Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: IFNA1
Cytogenetic location: 9p21.3 Genomic coordinates (GRCh38): 9:21,440,439-21,441,316 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 9p21.3 | Interferon, alpha, deficiency | 1 |
Leukocyte interferon is produced predominantly by B lymphocytes. Immune interferon (IFN-gamma; 147570) is produced by mitogen- or antigen-stimulated T lymphocytes.
Streuli et al. (1980) showed that at least 3 different IFN-alpha genes are expressed in man. Furthermore, study of genomic DNA revealed the presence of at least 8 IFN genes. Nagata et al. (1980) found that the alpha-interferon genes are devoid of intervening sequences. Using radioactive probes from purified cDNA clones of interferons, Owerbach et al. (1981) located at least 8 leukocyte interferon genes and a fibroblast interferon gene on chromosome 9. Shows et al. (1982) found that the alpha- and beta-interferon genes are on 9p. The mapping to 9pter-q12 was accomplished by blot hybridization of cloned interferon cDNA to DNA from human-mouse cell hybrids with a translocation involving chromosome 9. There are about 10 linked genes for IFA. Lawn et al. (1981) sequenced 2 closely linked genes for leukocyte interferon. They were about 12 kb apart and each had no intervening sequences. Two other IFAs are known to be about 5 kb apart. Homology exists among the interferon genes.
By in situ hybridization, Trent et al. (1982) localized IFL and IFF (147640) to 9pter-p21 and IFI to 12q24.1. From studies of patients with acute monocytic leukemia and t(9;11)(p22;q23), Diaz et al. (1986) concluded that alpha-interferon is in region 9p21-p13. Ohlsson et al. (1985) put the number of IFL genes at 15 to 30 but indicated that to some extent the large number of different sequences that have been identified may be on the basis of polymorphism. They demonstrated a number of DNA polymorphisms (RFLPs) and used them to show close proximity of the IFL and IFF loci. To define better the rearrangements and deletions in the region of the interferon genes on 9p in malignancies, Fountain et al. (1992) did linkage, pulsed field gel electrophoresis, and fluorescence in situ hybridization of markers in that vicinity. Olopade et al. (1992) referred to the location of the cluster of interferon genes as 9p22. The interferon cluster comprises about 26 interferon-alpha, -omega (IFNW; 147553), and -beta-1 (IFNB1; 147640) genes, as well as the gene for methylthioadenosine phosphorylase (MTAP; 156540). The IFNB1 gene is present in single copy, whereas the IFNA and IFNW genes are present in multiple functional copies as well as pseudogenes, which are interspersed. Olopade et al. (1992) found by deletion mapping that the IFNA1 gene is at the extreme centromeric end of the cluster, whereas IFNB1 is at the extreme telomeric end. From a YAC clone contig located on 9p, Diaz et al. (1994) mapped 26 interferon genes and pseudogenes, accounting for all except 1 of the IFN sequences previously reported by other authors, plus an additional IFN-omega pseudogene. The most distal gene on 9p is IFNB and the most proximal one is the pseudogene IFNWP19. The direction of transcription for the 20 most distal IFN sequences is toward the telomere and for the 6 most proximal sequences, toward the centromere. Several regions of the cluster show evidence of ancestral duplication events.
Pseudogenes
The IFNAP22 locus was positioned in the cluster of interferon genes on 9p22 by deletion mapping (Olopade et al., 1992). In their tabulation of nomenclature of the human interferon genes, Diaz and Bohlander (1993) listed this as a pseudogene.
Interferon was characterized as an antiviral entity by Isaacs et al. (1957).
By recombinant DNA techniques, Nagata et al. (1980) synthesized in E. coli a polypeptide with human leukocyte interferon activity.
Isaacs et al. (1981) studied 30 children with recurrent respiratory infections and found that 4 had deficient production of leukocyte interferon by lymphocytes stimulated with virus in vitro and in their nasopharyngeal secretions in response to rhinovirus infection in vivo. Deficiency of production of immune interferon, associated with absent natural killer (NK) activity, was described in a child with persistent Epstein-Barr virus infection who developed a fatal lymphoproliferative disorder (Virelizier et al., 1978). Lipinski et al. (1980) described other children with deficient production of immune interferon; all had markedly depressed NK activity. The report of Isaacs et al. (1981) was the first concerning a defect in alpha-IFN production. Two sibs of their alpha-IFN-deficient patients had undetectable or absent alpha-IFN production; without in vivo evidence from nasopharyngeal aspirates, it was impossible to be certain that these sibs had deficiency of leukocyte IFN. Virelizier and Griscelli (1981) described a patient with a selective defect in production of leukocyte interferon. The natural killer activity of the patient's leukocytes was restored in vitro by incubation with interferon and in vivo by administration of 200,000 units per kilogram of body weight daily for 5 days.
Siegal et al. (1999) demonstrated that purified interferon-producing cells were the CD4(+)CD11c(-) type 2 dendritic cell precursors, which produce 200 to 1,000 times more interferon than other blood cells after microbial challenge. Dendritic cell precursors are thus an effector cell type of the immune system, critical for antiviral and antitumor immune responses.
Takaoka et al. (2003) demonstrated that transcription of the p53 gene (191170) is induced by IFNA/IFNB (147640), accompanied by an increase in p53 protein level. IFNA/B signaling itself does not activate p53, but contributes to boosting p53 responses to stress signals. Takaoka et al. (2003) showed examples in which p53 gene induction by IFNA/B indeed contributed to tumor suppression. Furthermore, they showed that p53 is activated in virally infected cells to evoke an apoptotic response and that p53 is critical for antiviral defense of the host. Takaoka et al. (2003) showed that the p53 gene is transcriptionally induced by IFNA/B through ISGF3 (147574), demonstrating p53 gene induction by its cytokine. Whereas IFNA/B induce p53 mRNA and increase its protein level, p53-mediated responses such as cell cycle arrest or apoptosis were not observed in cells treated with IFNA/B alone.
Using surface plasmon resonance analysis and ELISA, Asokan et al. (2006) showed that IFNA bound complement component receptor-2 (CR2; 120650) in the same affinity range as other CR2 ligands. IFNA interacted with short consensus repeat-1 (SCR1) and SCR2 within the same region of CR2 that serves as the binding site for other CR2 ligands. Treatment of B cells with anti-CR2 diminished induction of IFNA-responsive genes. Asokan et al. (2006) proposed that the roles of CR2 and IFNA in development of autoimmunity may be mechanistically linked to pathogenesis of systemic lupus erythematosus (SLE; 152700).
Wilson et al. (2013) demonstrated in mice infected with lymphocytic choriomeningitis virus (LCMV) that blockade of type I interferon (IFN-I) signaling diminished chronic immune activation and immune suppression, restored lymphoid tissue architecture, and increased immune parameters associated with control of virus replication, ultimately facilitating clearance of the persistent infection. The accelerated control of persistent infection induced by blocking IFN-I signaling required CD4 T cells and was associated with enhanced IFN-gamma (147570) production. Wilson et al. (2013) concluded that interfering with chronic IFN-I signaling during persistent infection redirects the immune environment to enable control of infection. Wilson et al. (2013) noted that human HIV and HCV infections are also associated with immune activation driven by chronic IFN-I signaling and suggested that a similar blockade of IFN-I may improve control of these infections.
Teijaro et al. (2013) demonstrated that blockade of type I interferon signaling using an IFN1 receptor (see 107450)-neutralizing antibody reduced immune system activation, decreased expression of negative immune regulatory molecules, and restored lymphoid architecture in mice persistently infected with LCMV. IFN-I blockade before and after establishment of persistent virus infection resulted in enhanced virus clearance and was CD4 T cell-dependent. Teijaro et al. (2013) concluded that they demonstrated a direct causal link between type I interferon signaling, immune activation, negative immune regulator expression, lymphoid tissue disorganization, and virus persistence.
Serum triglyceride (TG) level is a well-known risk factor for cardiovascular disease. In 485 Hutterites 14 years of age or older, Newman et al. (2003) measured serum TG and performed a genomewide scan to find genetic determinants of the observed variation in TG levels. The authors reported 2 highly significant associations with TG levels: alleles at D2S410 on 2q14 (locus p = 0.0000058, genomewide p = 0.005) (see 608316) and at IFNA (locus p = 0.000043, genomewide p = 0.024). In each case, homozygosity at the locus was associated with low TG levels, suggesting that alleles at nearby loci may protect against high TG levels.
To clarify mechanisms governing the anxiety seen in SLE, an autoimmune multigenic multisystemic disease, Nakamura et al. (2003) carried out genomewide scans in mice. They found that the region including interferon-alpha on chromosome 4 in New Zealand black (NZB) mice was significantly linked to the anxiety-like behavior seen in SLE-prone F1 hybrids of NZB and New Zealand white (NZW) mice (BWF1 mice). This finding was confirmed by anxiety-like performances of mice with heterozygous NZB/NZW alleles in the susceptibility region bred onto the NZW background. In BWF1 mice, neuronal IFN-alpha levels were elevated and blockade of the mu-1 opioid receptor (OPRM1; 600018) or corticotropin-releasing hormone receptor-1 (CRHR1; 122561), possible downstream effectors for IFN-alpha in the brain, partially overcame the anxiety-like behavior seen in these mice. Neuronal corticotropin-releasing hormone levels were consistently higher in BWF1 than NZW mice. Furthermore, pretreatment of mu-1 opioid receptor antagonist abolished anxiety-like behavior seen in IFN-alpha-treated NZW mice. Nakamura et al. (2003) concluded that a genetically determined endogenous excess amount of IFN-alpha in the brain may form 1 aspect of anxiety-like behavior seen in SLE-prone mice.
Diaz and Bohlander (1993) tabulated the nomenclature of the human interferon genes. Thirteen functional genes and 1 pseudogene (IFNAP22) in the alpha-interferon family of type I interferon genes were listed. Diaz et al. (1994) and Diaz et al. (1996) provided an update of the nomenclature of the interferon genes and pseudogenes.
Early Mapping Studies
Early studies (Tan et al., 1974) assigned an interferon locus to chromosome 2 and another to chromosome 5--conclusions which subsequent studies indicated were probably in error. In the African green monkey, Cassingena et al. (1971) assigned the structural gene for interferon to a small subtelocentric chromosome, probably A8 or A9. According to Stock and Hsu (1973), these chromosomes are homologous to human chromosome 5. Slate and Ruddle (1979) likewise concluded that both chromosome 2 and chromosome 5 carry information for fibroblast interferon and further localized the genes to 2q and 5p. They could not map leukocyte interferon genes to these chromosomes, however.
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Isaacs, D., Clarke, J. R., Tyrrell, D. A. J., Webster, A. D. B., Valman, H. B. Deficient production of leucocyte interferon (interferon-alpha) in vitro and in vivo in children with recurrent respiratory tract infections. Lancet 318: 950-952, 1981. Note: Originally Volume II. [PubMed: 6170851] [Full Text: https://doi.org/10.1016/s0140-6736(81)91153-3]
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