Alternative titles; symbols
HGNC Approved Gene Symbol: NFKBIL1
Cytogenetic location: 6p21.33 Genomic coordinates (GRCh38): 6:31,546,851-31,558,829 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6p21.33 | {Rheumatoid arthritis, susceptibility to} | 180300 | 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, 164008 or NFKBIB, 604495), which inactivate NF-kappa-B by trapping it in the cytoplasm. Phosphorylation of serine residues on the I-kappa-B proteins by kinases (IKBKA, 600664 or IKBKB, 603258) marks them for destruction via the ubiquitination pathway, 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).
Albertella and Campbell (1994) identified a gene, designated IKBL (I-kappa-B-like) by them, in the human major histocompatibility complex between BAT1 (142560) and the TNFB (153440) and TNFA (191160) cluster on 6p21.3. A cDNA was isolated from a U937 premonocytic leukemia cell line library and was predicted to code for a 381-amino acid protein. The protein contains ankyrin motifs similar to those of the I-kappa-B (164008) family of proteins. The gene spans 13.5 kb of genomic DNA and its 3-prime end is about 12 kb from the 5-prime end of TNFB. Northern blot analysis detected a 1.6-kb mRNA in several cell types, including monocytes, T cells, B cells, and hepatocytes.
Okamoto et al. (2003) identified a diallelic polymorphism in the promoter region of the NFKBIL1 gene (601022.0001) that represented the second rheumatoid arthritis (RA; 180300) susceptibility locus within the HLA region, the first being HLA-DRB1 (142857). The nucleotide sequence surrounding the RA-susceptible allele, -62T, is a putative binding site for the transcription factor delta-EF1 (TCF8; 189909) (Allcock et al., 2001). Examination of 41 delta-EF-binding sites showed that all contained a T allele at this position (Sekido et al., 1994). In contrast, the nonsusceptible allele, -62A, is likely to disrupt this motif for delta-EF1.
For a discussion of a possible association between variation in the NFKBIL1 gene and chronic thromboembolic pulmonary hypertension (CTEPH) without deep vein thrombosis, see 612862.
Allcock et al. (1999) sequenced RT-PCR products derived from central MHC genes in well-characterized and conserved ancestral haplotypes. They found that the IKBL gene, which lies near the TNF cluster at the telomeric end of the central MHC, has been conserved between most ancestral haplotypes; however, several changes were observed.
Okamoto et al. (2003) identified a non-HLA-DRB1 (142857) major histocompatibility complex-linked susceptibility allele for rheumatoid arthritis (180300): the T allele of the -62T/A SNP of the NFKBIL1 gene.
Albertella, M. R., Campbell, R. D. Characterization of a novel gene in the human major histocompatibility complex that encodes a potential new member of the I kappa B family of proteins. Hum. Molec. Genet. 3: 793-799, 1994. [PubMed: 8081366] [Full Text: https://doi.org/10.1093/hmg/3.5.793]
Allcock, R. J. N., Baluchova, K., Cheong, K. Y. M., Price, P. Haplotypic single nucleotide polymorphisms in the central MHC gene IKBL, a potential regulator of NF-kappa-B function. Immunogenetics 52: 289-293, 2001. [PubMed: 11220632] [Full Text: https://doi.org/10.1007/s002510000280]
Allcock, R. J. N., Christiansen, F. T., Price, P. The central MHC gene IKBL carries a structural polymorphism that is associated with HLA-A3,B7,DR15. Immunogenetics 49: 660-665, 1999. [PubMed: 10369924] [Full Text: https://doi.org/10.1007/s002510050662]
Okamoto, K., Makino, S., Yoshikawa, Y., Takaki, A., Nagatsuka, Y., Ota, M., Tamiya, G., Kimura, A., Bahram, S., Inoko, H. Identification of I-kappa-BL as the second major histocompatibility complex-linked susceptibility locus for rheumatoid arthritis. Am. J. Hum. Genet. 72: 303-312, 2003. [PubMed: 12509789] [Full Text: https://doi.org/10.1086/346067]
Sekido, R., Murai, K., Funahashi, J., Kamachi, Y., Fujisawa-Sehara, A., Nabeshima, Y., Kondoh, H. The delta-crystallin enhancer-binding protein delta EF1 is a repressor of E2-box-mediated gene activation. Molec. Cell. Biol. 14: 5692-5700, 1994. [PubMed: 8065305] [Full Text: https://doi.org/10.1128/mcb.14.9.5692-5700.1994]