMO gene normally associated with male lethality in utero. Survival in 1 patient was explained by a 47,XXY karyotype and skewed X inactivation. Three other patients possessed a normal 46,XY karyotype. It was demonstrated that these patients had both wildtype and deleted copies of the NEMO gene, indicating mosaicism for the common mutation. Therefore, the repeat-mediated rearrangement leading to the common deletion does not require meiotic division. Thus there are 3 mechanisms for survival of males carrying a NEMO mutation: hypomorphic alleles, a 47,XXY karyotype, and somatic mosaicism.
In an examination of families transmitting the recurrent deletion of exons 4 through 10 of the NEMO gene (300248.0001), Aradhya et al. (2001) revealed that the rearrangement occurred in the paternal germline in 70% of cases, indicating that it arises predominantly by intrachromosomal misalignment during meiosis. Expression analysis of human and mouse NEMO/Nemo showed that the gene becomes active early during embryogenesis and is expressed ubiquitously. The authors proposed a model to explain the pathophysiology of IP in terms of disruption of the NF-kappa-B signaling pathway.
Bardaro et al. (2003) presented instances in which the exon 4 to 10 delta-NEMO pseudogene deletion occurred in unaffected parents of 2 females with clinically characteristic IP, confusing the genetic analysis. They described a new PCR-based test that permitted unambiguous molecular diagnosis and proper familial genetic counseling for IP.
Fusco et al. (2004) identified NEMO mutations in 83 of 122 IP patients and measured the effects of NEMO point mutations on NFKB signaling in Nemo-deficient murine pre-B cells. A mutation in the N-terminal domain, required for IKK assembly, reduced but did not abolish NFKB activation following LPS stimulation. Mutations that disrupt the C-terminal domain (required for the recruitment of upstream factors) showed lower or no NFKB activation. There was no phenotype-genotype correlation observed; 64% of patients exhibited an extremely skewed X-inactivation pattern (80:20). Fusco et al. (2004) concluded that IP pathogenesis may depend on a combination of X inactivation and protein domain that recruits upstream factors and activates NFKB.
In a female infant who presented at birth with features of IP, Martinez-Pomar et al. (2005) identified a heterozygous mutation in the IKBKG gene (300248.0017). She also developed transient immunodeficiency that resolved spontaneously in the first years of life. The X-inactivation status of peripheral blood cells from the patient was evaluated at 24, 30, 38, and 48 months of age and was found to have progressed from random at 24 and 30 months to skewed at 38 and 48 months of age, at which point her immunodeficiency had disappeared. Martinez-Pomar et al. (2005) stated that this was the first time that selection against the mutated X chromosome in X-linked disease had been documented in vivo.
Ectodermal Dysplasia and Immunodeficiency 1
In affected males from 4 unrelated families with X-linked recessive hypohidrotic ectodermal dysplasia and immunodeficiency-1 (EDAID1; 300291), Zonana et al. (2000) identified hemizygous mutations in the IKBKG gene (300248.0007-300248.0010). All mutations occurred in exon 10 of the gene, which encodes the C-terminal zinc finger domain, and were predicted to result in a loss of NFKB activation. Since heterozygous mutations in this gene cause IP in females and are usually lethal in males, Zonana et al. (2000) hypothesized that the mutations identified in males with EDAID1 are hypomorphic; functional studies of the variants were not performed. Affected males showed dysgammaglobulinemia and, despite therapy, had significant morbidity and mortality from recurrent infections.
Doffinger et al. (2001) identified 5 novel mutations (see, e.g., 300248.0020) in IKBKG in affected males from 5 kindreds with anhidrotic ectodermal dysplasia and immune deficiency. Doffinger et al. (2001) also showed that the ectodysplasin receptor (EDAR; 604095) triggers NF-kappa-B through the NEMO protein, indicating that anhidrotic ectodermal dysplasia results from impaired NF-kappa-B signaling.
In 2 boys with EDAID1 associated with increased IgM, Jain et al. (2001) identified hemizygous missense mutations in the NEMO gene (C417R, 300248.0009 and D406V, 300248.0011). Both mutations occurred in the putative zinc finger domain, a potentially shared intracellular signaling component for EDAR and CD40L (300386). Although stimulation of patient monocytes with TNF and LPS resulted in responses similar to those of normal controls, stimulation with CD40L failed to induce phosphorylation of I-kappa-B-alpha (IKBA; 164008) and failed to upregulate expression of CD54 (ICAM1; 147840). CD40L stimulation also failed to induce class switching in patient B cells and failed to result in IL12 and TNF production. T-cell function and maturation appeared to be normal in the patients, and they had no history of opportunistic infections suggestive of T-cell dysfunction. Jain et al. (2001) concluded that NEMO has a regulatory function in NFKB activation and B-cell Ig class switching.
Jain et al. (2004) showed that 3 patients with EDAID1 due to missense mutations affecting cys417 of NEMO had markedly diminished levels of serum IgG and IgE. Activation of patient B cells with soluble CD40L and IL4 (147780) induced normal levels of I-epsilon and C-epsilon germline transcripts and expression of AID (AICDA; 605257), suggesting that expression of additional genes, possibly regulated by CD40-mediated REL (164910) activation, are necessary for Ig class switch recombination. Microarray analysis of EDAID1 B cells showed impairments in the expression of RAD50 (604040), LYL1 (151440), LIG4 (601837), and other factors relating to nonhomologous recombination but not previously linked to B-cell differentiation. Jain et al. (2004) proposed that IL4 augments some (e.g., RELA; 164014) but not all NEMO-dependent NFKB signaling.
In 3 unrelated boys with EDAID1, Orange et al. (2002) identified hemizygous mutations in the IKBKG gene. Two mutations occurred in the zinc finger domain (C417R, 300248.0009 and Q403X, 300248.0015), and 1 occurred in the first coiled-coil domain (L153R; 300248.0014). Patient cells showed defective CD40 signaling, as well as impaired natural killer (NK) cell activity, in spite of normal levels of peripheral blood NK numbers. Addition of IL2 (147680) induced NFKB activation and partially reversed the NK activity defect in vitro. Intravenous administration of IL2 to one of the patients, who had the L153R mutation and persistent cytomegalovirus infection, resulted in enhanced NK cell activity. Orange et al. (2002) proposed that NEMO is important for NFKB activation as well as NK cell cytotoxicity, and that IL2 may benefit patients with NEMO mutations.
In a family with ectodermal dysplasia and immunodeficiency previously reported by Lie et al. (1978), Orstavik et al. (2006) identified a splice site mutation in the NEMO gene (300248.0016). The family had 3 stillborn males, 3 affected males who were small for gestational age and died within 8 months, and 1 male who died at age 5 years. The 5-year-old boy had cone-shaped teeth, oligodontia, serious bacterial infections, and inflammatory bowel disease. Isolated subtle tooth anomalies were found in 3 female carriers examined, of whom 2 had random X inactivation and 1 had extreme skewing. Orstavik et al. (2006) stated that this was the first report of random X inactivation in carriers of EDAID.
Takada et al. (2010) analyzed the NEMO gene in a family in which a boy with EDAID1 died at 9 years of age from gastrointestinal bleeding, and his 6-year-old sister and mother were found to have incontinentia pigmenti and entero-Behcet disease (see 109650); all 3 carried the D406V (300248.0011) mutation. Takada et al. (2010) noted that these patients exhibited several unusual features, including the occurrence of incontinentia pigmenti and EDAID1 in a family; the presence of hypopigmented skin lesions in early infancy in the mother and daughter, since they are usually observed in the second decade to adulthood; and a lack of extremely skewed X-chromosome inactivation in the mother and daughter.
In a boy with EDAID1, Roberts et al. (2010) identified a hemizygous 2-bp deletion (c.1182_1183delTT; 300248.0027) in the IKBKG gene, predicted to result in a frameshift and premature termination. His mother, who carried the mutation in heterozygous state, showed signs of IP since childhood. Functional studies of the variant were not performed.
In a male infant with lethal EDAID1, Johnston et al. (2016) identified a hemizygous splice site mutation in the IKBKG gene (300248.0028). Western blot analysis of patient cells showed reduced size of the IKBKG protein, consistent with a frameshift and premature termination.
In a boy (patient 1) with EDAID1, Heller et al. (2020) identified a hemizygous splice site mutation (300248.0031) in the IKBKG gene, resulting in a frameshift and premature termination with loss of the zinc finger domain. Patient cells showed decreased IKBKG levels compared to controls; in vitro studies showed impaired degradation of IKBA and impaired IL6 production upon stimulation with IL1B and TNFA. His mother and sister, who were heterozygous for the mutation, had incontinentia pigmenti.
Immunodeficiency 33
Two unrelated male patients with immunodeficiency-33 (IMD33; 300636) without ectodermal dysplasia were described by Niehues et al. (2004) and Orange et al. (2004). The patient reported by Orange et al. (2004) was found to have a hemizygous splice mutation that resulted in the skipping of exon 9 of the NEMO gene, affecting the LZ domain (300248.0018) but leaving the zinc finger domain intact. In the patient reported by Niehues et al. (2004), Puel et al. (2006) identified a hemizygous 1-bp insertion in exon 2 of the NEMO gene (300248.0019). Puel et al. (2006) showed that a Kozakian methionine codon located immediately downstream from the insertion allowed the reinitiation of translation. The residual production of an NH2-truncated NEMO protein was sufficient for normal fetal development and for the subsequent normal development of skin appendages, but was insufficient for the development of protective immune responses.
In 2 unrelated boys with IMD33, Ku et al. (2005) identified hemizygous mutations in the IKBKG gene: an 18-bp deletion (300248.0025) and a missense mutation (L80P, 300248.0026). The mutations occurred in the coiled-coil domains of the protein. Western blot analysis of patient cells showed the presence of the IKBKG protein, but fibroblasts had poor IL6 production in response to TNFA and IL1B compared to controls. The findings were consistent with a hypomorphic allele. The patients had hypodontia and conical teeth, but no other features of ectodermal dysplasia. One carrier mother also had conical teeth.
In a Belgian boy with IMD33, Ku et al. (2007) identified a hemizygous splice site mutation in the IKBKG gene (300248.0023). Western blot analysis showed decreased levels of the protein compared to controls, consistent with partial IKBKG deficiency. The mother was heterozygous for this mutation.
In affected males from 3 unrelated kindreds with IMD33 manifest as susceptibility to mycobacterial infection, Filipe-Santos et al. (2006) identified 2 hemizygous missense mutations in the NEMO gene (E315A, 300248.0021 and R319Q, 300248.0022), both of which occurred in the leucine zipper (LZ) domain and were predicted to disrupt a salt bridge. Western blot and flow cytometric analyses showed normal expression of the mutant NEMO proteins. Patient mononuclear cells responded normally to most stimuli, but IFNG (147570) and IL12 (see 161561) production in response to PHA mitogen was impaired due to defective CD40 (109535) signaling in monocytes and dendritic cells. Filipe-Santos et al. (2006) concluded that mutations in NEMO that disrupt the leucine zipper domain provide a genetic etiology to X-linked recessive immunodeficiency with a particular susceptibility to mycobacterial disease.
In a 2-year-old boy with IMD33, Frans et al. (2017) identified a hemizygous missense mutation in the IKBKG gene (E57K; 300248.0029). The mutation affected the N-terminal domain of the protein. His mother, who also carried the mutation, had a history of recurrent sinorespiratory infections, but no signs of IP. The variant was present at a low frequency (0.001) in the ExAC database. Patient peripheral blood cells showed mildly decreased IL6 production after stimulation with IL1B compared to controls. However, NEMO expression in patient fibroblasts was normal, and IKBA was degraded normally upon stimulation with IL1B or TNFA, suggesting a specific effect of the mutation. In vitro functional expression studies in IKBKG-null cells transfected with the mutation showed mildly impaired IL6 production after stimulation with TNFA or IL1B compared to controls. Frans et al. (2017) noted that mutations affecting the N terminus of NEMO tend to lead to decreased production of immunoglobulins; the authors postulated a hypomorphic effect of this variant.
In 4 adult males from 3 unrelated families with IMD33 manifest as disseminated mycobacterial infections, Hsu et al. (2018) identified hemizygous splice site mutations in the 5-prime untranslated region of the IKBKG gene. Three patients from 2 families (families A and B) carried a c.1-16G-C transversion (300248.0030) at the last base of the first untranslated exon. The patient from family C carried a hemizygous c.1-16+G-T in the adjacent intron. Analysis of cells from the patient with the c.1-16G-C mutation showed a splicing abnormality, resulting in a 110-bp deletion at the 3-prime end of exon 1. This molecular defect resulted in decreased transcript and protein levels compared to controls (about 30%). Cells derived from the patients in families A and B failed to upregulate cytokines in response to certain TLR agonists, suggesting that this IKBKG mutation is hypomorphic.
In 3 boys from 2 unrelated families of European and Japanese descent with fatal IMD33, Boisson et al. (2019) identified a deep intronic mutation in the IKBKG gene (IVS4+866C-T; 300248.0024) that created a new splice donor site and resulted in a 44-nucleotide pseudoexon that produced a frameshift. The boy in the European family inherited the mutation from his mother, who had mild incontinentia pigmenti. The mutation in the Japanese boy occurred de novo. The variant was not found in the 1000 Genomes Project or gnomAD databases.
In a boy (patient 1) with IMD33, Abbott et al. (2014) identified a hemizygous missense mutation in the first coiled-coil domain of NEMO (D113N; 300248.0032). The patient had previously been reported in detail by Salt et al. (2008); his unaffected mother also carried the mutation.
Heller et al. (2020) identified hemizygosity for the D113N mutation in a boy with IMD33. His mother and grandmother, who were presumably unaffected, were heterozygous for the mutation. However, the proband's 40-year-old male cousin, who did not have recurrent infections and had normal response to polysaccharide antibodies, was hemizygous for D113N. Heller et al. (2020) noted that the allele frequency for this variant is rather high (0.009572), and that some suggest it may be a polymorphism (see Fusco et al., 2004).
X-linked Systemic Autoinflammatory Disease
In 3 unrelated boys (P1-P3) and a girl (P4) with X-linked systemic autoinflammatory disease (SAIDX; 301081), de Jesus et al. (2020) identified de novo hemizygous or heterozygous mutations in the IKBKG, all of which were predicted to disrupt splicing and result in the deletion of exon 5 (300248.0033-300248.0036). Functional studies of the variants were not performed. The patients were ascertained from a cohort of patients with autoinflammatory disease and a moderately elevated type I interferon signature.
In 3 unrelated boys with SAIDX, Lee et al. (2022) identified de novo hemizygous mutations in the IKBKG gene (300248.0033-300248.0035). The mutations, which were confirmed by Sanger sequencing, all led to overexpression of a NEMO protein lacking the domain encoded by exon 5 (NEMOdelEx5). In vitro studies showed that this splice isoform failed to associate with TANK binding kinase-1 (TBK1; 604834). Dermal fibroblasts from affected patients activated NFKB in response to TNF (191160), but showed impaired NFKB activation to TLR3 (603029) or RIGI-like receptor (RLR) stimulation with poly(I:C) positively correlated with levels of the NEMOdelEx5 splice isoform. By contrast, T cells, monocytes, and macrophages that expressed the splice site variant exhibited increased NFKB activation and IFN production. Blood cells from these patients expressed a strong IFN and NFKB transcriptional signature. Immune cells and TNF-stimulated dermal fibroblasts upregulated the inducible IKK protein (IKKi; 605048) that was stabilized by the splice variant, promoting type I IFN induction and antiviral responses. These data showed that IKBKG mutations that lead to alternative splicing of skipping exon 5 cause an autoinflammatory disorder, which the authors termed 'NEMO deleted exon 5 autoinflammatory syndrome (NDAS),' noting that it is distinct from the immunodeficiency syndrome resulting from loss-of-function IKBKG mutations.
In general, males with NKBKG mutations affecting the C-terminal zinc finger domain have a more severe clinical course with immunodeficiency and ectodermal dysplasia, whereas patients with mutations affecting the leucine zipper domain or the more N-terminal coiled-coil domains have a less severe clinical course and do not show features of ectodermal dysplasia, although isolated hypotonia and/or conical teeth may be present (Orange et al., 2004, Heller et al., 2020).
Rudolph et al. (2000) generated NEMO/IKK-gamma-deficient mice by gene targeting. Mutant embryos died at embryonic day 12.5-13 from severe liver damage due to apoptosis. NEMO/IKK-gamma-deficient primary murine embryonic fibroblasts (MEFs) lacked detectable NF-kappa-B DNA-binding activity in response to TNF-alpha, IL1 (see 147760), bacterial lipopolysaccharide, and poly(IC) and did not show stimulus-dependent I-kappa-B kinase activity, which correlated with a lack of phosphorylation and degradation of I-kappa-B-alpha (164008). Consistent with these data, mutant MEFs showed increased sensitivity to TNF-alpha-induced apoptosis. Rudolph et al. (2000) concluded that their data provided in vivo evidence that NEMO is the first essential noncatalytic component of the IKK complex.
Makris et al. (2000) showed that female mice heterozygous for Ikbkg deficiency develop a unique dermatopathy characterized by keratinocyte hyperproliferation, skin inflammation, hyperkeratosis, and increased apoptosis. Although Ikbkg +/- females eventually recovered, IKBKG -/- males died in utero. The symptoms and inheritance pattern were very similar to those of IP. Indeed, biopsies and cells from IP patients exhibited defective IKBKG expression but normal expression of IKK catalytic subunits. The authors proposed that the IKBKG-deficient cells trigger an inflammatory reaction that eventually leads to their death.
Schmidt-Supprian et al. (2000) found that disruption of the mouse Ikbkg gene produces male embryonic lethality, completely blocks NF-kappa-B activation by proinflammatory cytokines, and interferes with the generation and/or persistence of lymphocytes. Heterozygous female mice developed patchy skin lesions with massive granulocyte infiltration and hyperproliferation and increased apoptosis of keratinocytes. Diseased animals presented severe growth retardation and early mortality. Surviving mice recovered almost completely, presumably through clearing the skin of Ikbkg-deficient keratinocytes. The authors stated that male lethality and strikingly similar skin lesions in heterozygous females are hallmarks of the human genetic disorder IP.
Using a chemical mutagenesis screen in mice, Siggs et al. (2010) identified an X-linked recessive phenotype, termed 'pan resistance-2' (panr2), marked by diminished secretion of Tnf and other Nfkb-dependent cytokines by macrophages in response to ligands for Tlr3 (603029), Tlr4, Tlr7 (300365), and Tlr9 (605474), as well as for the TLR heterodimers Tlr1 (601194)/Tlr2 (603028) and Tlr2/Tlr6 (605403). They identified the panr2 mutation as a 473T-C transition in exon 4 of the Ikbkg gene, which results in a leu153-to-pro (L153P) substitution within the first coiled-coil domain of the protein. Panr2 mutant males were viable but azoospermic, and they usually lacked inguinal lymph nodes. Other tissues were normal, although serum lacked all Ig isotypes. Panr2 mutant mice had an impairment of MAPK phosphorylation and Nfkb p65 translocation, but not of Ikba degradation. Siggs et al. (2010) concluded that IKBKG-regulated pathways are of immunologic importance beyond IKBA degradation and may account for other immunodeficiencies.
In male and female fetuses with incontinentia pigmenti (IP; 308300), The International Incontinentia Pigmenti Consortium (2000) found a genomic rearrangement resulting in deletion of part of the NEMO gene. An 870-bp region of identity corresponding to an MER67B repeat exists in the NEMO gene both in intron 3 and 3-prime to exon 10; recombinations between the regions of identity delete exons 4 though 10 of NEMO. The International Incontinentia Pigmenti Consortium (2000) stated that this rearrangement accounts for 80% of new IP mutations. This rearrangement would result in a truncated molecule carrying the 133 N-terminal amino acids of NEMO plus at least 26 novel amino acids. It was predicted that this molecule would contain part of the first coiled-coil domain, and may still interact with IKK2 (603258), but would be unlikely to respond to upstream signals. Failure of I-kappa-B-alpha (164008) degradation and lack of NF-kappa-B (see 164011) activation were demonstrated in IP embryonic fibroblasts.
Aradhya et al. (2001) identified 277 mutations in 357 unrelated IP patients. The recurrent deletion of exons 4 to 10 accounted for 90% of the identified mutations. The remaining mutations were small duplications, substitutions, and deletions.
In a male infant (patient IP85) with ectodermal dysplasia and immunodeficiency-1 (EDAID1; 300291), The International Incontinentia Pigmenti Consortium (2000) identified a hemizygous c.1259A-G transition in exon 10 of the IKBKG gene, resulting in a stop420-to-trp (X420W) substitution. This change results in the addition of 27 residues to the C terminus of the mature protein. The mutation was also found in heterozygous state in his mother, who had incontinentia pigmenti (IP; 308300). In addition to recurrent infections, the boy also had osteopetrosis and lymphedema. He died at age 2.5 years from a tuberculosis infection.
Doffinger et al. (2001) studied patient IP85 reported by The International Incontinentia Pigmenti Consortium (2000) as well as another boy, of French descent, with the hemizygous X420W mutation and classified both as having anhidrotic ectodermal dysplasia with immunodeficiency, osteopetrosis, and lymphedema (OLEDAID; see 300291), which is within the phenotypic spectrum of EDAID1. Infections in the French boy, who died at the age of 1.5 years, included atypical mycobacteria and pneumococcus; he also had osteopetrosis and lymphedema, indicating that these additional features are associated with this specific mutation. His mother, who carried the mutation in heterozygous state, had mild IP. Detailed in vitro functional expression studies showed that the X420W mutation resulted in a 50 to 60% reduction of NF-kappa-B activation. Cells from both male patients with this mutation showed impaired cellular responses to LPS, IL1B, and TNFA. The findings indicated that the X420W mutation impairs, but does not abolish, NFKB activation, consistent with a hypomorphic allele and postnatal survival of the boys.
In an incontinentia pigmenti (IP; 308300) proband and her affected mother, but not in unaffected sibs, The International Incontinentia Pigmenti Consortium (2000) identified a 10-bp insertion in exon 2 of the IKBKG gene, between nucleotides 127 and 128. The insertion, an exact duplication of the previous 10 nucleotides, shifts the reading frame of the protein to add 8 amino acids after residue 43 and then truncates the protein at the next in-frame stop codon.
In a family with incontinentia pigmenti (IP; 308300), The International Incontinentia Pigmenti Consortium (2000) identified a single C insertion between nucleotides 1110 and 1111 that segregated with the disease. This frameshift mutation would putatively append 23 new amino acids onto proline residue 370 in the translated protein.
In a female with incontinentia pigmenti (IP; 308300), The International Incontinentia Pigmenti Consortium (2000) identified an A-to-G transition in exon 10 of the IKBKG gene that changed methionine to valine at codon 407. SSCP analysis showed that this relatively conservative change segregated with the disease through a 3-generation pedigree.
In a family with incontinentia pigmenti (IP; 308300), The International Incontinentia Pigmenti Consortium (2000) identified a C-to-T transition at nucleotide 184 of the IKBKG gene resulting in a proline-to-stop mutation in exon 2.
In 3 affected boys from a family (family 2) with hypohidrotic ectodermal dysplasia and immunodeficiency (EDAID1; 300291), Zonana et al. (2000) identified a hemizygous c.1171G-T transversion in exon 10 of the IKBKG gene, resulting in a glu391-to-ter (E391X) substitution within the C-terminal end of the protein. The truncated protein was predicted to lack the putative zinc finger domain. Western blot analysis of patient cells showed that a protein was expressed. Additional functional studies were not performed, but the authors postulated that the mutation preserves some function. Two female carriers in the family had conical teeth, some variable hyperpigmented skin lesions, and increased IgA, but no immune defects.
In 2 brothers (family 4) with lethal hypohidrotic ectodermal dysplasia with immune deficiency-1 (EDAID1; 300291), Zonana et al. (2000) identified a hemizygous 1-bp duplication (c.1167_1168dupC) in exon 10 of the IKBKG gene, predicted to result in a frameshift, the addition of novel amino acids at codons 390-393, and premature termination at codon 394. The duplication resulted from an insertion of a cytosine within a wildtype run of 7 cytosines in exon 10. The mutation was predicted to delete the putative zinc finger domain. The patients also had osteopetrosis and died of mycobacterial infection.
Kosaki et al. (2001) described an unusual family in which a girl with this heterozygous mutation had skin abnormalities with streaky hyperpigmented macules, features of ectodermal dysplasia, including decreased sweating, thin hair, and hypodontia, and onset of recurrent infections around 4 years of age. She later developed pulmonary and renovascular hypertension, and died at age 11 years after cardiac catheterization. IgD and IgE were increased. X-inactivation studies of peripheral blood leukocytes showed a random pattern. The mother had hyperpigmented macules in a streaky configuration on the trunk and limbs at several weeks of age, but never developed immunodeficiency; DNA from the mother was not studied. The family had previously been reported by Akiyama et al. (1994) as having 'linear and whorled nevoid hypermelanosis (see 614323). Zonana and Ferguson (2001) noted that the findings of random X inactivation in the girl reported by Kosaki et al. (2001) was unusual, and postulated that other molecular mechanisms may have been at play, including the possibility of skewed X inactivation in different leukocyte subsets. These authors emphasized that this phenotype in females is a very rare occurrence, and that generally, only males are affected.
Aradhya et al. (2001) identified the same frameshift mutation, referred to as a 1-bp duplication in the 7-cytosine tract (1161_1162dupC) of the IKBKG gene, in a male patient (family XL344) with EDAID1. Female members of the family, who were heterozygous for the mutation, had typical signs of incontinentia pigmenti (IP; 308300). The affected male exhibited skin pigmentation, dental problems, and immune dysfunction. He suffered multiple episodes of infection, including meningitis and pneumonia, due to poor lymphocyte function and remarkably low levels of circulating IgG. He also exhibited heat intolerance with hyperthermia, anhidrosis, eczema, and fine sparse hair, which led to a diagnosis of ectodermal dysplasia. At the age of 3 years he was receiving routine supplements of IgG to prevent recurrent infections. He showed hepatosplenomegaly and had contracted Mycobacterium avium intracellulare, an infection common among patients with AIDS. Aradhya et al. (2001) identified a different mutation involving the same C(7) tract in another family; see 300248.0012.
In 2 brothers (family 1) with hypohidrotic ectodermal dysplasia and immunodeficiency-1 (EDAID1; 300291), Zonana et al. (2000) identified a hemizygous c.1249T-C transition in exon 10 of the IKBKG gene, resulting in a cys417-to-arg (C417R) substitution in the putative zinc finger domain. The mother, who carried the mutation in heterozygous state, was unaffected.
Orange et al. (2002) identified the C417R mutation in a 16-year-old boy (patient 3) with EDAID1 with recurrent sinopulmonary infections and bacteremia. Tetanus vaccination failed to confer detectable serologic or delayed hypersensitivity responses. The patient also had reduced natural killer cell function.
In a male patient with EDAID1, Jain et al. (2001) identified hemizygosity for the C417R mutation, which occurred in the putative zinc finger domain.
In a boy (family 3) with hypohidrotic ectodermal dysplasia and immunodeficiency-1 (EDAID1; 300291), Zonana et al. (2000) identified a hemizygous c.1250G-T transversion in exon 10 of the IKBKG gene, resulting in a cys417-to-phe (C417F) substitution in the zinc finger domain. The patient's mother, who carried the mutation, had mild tooth anomalies and a 'large patch of skin with neither hair nor sweating response.'
In a male patient with ectodermal dysplasia and immunodeficiency-1 (EDAID1; 300291), Jain et al. (2001) identified a hemizygous c.1217A-T transversion in exon 10 of the IKBKG gene, resulting in an asp406-to-val (D406V) substitution. The mutation occurred in the putative zinc finger domain.
In a family in which a boy with ectodermal dysplasia with immune deficiency-1 died at 9 years of age from gastrointestinal bleeding and his sister and mother were found to have incontinentia pigmenti (IP; 308300) and to fulfill the criteria for entero-Behcet disease (see 109650), Takada et al. (2010) identified the D406V mutation in the NEMO gene. The 6-year-old sister developed oral and perianal ulcers at 5.5 years of age and had hypopigmented lesions without atrophy in the abdominal area and extremities that had been present since early infancy. Endoscopy showed multiple ulcerative lesions in the colon, which had no reactive changes at the margins and showed chronic active inflammation on histology. The authors stated that the patient's findings fulfilled diagnostic criteria for the enteric form of Behcet disease. The 42-year-old mother developed oral and perianal ulcers at 8 years of age and was diagnosed with Behcet disease at age 12. She also had hypopigmented skin lesions in the abdominal area and extremities that had been observed since early infancy. Skewed X-chromosome inactivation was not seen in the peripheral blood mononuclear cells or in oral or intestinal mucosa of these patients.
In affected women from a family (family XL320) with incontinentia pigmenti (IP; 308300), Aradhya et al. (2001) identified a heterozygous 13-bp duplication (c.1166_1178dup) at the end of a cytosine tract (a C(7) tract) in exon 10 of the IKBKG gene. This duplication was predicted to cause a frameshift after amino acid P393 and protein truncation after addition of 4 novel amino acids, resulting in absence of the zinc finger domain. The family had previously been studied by Roberts et al. (1998), who reported that an affected male carrying the hemizygous mutation was carried to term, but died from severe hemorrhage 24 hours after birth. In a subsequent pregnancy, the mother experienced severe bleeding during an elective abortion, suggesting that the mutation in this family disrupted hemostasis.
In a 2-year-old boy with hypohidrotic ectodermal dysplasia and immune deficiency-1 (EDAID1; 300291), Nishikomori et al. (2004) identified a hemizygous 4.4-kb duplication of genomic sequence of a segment extending from intron 3 to exon 6 in the IKBKG gene, resulting in reduced expression of the protein. The patient had atypical features of very few naive T cells and defective mitogen-induced proliferation of peripheral blood mononuclear cells. Specific cell lineages (monocytes and neutrophils) expressed reduced levels of IKBKG, but 2 populations of T, B, and NK cells were detected, 1 with normal and 1 with reduced expression of IKBKG. This was thought most likely to be due to postzygotic reversion. The patient had hypohidrosis, coarse hair, delayed eruption of teeth, and transient lower extremity lymphedema, but did not develop the skin lesions typical of incontinentia pigmenti. At age 3 months, he was admitted to hospital because of interstitial pneumonitis. Thereafter he had frequent bacterial infections and febrile episodes due to skin abscess, pneumonia, pneumococcal sepsis, otitis media, and sepsis. He also suffered from intractable diarrhea that resulted in failure to thrive. One oral live polio vaccination resulted in no detectable anti-poliovirus titers.
In a patient (patient 1) under 24 months of age who had ectodermal dysplasia with immunodeficiency-1 (EDAID1; 300291), Orange et al. (2002) identified a hemizygous c.458T-G transversion in exon 4 of the IKBKG gene, resulting in a leu153-to-arg (L153R) substitution within the first coiled-coil domain of the protein. In vitro functional expression studies showed impaired CD40-mediated activation of NFKB compared to controls. The patient had bacterial and viral sepsis, as well as Streptococcal bovis meningitis and cytomegalovirus colitis. He was noted to have absent sweat glands on skin biopsy in the 'Methods' section, but additional features of ectodermal dysplasia were not noted. Orange et al. (2004) also reported this patient and noted that he had 'characteristics' of ectodermal dysplasia; his mother carried the mutation and had oligodontia, some alopecia, and skin hyperpigmentation, consistent with mild features of incontinentia pigmenti.
In a 17-year-old patient (patient 2) with hypohidrotic ectodermal dysplasia with immunodeficiency-1 (EDAID1; 300291), Orange et al. (2002) identified a hemizygous c.1207C-T transition in exon 10 of the IKBKG gene, resulting in a gln403-to-ter (Q403X) truncation within the zinc finger domain of the protein. The patient had a history of cutaneous granulomas and the presence of Mycobacterium avium-intracellulare in blood, bone marrow, and skin, as well as deficient specific antibody and lymphoproliferative responses and reduced natural killer cell function.
In affected members and obligate carriers of a family with ectodermal dysplasia and immunodeficiency-1 (EDAID1; 300291), originally reported by Lie et al. (1978), Orstavik et al. (2006) identified a +5G-A transition in the splice donor site of exon 6 of the IKBKG gene. The mutation was not found in unaffected family members or 140 control chromosomes. RT-PCR analysis of fibroblast RNA from an aborted affected male fetus demonstrated skipping of exons 4, 5, and 6, which resulted in a truncated protein of about 35 kD. IKBA degradation was strongly impaired in the fetal fibroblasts, suggesting impaired NFKB signaling. One healthy carrier female had a completely skewed X-inactivation pattern with the normal X active, whereas the 2 other female carriers had a random X-inactivation pattern.
In a female infant with incontinentia pigmenti (IP; 308300) and transient immunodeficiency (see 300291), Martinez-Pomar et al. (2005) identified a 1-bp duplication (c.1049dupA) in exon 7 of the IKBKG gene, within a run of 3 adenosines. The mutation resulted in a frameshift and a premature stop codon at position 284. The X-inactivation status of peripheral blood cells from the patient was evaluated at 24, 30, 38, and 48 months of age and was found to have progressed from random at 24 and 30 months to skewed at 38 and 48 months of age, at which point her immunodeficiency had disappeared. Martinez-Pomar et al. (2005) stated that this was the first time that selection against the mutated X chromosome in X-linked disease had been documented in vivo.
In a 15-year-old boy with immunodeficiency-33 (IMD33; 300636), Orange et al. (2004) identified a de novo hemizygous G-to-A transition in intron 8 of the IKBKG gene (c.1056-1G-A), resulting in the skipping of exon 9 and the deletion of 19 residues (353_373). Analysis of patient peripheral blood and buccal epithelial cells showed presence of both mutant and wildtype transcripts. Western blot analysis using an antibody against the LZ domain showed barely detectable IKBKG protein levels in patient cells, whereas an antibody against the zinc finger domain showed normal protein levels. Presence of some normal transcripts may explain immunodeficiency without signs of ectodermal dysplasia in this patient. In vitro functional expression studies showed impaired, but not absent, nuclear translocation of NFKB in stimulated patient B cells compared to controls, as well as variable response to TNFA. Orange et al. (2004) postulated that exon 9 may be dispensable for ectodermal development.
In a patient with immunodeficiency-33 (IMD33; 300636), originally reported by Niehues et al. (2004), Puel et al. (2006) identified a hemizygous 1-bp insertion in exon 2 of the IKBKG gene (c.110_111insC) that resulted in the most-upstream premature translation termination codon of any NEMO mutation described to that time (Met38fsTer48). An almost canonically Kozakian methionine AUG start codon (Kozak, 2002) is located at nucleotide positions 112-114, corresponding to methionine-38 in the NEMO protein. The likelihood of this AUG codon acting as a translation initiation site was estimated at 0.27 and increased to 0.51 in the sequence context found in the patient studied by Puel et al. (2006), versus 0.63 for the first AUG codon. The reinitiation of translation would result in the synthesis of a protein approximately 45 kD in size. This protein was the only isoform detected in the patient's cells.
In a 2-year-old boy (patient 10) with anhidrotic ectodermal dysplasia and immunodeficiency-1 (EDAID1; 300291), Doffinger et al. (2001) identified a hemizygous c.863C-G transversion in the IKBKG gene, resulting in an ala288-to-gly (A288G) substitution in the second coiled-coil domain. The mutation was not found in 200 control chromosomes, and the patient's mother, who carried the mutation, showed skewed X inactivation in her blood cells. Functional studies of the variant were not performed.
Using temperature-induced unfolding, Vinolo et al. (2006) demonstrated that the A281G murine mutation in NEMO, corresponding to the human A288G mutation, causes an important loss in oligomer stability. Fluorescence studies showed that the tyrosine located in the adjacent zinc finger domain exhibits an alteration in its spectral properties. Functional complementation assays using NEMO-deficient pre-B and T lymphocytes showed that the pathogenic mutation reduces TNF-alpha (191160) and lipopolysaccharide-induced NFKB (see 164011) activation by altering the assembly of the IKK complex.
In 4 affected members of an American family with immunodeficiency-33 (IMD33; 300636), Filipe-Santos et al. (2006) identified a hemizygous c.944A-C transversion in the IKBKG gene, resulting in a glu315-to-ala (E315A) substitution in the leucine zipper domain of the protein. The proband was a non-BCG-vaccinated adolescent with severe, persistent M. avium infection who did not respond well to antibiotic treatment.
In affected males from 2 unrelated French and German families with immunodeficiency-33 (IMD33; 300636), Filipe-Santos et al. (2006) identified a hemizygous c.956G-A transition in the IKBKG gene, resulting in an arg319-to-gln (R319Q) substitution in the leucine zipper domain of the protein. The proband of the French family was a child with disseminated BCG who was well at age 8 years after treatment with antituberculosis antibiotics. The proband of the German family was a young non-BCG-vaccinated boy diagnosed with mycobacterial disease.
In a 4.5-year-old boy, born to unrelated Belgian parents, with immunodeficiency-33 (IMD33; 300636), Ku et al. (2007) identified a hemizygous c.518C-G transversion at the end of exon 4 of the NEMO gene, predicted to result in an arg173-to-gly (R173G) substitution at a conserved residue in the first coiled-coil domain. The mother was heterozygous for this mutation. RT-PCR analysis of patient cells showed the presence of 2 abnormal splicing products corresponding to the skipping of exons 4-6 and exons 5-6. Since the mutation occurred 2 nucleotides away from the end of the exon, it had abnormal splicing effects. Western blot analysis of patient cells showed decreased levels of NEMO compared to controls, suggesting partial NEMO deficiency. Patient fibroblasts showed impaired responses to IL1B and TNFA, suggesting impaired activation of NF-kappa-B. There was also an impaired cellular response to interleukin-1 receptor (IL1R; 147810), Toll-like receptor (TLR; see 601194), and tumor necrosis factor receptor (TNFR; see 191190) stimulation.
In 3 boys from 2 unrelated families of European and Japanese descent with fatal immunodeficiency-33 (IMD33; 300636), Boisson et al. (2019) identified a deep intronic mutation (IVS4+866C-T) in the IKBKG gene (chrX.153,787,731C-T, GRCh37). The boy in the European family inherited the mutation from his mother, who had mild features of incontinentia pigmenti (IP; 308300). The mutation in the Japanese boy occurred de novo. The mutation was shown to create a new splicing donor site that resulted in a 44-nucleotide pseudoexon that produced a frameshift. Patient fibroblasts showed decreased levels of mutant transcript due to nonsense-mediated mRNA decay; there were also decreased levels of the mutant protein, suggesting a quantitative defect. The amount of aberrant splicing varied between cell types in the affected boys. In leukocytes, the abnormal splice variant predominated at approximately 97%, while in fibroblasts and iPSC-derived neuronal precursor cells, the abnormal RNA was measured at about 65%. The splicing factor SRSF6 (601944) was shown to bind to the pseudoexon, resulting in its inclusion in the mature mRNA. By knocking down SFSF6 or CLK (see 601951), a protein that phosphorylates SR proteins, the authors were able to restore wildtype expression in mutant cells. The variant segregated with the disorder in both families and was not found in the 1000 Genomes Project or gnomAD databases.
In a 6.5-year-old French boy (patient 1) with immunodeficiency-33 (IMD33; 300636), Ku et al. (2005) identified a hemizygous 18-bp in-frame deletion (c.811_828del) in exon 7 of the IKBKG gene, resulting in the deletion of residues 271 to 276 in the coiled-coil 2 domain. The patient's mother, who had conical teeth, was heterozygous for the mutation; blood analysis showed random X inactivation. Western blot analysis of patient cells showed presence of the IKBKG protein, but fibroblasts responded weakly to stimulation with TNFA and IL1B compared to controls. The findings were consistent with a hypomorphic allele. The patient had hypodontia and conical teeth, but no other features of ectodermal dysplasia.
In an 11-year-old German boy (patient 2) with ectodermal dysplasia and immunodeficiency-33 (IMD33; 300636), Ku et al. (2005) identified a hemizygous c.239T-C transition in exon 3 of the IKBKG gene, resulting in a leu80-to-pro (L80P) substitution in the first coiled-coil domain. The patient's unaffected mother was heterozygous for the mutation; blood analysis showed skewed X-inactivation. Western blot analysis of patient cells showed presence of the IKBKG protein, but fibroblasts responded weakly to stimulation with TNFA and IL1B compared to controls. The findings were consistent with a hypomorphic allele. The patient had hypodontia and conical teeth, but no other features of ectodermal dysplasia.
In a 6-year-old boy with ectodermal dysplasia and immunodeficiency-1 (EDAID1; 300291), Roberts et al. (2010) identified a hemizygous 2-bp deletion (c.1182_1183delTT) in the IKBKG gene, predicted to result in a frameshift and premature termination affecting the zinc finger domain. The mutation was inherited from the patient's mother, who had features of incontinentia pigmenti (IP; 308300). Functional studies of the variant and studies of patient cells were not performed. The boy also had the additional features of osteopetrosis and edema, as well as some skin features of IP. Roberts et al. (2010) described the patient as having OLEDAID.
In a male infant with lethal ectodermal dysplasia and immunodeficiency-1 (EDAID1; 300291), Johnston et al. (2016) identified a hemizygous G-to-C transversion (c.1117+5G-C) in intron 8 of the IKBKG gene, predicted to result in a splice site alteration, the skipping of exon 9, and a frameshift with premature termination of the C-terminal region (Arg352SerfsTer22). The mutation was inherited from his mother who had features of incontinentia pigmenti (IP; 308300); X-chromosome inactivation studies showed nonrandom maternal X inactivation with expression only of the wildtype allele. Western blot analysis of the proband's cells showed reduced-sized mutant IKBKG, consistent with the predicted truncated protein.
In a 2-year-old boy with immunodeficiency-33 (IMD33; 300636), Frans et al. (2017) identified a hemizygous c.169G-A transition (c.169G-A, NM_003639) in the IKBKG gene, resulting in a glu57-to-lys (E57K) substitution in the N-terminal domain. His mother, who also carried the mutation, had a history of recurrent sinorespiratory infections but no signs of IP. The variant was present at a frequency of 0.001 in the European population in the ExAC database (August, 2016). Patient peripheral blood cells showed mildly decreased IL6 production after stimulation with IL1B compared to controls. However, NEMO expression in patient fibroblasts was normal, and IKBA was degraded normally upon stimulation with IL1B or TNFA, suggesting a specific effect of the mutation. In vitro functional expression studies in IKBKG-null cells transfected with the mutation showed impaired IL6 production after stimulation with TNFA or IL1B compared to controls. Frans et al. (2017) noted that mutations affecting the N terminus of NEMO tend to lead to decreased production of immunoglobulins; the authors postulated a hypomorphic effect of this variant.
In 3 adult males from 2 unrelated families (families A and B) with immunodeficiency-33 (IMD33; 300636) manifest as disseminated mycobacterial infections, Hsu et al. (2018) identified a hemizygous c.1-16G-C transversion at the last base of the first untranslated exon. Analysis of patient cells showed a splicing abnormality, resulting in a 110-bp deletion at the 3-prime end of exon 1. This molecular defect resulted in decreased transcript and protein levels compared to controls (about 30%). Cells derived from the patients in families A and B failed to upregulate cytokines in response to certain TLR agonists, suggesting that this IKBKG mutation is hypomorphic.
In a 2-year-old boy (P1) with ectodermal dysplasia and immunodeficiency-1 (EDAID1; 300291), Heller et al. (2020) identified a hemizygous G-to-A transition in intron 9 of the IKBKG gene. The mutation caused the skipping of exon 9, a frameshift, and premature termination (Arg352Serfs373Ter), with loss of the zinc finger domain. Patient cells showed decreased IKBKG levels compared to controls; in vitro studies showed impaired degradation of IKBA and impaired IL6 production upon stimulation with IL1B and TNFA. The patient had a severe phenotype with functional T- and B-cell deficiency. He underwent hematopoietic stem cell transplant. His mother and sister, who were heterozygous for the mutation, had incontinentia pigmenti (IP; 308300).
In a boy (patient 1) with immunodeficiency-33 (IMD33; 300636), Abbott et al. (2014) identified a hemizygous c.337G-A transition in the IKBKG gene, resulting in an asp113-to-asn (D113N) substitution in the first coiled-coil domain. The patient had impaired NK cell function and impaired T-cell receptor signaling with decreased NFKB activity, but Toll-like receptor signaling appeared to be intact. He underwent successful bone marrow transplant. The patient had previously been reported in detail by Salt et al. (2008); his unaffected mother also carried the mutation.
Heller et al. (2020) identified a hemizygous D113N mutation in a boy with IMD33. His mother and grandmother, who were presumably unaffected, carried the heterozygous mutation. However, the proband's 40-year-old male cousin, who did not have recurrent infections and had normal response to polysaccharide antibodies, was hemizygous for D113N. Heller et al. (2020) noted that the allele frequency for this variant is rather high (0.009572), and that some suggest it may be a polymorphism (see Fusco et al., 2004).
In a boy (P1) with X-linked systemic autoinflammatory disease (SAIDX; 301081), de Jesus et al. (2020) identified a de novo hemizygous c.597G-A transition in exon 5 of the IKBKG gene, predicted to result in a silent substitution (V199V), but also predicted to disrupt an exonic splicing enhancer and an exon-identity element in exon 5, resulting in alternative splicing. The patient had lymphohistiocytic panniculitis, chorioretinitis, progressive B cell lymphopenia, hypogammaglobulinemia, and conical teeth, prompting targeted sequencing of the IKBKG gene. Functional studies of the variant were not performed.
In a 9-year-old boy (P1) with SAIDX, Lee et al. (2022) identified a de novo heterozygous c.597G-A transition in the IKBKG gene. Analysis of patient cells detected a shorter NEMO mRNA splice variant lacking the 153 nucleotides of exon 5. Patient cells showed a higher ratio of mutant to full-length cDNA compared to healthy controls. The mutation, which was found by targeted sequencing of NEMO and further confirmed by Sanger sequencing of genomic DNA, was not present in 1,150 healthy individuals. In vitro functional expression studies in patient peripheral blood cells showed that stimulation with poly(I:C) or viral infection resulted in enhanced type I IFN production likely due to a stabilized complex of mutant IKBKG and IKKi (605048). The patient had panniculitis, optic neuritis, chorioretinitis, hypogammaglobulinemia, conical teeth, and CNS hemorrhage.
In a boy (P3) with X-linked systemic autoinflammatory disease (SAIDX; 301081), de Jesus et al. (2020) identified a de novo hemizygous T-to-G transversion in intron 5 of the IKBKG gene (c.671+2T-G), predicted to result in the deletion of exon 5. Functional studies of the variant were not performed. The patient had panniculitis, progressive B cell lymphopenia, thrombocytopenia, and hypogammaglobulinemia without major infections.
In a 5-year-old boy (P2) with SAIDX, Lee et al. (2022) identified a de novo hemizygous T-to-G transversion in intron 5 of the IKBKG gene (chrX:153,788,776T-G), disrupting a splice site and resulting in the production of a mutant transcript lacking exon 5. Analysis of patient cells detected a shorter NEMO mRNA splice variant lacking the 153 nucleotides of exon 5. Patient cells showed a higher ratio of mutant to full-length cDNA compared to healthy controls. The mutation, which was found by targeted sequencing of NEMO and further confirmed by Sanger sequencing of genomic DNA, was not present in 1,150 healthy individuals. In vitro functional expression studies in patient peripheral blood cells showed that stimulation with poly(I:C) or viral infection resulted in enhanced type I IFN production likely due to a stabilized complex of mutant IKBKG and IKKi (605048). The patient had lymphocytic panniculitis, hypogammaglobulinemia, and a CNS cortical bleed.
In a boy (P2) with X-linked systemic autoinflammatory disease (SAIDX; 301081), de Jesus et al. (2020) identified a de novo hemizygous G-to-A transition in intron 5 of the IKBKG gene (c.671+5G-A), predicted to result in the deletion of exon 5. Functional studies of the variant were not performed. The patient had panniculitis, uveitis, progressive B cell lymphopenia, and hypogammaglobulinemia without major infections.
In a 3-year-old boy (P3) with SAIDX, Lee et al. (2022) identified a de novo heterozygous G-to-A transition (chrX:153,788,779G-A) in the IKBKG gene, resulting in a splice site alteration and the deletion of exon 5. Analysis of patient cells detected a shorter NEMO mRNA splice variant lacking the 153 nucleotides of exon 5. Patient cells showed a higher ratio of mutant to full-length cDNA compared to healthy controls. The mutation, which was found by targeted sequencing of NEMO and further confirmed by Sanger sequencing of genomic DNA, was not present in 1,150 healthy individuals. In vitro functional expression studies in patient peripheral blood cells showed that stimulation with poly(I:C) or viral infection resulted in enhanced type I IFN production likely due to a stabilized complex of mutant IKBKG and IKKi (605048). The patient had panniculitis, uveitis, lymphopenia, hypogammaglobulinemia, and a CNS hemorrhage.
In a girl (P4) with X-linked systemic autoinflammatory disease (SAIDX; 301081), de Jesus et al. (2020) identified a de novo heterozygous A-to-G transition in intron 5 of the IKBKG gene (c.519-2A-G), predicted to result in the deletion of exon 5. Functional studies of the variant were not performed. The patient had panniculitis, lipodystrophy, anemia, myositis, and progressive B cell lymphopenia without hypogammaglobulinemia.
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