HGNC Approved Gene Symbol: IRF1
Cytogenetic location: 5q31.1 Genomic coordinates (GRCh38): 5:132,481,609-132,490,773 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5q31.1 | Gastric cancer, somatic | 613659 | 3 | |
| Immunodeficiency 117, mycobacteriosis, autosomal recessive | 620668 | Autosomal recessive | 3 | |
| Nonsmall cell lung cancer, somatic | 211980 | 3 |
The IRF1 gene encodes a transcription factor induced by gamma-interferon (IFNG; 147570) that plays a role in the immune response to certain viral and mycobacterial infections (summary by Rosain et al., 2023).
Miyamoto et al. (1988) cloned mouse and human IRF1 from L929 fibroblast and Jurkat cell cDNA libraries, respectively. The deduced mouse and human proteins contain 329 and 325 amino acids, respectively. They share 95% amino acid identity in their N-terminal halves, which are rich in lysine and arginine. RNA blot analysis detected low Irf1 expression in most mouse tissues examined.
Yamada et al. (1991) reported that the IRF1 gene contains 10 exons.
Yamada et al. (1991) stated that the IRF1 gene had been assigned to chromosome 5q23-q31 by linkage studies using RFLPs. Itoh et al. (1991) also mapped IRF1 to chromosome 5 by analysis of mouse-human somatic cell hybrids.
Willman et al. (1993) mapped the IRF1 gene to chromosome 5q31.1 by pulsed-field gel electrophoresis. They determined that the IRF1 gene is approximately 200 kb telomeric to IL5 (147850) and 100 kb centromeric to CDC25C (157680); the IL3 (147740) and GMCSF (CSF2; 138960) genes are located at least 200 kb, but not more than 1,600 kb, telomeric to this region. Willman et al. (1993) also mapped the gene by fluorescence in situ hybridization.
Buckwalter et al. (1992) showed that the Irf1 gene is located on mouse chromosome 11.
Using a DNA competition assay, Miyamoto et al. (1988) showed that mouse Irf1 bound to upstream cis elements of the human interferon-alpha (IFNA1; 147660) and interferon-beta (IFNB1; 147640) genes. Expression of Irf1 was induced by Newcastle disease virus and concanavilin A in mouse L929 cells and splenic lymphocytes, respectively.
Harada et al. (1989) found that mouse Irf2 (147576) antagonized transcriptional activation by Irf1 by competing for the same cis elements. Expression of mouse Irf1, but not mouse Irf2, induced expression of the endogenous Ifna and Ifnb genes in COS cells. Both Irf1 and Irf2 were induced by virus and human IFNB in mouse L929 cells.
Harada et al. (1990) showed that Irf1 and Irf2 were expressed in mouse embryonal carcinoma (EC) cells only after cell differentiation. Expression of mouse Irf1 in Irf-negative EC cells resulted in efficient activation of the endogenous Ifna gene, as well as cotransfected human IFNA1 and IFNB. Activation of all of these genes was repressed by coexpression of IRF2.
To assess the role of IRF1 in the regulation of cell growth and differentiation, Yamada et al. (1991) generated transgenic mice carrying the human IRF1 gene, the constitutive expression of which was driven at a high level by the juxtaposed human immunoglobulin heavy-chain enhancer. They found that these transgenic mice showed a dramatic reduction in the number of B lymphocytes.
Neointima formation, the leading cause of restenosis after catheter angioplasty, is a paradigm for vascular proliferative responses. Wessely et al. (2003) demonstrated that IRF1 is highly regulated in human vascular lesions and exhibits a growth inhibitory function in coronary artery smooth muscle cells. Irf1-deficient mice displayed a high grade of susceptibility toward neointima formation following vessel injury. IRF1 led to G1 cell cycle arrest in coronary artery smooth muscle cells and induced the CDK inhibitor p21 (CDKN1A; 116899). In addition, IRF1 induced nitric oxide production, which is known to attenuate endothelial dysfunction. Mitogen-mediated cellular migration was abrogated by IRF1. Wessely et al. (2003) hypothesized that IRF1 may play an important role as an endogenous inhibitor of neointimal growth following vessel injury, and may also play a role in the pathophysiology of primary atherosclerosis.
Immunodeficiency 117
In 2 unrelated patients, each born of consanguineous parents, with immunodeficiency-117 and susceptibility to mycobacterial infections (IMD117; 620668), Rosain et al. (2023) identified homozygous nonsense mutations in the IRF1 gene (R129X, 147575.0003 and Q35X, 147575.0004). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the families. In vitro studies showed that both mutations resulted in a loss of function. Patient leukocytes showed mildly impaired gamma-IFN (IFNG; 147570) secretion, and fibroblasts and myeloid cells showed impaired response to gamma-IFN with impaired signaling downstream of STAT1 (600555) and deficient expression of target genes involved in immune activation. Transcriptome analysis of patient cells showed impaired development of T and NK cells, also with abnormal expression of target genes. The findings suggested that IRF1 controls the enhancement of the second wave of response to IFNG, downstream of STAT1, particularly in mononuclear myeloid cells. In contrast, cellular responses to alpha (IFNA; 147660)- and beta (IFNB; 147640)-interferon were only mildly affected, and patient cells showed normal antiviral activity to several pathogens in vitro, including SARS-CoV-2.
Somatic Mutations
An interstitial deletion within chromosome 5q or loss of the entirety of chromosome 5 are among the most frequent cytogenetic abnormalities in human leukemia and the preleukemic myelodysplastic syndromes (MDS). Deletion in 5q, initially described as the hallmark of a unique type of MDS with refractory anemia, the 5q- syndrome (153550), subsequently was demonstrated to occur in 30% of patients with MDS, in 50% of patients with acute myelogenous leukemia (AML) arising secondary to MDS or to prior chemotherapy, in 15% of de novo AMLs, and in 2% of de novo acute lymphocytic leukemias (ALL). The smallest commonly deleted segment was 5q31; rare de novo AMLs with translocations involving 5q31 were also described. Thus, a tumor suppressor gene was hypothesized to lie in the 5q31 region. Willman et al. (1993) presented convincing evidence that IRF1 is that tumor suppressor gene. Among the genes in the 5q31.1 region, only IRF1 was consistently deleted at 1 or both alleles in 13 cases of leukemia or myelodysplasia with aberrations of 5q31. In 1 case of acute leukemia, Willman et al. (1993) identified inactivating rearrangements of 1 IRF1 allele, accompanied by deletion of the second allele.
Loss of heterozygosity (LOH) at the IRF1 locus occurs frequently in human gastric cancer (137215) (Tamura et al., 1996). Nozawa et al. (1998) identified a point mutation in a human gastric cancer cell line (147575.0001) that changed methionine at codon 8 to leucine and produced an IRF1 protein with reduced transcriptional activity, but unaltered DNA-binding activity. In addition, Harada et al. (1994) had observed alternative splicing of IRF1 mRNA, producing nonfunctional IRF1 protein at high frequencies in patients with myelodysplastic syndrome and acute myelogenous leukemia.
Associations Pending Confirmation
In an association study of 192 Chinese patients with Graves disease (275000), Yang et al. (2005) screened SNPs in the AITD2 locus (608174) on chromosome 5q31-q33 and observed a lower age of onset in patients carrying TT at the 6477T/G polymorphism (rs2070729) in the IRF1 gene than those with a variant allele (TG or GG, p = 0.005).
Nozawa et al. (1999) found that spontaneous tumor development in Irf1 -/- mice did not differ significantly from that in wildtype mice. However, loss of Irf1 dramatically exacerbated tumor development in mice carrying the human HRAS (190020) transgene and in p53 (TP53; 191170) -/- mice. Irf1 -/- p53 -/- mice showed grossly altered tumor spectrum compared with p53 -/- mice, and cells from Irf1 -/- p53 -/- mice showed a significantly higher mutation rate.
Ko et al. (2002) noted that Irf1 -/- mice are deficient in Inos (163730), Il12b (161561), Cd8 (see 186910)-positive T cells, and natural killer (NK) cells, whereas Irf2 -/- mice are deficient in NK cells and have dysregulated Il12b induction. Icsbp (601565) -/- mice are deficient in Il12b, Irf2, and reactive oxygen intermediates (ROIs). The Irf1, Irf2, and Icsbp genes are all inducible by gamma-interferon (Ifng; 147570). Irf1-, Irf2-, and Icsbp-deficient mouse strains have varying susceptibility to different intracellular bacterial and protozoan pathogens. Ko et al. (2002) determined that Irf1 -/- mice are highly susceptible to fatal liver damage from Brucella abortus, the causative agent of brucellosis, which manifests as arthritis, endocarditis, and meningitis in humans. In contrast, Irf2 -/- mice are highly resistant to Brucella, whereas Icsbp -/- mice maintain a plateau of infection similar to that seen in Il12b -/- mice. The authors concluded that IL12, reactive nitrogen intermediates, and ROIs are probably crucial immune components in resistance to Brucella infection.
In a human gastric cancer tissue (137215), Nozawa et al. (1998) found a somatic point mutation in the IRF1 gene that substituted the methionine at codon 8 with leucine (M8L) and produced an IRF1 protein with reduced transcriptional activity, but unaltered DNA-binding activity.
In a nonsmall cell lung carcinoma cell line, Eason et al. (1999) found a change in codon 11 of the IRF1 gene from TGG (trp) to CGG (arg). They demonstrated that the trp11-to-arg (W11R) mutation abolished DNA binding.
In a girl (P1), born of consanguineous parents (family A), with immunodeficiency-117 (IMD117; 620668), Rosain et al. (2023) identified a homozygous c.385C-T transition (c.385C-T, NM_002198.2) in the IRF1 gene, resulting in an arg129-to-ter (R129X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was found in heterozygous state in the unaffected mother; DNA from the unaffected father was not available. Expression of the R129X mutation in HEK293T cells showed that it encoded a truncated protein that localized to the nucleus and was able to bind to DNA, although there was no transcriptional activity. Patient cells had low levels of IRF1 mRNA, suggesting nonsense-mediated mRNA decay, and absent IRF1 protein, consistent with a loss-of-function effect.
In a girl (P2), born of consanguineous parents (family B), with immunodeficiency-117 (IMD117; 620668), Rosain et al. (2023) identified a homozygous c.103C-T transition (c.103C-T, NM_002198.2) in the IRF1 gene, resulting in a gln35-to-ter (Q35X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Expression of the Q35X mutation in HEK293T cells showed that translation was reinitiated at a start codon downstream of the mutation, resulting in the production of a protein lacking the first 84 residues of the DNA-binding domain. The mutant protein localized to the nucleus, but was unable to bind DNA and had no transcriptional activity. Patient cells showed low levels of the mutant IRF1 protein, consistent with a loss-of-function effect.
Buckwalter, M. S., Lossie, A. C., Scarlett, L. M., Camper, S. A. Localization of the human chromosome 5q genes Gabra-1, Gabrg-2, I1-4, I1-5, and Irf-1 on mouse chromosome 11. Mammalian Genome 3: 604-607, 1992. [PubMed: 1358285] [Full Text: https://doi.org/10.1007/BF00350629]
Eason, D. D., Shepherd, A. T., Blanck, G. Interferon regulatory factor 1 tryptophan 11 to arginine point mutation abolishes DNA binding. Biochim. Biophys. Acta 1446: 140-144, 1999. [PubMed: 10395927] [Full Text: https://doi.org/10.1016/s0167-4781(99)00078-0]
Harada, H., Fujita, T., Miyamoto, M., Kimura, Y., Maruyama, M., Furia, A., Miyata, T., Taniguchi, T. Structurally similar but functionally distinct factors, IRF-1 and IRF-2, bind to the same regulatory elements of IFN and IFN-inducible genes. Cell 58: 729-739, 1989. [PubMed: 2475256] [Full Text: https://doi.org/10.1016/0092-8674(89)90107-4]
Harada, H., Kondo, T., Ogawa, S., Tamura, T., Kitagawa, M., Tanaka, N., Lamphier, M. S., Hirai, H., Taniguchi, T. Accelerated exon skipping of IRF-1 mRNA in human myelodysplasia/leukemia: a possible mechanism of tumor suppressor inactivation. Oncogene 9: 3313-3320, 1994. [PubMed: 7936656]
Harada, H., Willison, K., Sakakibara, J., Miyamoto, M., Fujita, T., Taniguchi, T. Absence of the type I IFN system in EC cells: transcriptional activator (IRF-1) and repressor (IRF-2) genes are developmentally regulated. Cell 63: 303-312, 1990. [PubMed: 2208287] [Full Text: https://doi.org/10.1016/0092-8674(90)90163-9]
Itoh, S., Harada, H., Nakamura, Y., White, R., Taniguchi, T. Assignment of the human interferon regulatory factor-1 (IRF1) gene to chromosome 5q23-q31. Genomics 10: 1097-1099, 1991. [PubMed: 1680796] [Full Text: https://doi.org/10.1016/0888-7543(91)90208-v]
Ko, J., Gendron-Fitzpatrick, A., Splitter, G. A. Susceptibility of IFN regulatory factor-1 and IFN consensus sequence binding protein-deficient mice to brucellosis. J. Immun. 168: 2433-2440, 2002. [PubMed: 11859135] [Full Text: https://doi.org/10.4049/jimmunol.168.5.2433]
Miyamoto, M., Fujita, T., Kimura, Y., Maruyama, M., Harada, H., Sudo, Y., Miyata, T., Taniguchi, T. Regulated expression of a gene encoding a nuclear factor, IRF-1, that specifically binds to IFN-beta gene regulatory elements. Cell 54: 903-913, 1988. [PubMed: 3409321] [Full Text: https://doi.org/10.1016/s0092-8674(88)91307-4]
Nozawa, H., Oda, E., Nakao, K., Ishihara, M., Ueda, S., Yokochi, T., Ogasawara, K., Nakatsuru, Y., Shimizu, S., Ohira, Y., Hioki, K., Aizawa, S., Ishikawa, T., Katsuki, M., Muto, T., Taniguchi, T., Tanaka, N. Loss of transcription factor IRF-1 affects tumor susceptibility in mice carrying the Ha-ras transgene or nullizygosity for p53. Genes Dev. 13: 1240-1245, 1999. [PubMed: 10346812] [Full Text: https://doi.org/10.1101/gad.13.10.1240]
Nozawa, H., Oda, E., Ueda, S., Tamura, G., Maesawa, C., Muto, T., Taniguchi, T., Tanaka, N. Functionally inactivating point mutation in the tumor-suppressor IRF-1 gene identified in human gastric cancer. Int. J. Cancer 77: 522-527, 1998. [PubMed: 9679752] [Full Text: https://doi.org/10.1002/(sici)1097-0215(19980812)77:4<522::aid-ijc8>3.0.co;2-w]
Rosain, J., Neehus, A. L., Manry, J., Yang, R., Le Pen, J., Daher, W., Liu, Z., Chan, Y. H., Tahuil, N., Turel, O., Bourgey, M., Ogishi, M., and 73 others. Human IRF1 governs macrophagic IFN-gamma immunity to mycobacteria. Cell 186: 621-645.e33, 2023. [PubMed: 36736301] [Full Text: https://doi.org/10.1016/j.cell.2022.12.038]
Tamura, G., Sakata, K., Nishizuka, S., Maesawa, C., Suzuki, Y., Terashima, M., Eda, Y., Satodate, R. Allelotype of adenoma and differentiated adenocarcinoma of the stomach. J. Path. 180: 371-377, 1996. [PubMed: 9014856] [Full Text: https://doi.org/10.1002/(SICI)1096-9896(199612)180:4<371::AID-PATH704>3.0.CO;2-2]
Wessely, R., Hengst, L., Jaschke, B., Wegener, F., Richter, T., Lupetti, R., Paschalidis, M., Schomig, A., Brandl, R., Neumann, F.-J. A central role of interferon regulatory factor-1 for the limitation of neointimal hyperplasia. Hum. Molec. Genet. 12: 177-187, 2003. [PubMed: 12499398] [Full Text: https://doi.org/10.1093/hmg/ddg018]
Willman, C. L., Sever, C. E., Pallavicini, M. G., Harada, H., Tanaka, N., Slovak, M. L., Yamamoto, H., Harada, K., Meeker, T. C., List, A. F., Taniguchi, T. Deletion of IRF-1, mapping to chromosome 5q31.1, in human leukemia and preleukemic myelodysplasia. Science 259: 968-971, 1993. [PubMed: 8438156] [Full Text: https://doi.org/10.1126/science.8438156]
Yamada, G., Ogawa, M., Akagi, K., Miyamoto, H., Nakano, N., Itoh, S., Miyazaki, J., Nishikawa, S., Yamamura, K., Taniguchi, T. Specific depletion of the B-cell population induced by aberrant expression of human interferon regulatory factor 1 gene in transgenic mice. Proc. Nat. Acad. Sci. 88: 532-536, 1991. [PubMed: 1988951] [Full Text: https://doi.org/10.1073/pnas.88.2.532]
Yang, Y., Lingling, S., Ying, J., Yushu, L., Zhongyan, S., Wei, H., Weiping, T. Association study between the IL4, IL13, IRF1 and UGRP1 genes in chromosomal 5q31 region and Chinese Graves' disease. J. Hum. Genet. 50: 574-582, 2005. [PubMed: 16195814] [Full Text: https://doi.org/10.1007/s10038-005-0297-x]