RBCC Red Blood Cell Collection

IFNG [Confidence: low (only semi-automatic identification from reviews)]
Interferon gamma; IFN-gamma (Immune interferon; Flags: Precursor)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt P01579
ID IFNG_HUMAN Reviewed; 166 AA.
AC P01579; B5BU88; Q53ZV4;
DT 21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-APR-1988, sequence version 1.
DT 22-JAN-2014, entry version 162.
DE RecName: Full=Interferon gamma;
DE Short=IFN-gamma;
DE AltName: Full=Immune interferon;
DE Flags: Precursor;
GN Name=IFNG;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=6180322; DOI=10.1038/298859a0;
RA Gray P.W., Goeddel D.V.;
RT "Structure of the human immune interferon gene.";
RL Nature 298:859-863(1982).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=6173769; DOI=10.1038/295503a0;
RA Gray P.W., Leung D.W., Pennica D., Yelverton E., Najarian R.,
RA Simonsen C.C., Derynck R., Sherwood P.J., Wallace D.M., Berger S.L.,
RA Levinson A.D., Goeddel D.V.;
RT "Expression of human immune interferon cDNA in E. coli and monkey
RT cells.";
RL Nature 295:503-508(1982).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=2860101;
RA Nishi T., Fujita T., Nishi-Takaoka C., Saito A., Matsumoto T.,
RA Sato M., Oka T., Itoh S., Yip Y.K., Vilcek J., Taniguchi T.;
RT "Cloning and expression of a novel variant of human interferon-gamma
RT cDNA.";
RL J. Biochem. 97:153-159(1985).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=6329718;
RA Taya Y., Devos R., Tavernier J., Cheroutre H., Engler G., Fiers W.;
RT "Cloning and structure of the human immune interferon-gamma
RT chromosomal gene.";
RL EMBO J. 1:953-958(1982).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=6176945; DOI=10.1093/nar/10.8.2487;
RA Devos R., Cheroutre H., Taya Y., Degrave W., van Heuverswyn H.,
RA Fiers W.;
RT "Molecular cloning of human immune interferon cDNA and its expression
RT in eukaryotic cells.";
RL Nucleic Acids Res. 10:2487-2501(1982).
RN [6]
RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT GLN-160.
RA Chikara S.K., Jaiswal P., Sharma G.;
RL Submitted (MAR-2003) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RG SeattleSNPs variation discovery resource;
RL Submitted (JUN-2001) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RX PubMed=19054851; DOI=10.1038/nmeth.1273;
RA Goshima N., Kawamura Y., Fukumoto A., Miura A., Honma R., Satoh R.,
RA Wakamatsu A., Yamamoto J., Kimura K., Nishikawa T., Andoh T., Iida Y.,
RA Ishikawa K., Ito E., Kagawa N., Kaminaga C., Kanehori K., Kawakami B.,
RA Kenmochi K., Kimura R., Kobayashi M., Kuroita T., Kuwayama H.,
RA Maruyama Y., Matsuo K., Minami K., Mitsubori M., Mori M.,
RA Morishita R., Murase A., Nishikawa A., Nishikawa S., Okamoto T.,
RA Sakagami N., Sakamoto Y., Sasaki Y., Seki T., Sono S., Sugiyama A.,
RA Sumiya T., Takayama T., Takayama Y., Takeda H., Togashi T., Yahata K.,
RA Yamada H., Yanagisawa Y., Endo Y., Imamoto F., Kisu Y., Tanaka S.,
RA Isogai T., Imai J., Watanabe S., Nomura N.;
RT "Human protein factory for converting the transcriptome into an in
RT vitro-expressed proteome.";
RL Nat. Methods 5:1011-1017(2008).
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Blood;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [11]
RP PROTEIN SEQUENCE OF 24-157, AND GLYCOSYLATION AT ASN-48 AND ASN-120.
RX PubMed=6427223;
RA Rinderknecht E., O'Conner B.H., Rodriguez H.;
RT "Natural human interferon-gamma. Complete amino acid sequence and
RT determination of sites of glycosylation.";
RL J. Biol. Chem. 259:6790-6797(1984).
RN [12]
RP PROTEIN SEQUENCE OF 24-161, AND PROTEOLYTIC PROCESSING OF THE
RP C-TERMINUS.
RX PubMed=3109913; DOI=10.1111/j.1432-1033.1987.tb13494.x;
RA Pan Y.C.E., Stern A.S., Familletti P.C., Khan F.R., Chizzonite R.;
RT "Structural characterization of human interferon gamma. Heterogeneity
RT of the carboxyl terminus.";
RL Eur. J. Biochem. 166:145-149(1987).
RN [13]
RP STRUCTURE OF CARBOHYDRATES.
RX PubMed=2504704;
RA Yamamoto S., Hase S., Yamauchi H., Tanimoto T., Ikenaka T.;
RT "Studies on the sugar chains of interferon-gamma from human
RT peripheral-blood lymphocytes.";
RL J. Biochem. 105:1034-1039(1989).
RN [14]
RP X-RAY CRYSTALLOGRAPHY (3.5 ANGSTROMS).
RX PubMed=1902591; DOI=10.1126/science.1902591;
RA Ealick S.E., Cook W.J., Vijay-Kumar S., Carson M., Nagabhushan T.L.,
RA Trotta P.P., Bugg C.E.;
RT "Three-dimensional structure of recombinant human interferon-gamma.";
RL Science 252:698-702(1991).
RN [15]
RP X-RAY CRYSTALLOGRAPHY (2.9 ANGSTROMS).
RX PubMed=7617032; DOI=10.1038/376230a0;
RA Walter M.R., Windsor W.T., Nagabhushan T.L., Lundell D.J., Lunn C.A.,
RA Zauodny P.J., Narula S.K.;
RT "Crystal structure of a complex between interferon-gamma and its
RT soluble high-affinity receptor.";
RL Nature 376:230-235(1995).
RN [16]
RP X-RAY CRYSTALLOGRAPHY (2.9 ANGSTROMS).
RX PubMed=10860730; DOI=10.1006/jmbi.2000.3734;
RA Landar A., Curry B., Parker M.H., DiGiacomo R., Indelicato S.R.,
RA Nagabhushan T.L., Rizzi G., Walter M.R.;
RT "Design, characterization, and structure of a biologically active
RT single-chain mutant of human IFN-gamma.";
RL J. Mol. Biol. 299:169-179(2000).
RN [17]
RP X-RAY CRYSTALLOGRAPHY (2.9 ANGSTROMS) OF COMPLEX WITH RECEPTOR.
RX PubMed=10986460; DOI=10.1016/S0969-2126(00)00184-2;
RA Thiel D.J., le Du M.-H., Walter R.L., D'Arcy A., Chene C.,
RA Fountoulakis M., Garotta G., Winkler F.K., Ealick S.E.;
RT "Observation of an unexpected third receptor molecule in the crystal
RT structure of human interferon-gamma receptor complex.";
RL Structure 8:927-936(2000).
RN [18]
RP STRUCTURE BY NMR.
RX PubMed=1525157; DOI=10.1021/bi00150a009;
RA Grzesiek S., Doebeli H., Gentz R., Garotta G., Labhardt A.M., Bax A.;
RT "1H, 13C, and 15N NMR backbone assignments and secondary structure of
RT human interferon-gamma.";
RL Biochemistry 31:8180-8190(1992).
RN [19]
RP ASSOCIATION WITH APLASTIC ANEMIA.
RX PubMed=15327519; DOI=10.1111/j.1365-2141.2004.05102.x;
RA Dufour C., Capasso M., Svahn J., Marrone A., Haupt R., Bacigalupo A.,
RA Giordani L., Longoni D., Pillon M., Pistorio A., Di Michele P.,
RA Iori A.P., Pongiglione C., Lanciotti M., Iolascon A.;
RT "Homozygosis for (12) CA repeats in the first intron of the human IFN-
RT gamma gene is significantly associated with the risk of aplastic
RT anaemia in Caucasian population.";
RL Br. J. Haematol. 126:682-685(2004).
CC -!- FUNCTION: Produced by lymphocytes activated by specific antigens
CC or mitogens. IFN-gamma, in addition to having antiviral activity,
CC has important immunoregulatory functions. It is a potent activator
CC of macrophages, it has antiproliferative effects on transformed
CC cells and it can potentiate the antiviral and antitumor effects of
CC the type I interferons.
CC -!- SUBUNIT: Homodimer.
CC -!- SUBCELLULAR LOCATION: Secreted.
CC -!- TISSUE SPECIFICITY: Released primarily from activated T
CC lymphocytes.
CC -!- PTM: Proteolytic processing produces C-terminal heterogeneity,
CC with proteins ending alternatively at Gly-150, Met-157 or Gly-161.
CC -!- DISEASE: Aplastic anemia (AA) [MIM:609135]: A form of anemia in
CC which the bone marrow fails to produce adequate numbers of
CC peripheral blood elements. It is characterized by peripheral
CC pancytopenia and marrow hypoplasia. Note=Disease susceptibility
CC may be associated with variations affecting the gene represented
CC in this entry.
CC -!- PHARMACEUTICAL: Available under the name Actimmune (Genentech).
CC Used for reducing the frequency and severity of serious infections
CC associated with chronic granulomatous disease (CGD).
CC -!- SIMILARITY: Belongs to the type II (or gamma) interferon family.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/IFNG";
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Interferon gamma entry;
CC URL="http://en.wikipedia.org/wiki/Interferon_gamma";
CC -!- WEB RESOURCE: Name=SeattleSNPs;
CC URL="http://pga.gs.washington.edu/data/ifng/";
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DR EMBL; X13274; CAA31639.1; -; mRNA.
DR EMBL; J00219; AAB59534.1; -; Genomic_DNA.
DR EMBL; X01992; CAA26022.1; -; mRNA.
DR EMBL; V00543; CAA23804.1; -; mRNA.
DR EMBL; AY255837; AAP20098.1; -; mRNA.
DR EMBL; AF375790; AAK53058.1; -; Genomic_DNA.
DR EMBL; AB451324; BAG70138.1; -; mRNA.
DR EMBL; AB451453; BAG70267.1; -; mRNA.
DR EMBL; CH471054; EAW97180.1; -; Genomic_DNA.
DR EMBL; BC070256; AAH70256.1; -; mRNA.
DR PIR; A93284; IVHUG.
DR RefSeq; NP_000610.2; NM_000619.2.
DR UniGene; Hs.856; -.
DR PDB; 1EKU; X-ray; 2.90 A; A/B=26-161.
DR PDB; 1FG9; X-ray; 2.90 A; A/B=24-156.
DR PDB; 1FYH; X-ray; 2.04 A; A/D=24-156.
DR PDB; 1HIG; X-ray; 3.50 A; A/B/C/D=24-161.
DR PDB; 3BES; X-ray; 2.20 A; L=24-161.
DR PDBsum; 1EKU; -.
DR PDBsum; 1FG9; -.
DR PDBsum; 1FYH; -.
DR PDBsum; 1HIG; -.
DR PDBsum; 3BES; -.
DR ProteinModelPortal; P01579; -.
DR SMR; P01579; 24-155.
DR DIP; DIP-483N; -.
DR IntAct; P01579; 2.
DR MINT; MINT-1508034; -.
DR STRING; 9606.ENSP00000229135; -.
DR DrugBank; DB01296; Glucosamine.
DR DrugBank; DB00033; Interferon gamma-1b.
DR DrugBank; DB00641; Simvastatin.
DR PhosphoSite; P01579; -.
DR UniCarbKB; P01579; -.
DR DMDM; 124479; -.
DR PaxDb; P01579; -.
DR PRIDE; P01579; -.
DR DNASU; 3458; -.
DR Ensembl; ENST00000229135; ENSP00000229135; ENSG00000111537.
DR GeneID; 3458; -.
DR KEGG; hsa:3458; -.
DR UCSC; uc001stw.1; human.
DR CTD; 3458; -.
DR GeneCards; GC12M068548; -.
DR HGNC; HGNC:5438; IFNG.
DR HPA; CAB010344; -.
DR MIM; 147570; gene.
DR MIM; 609135; phenotype.
DR neXtProt; NX_P01579; -.
DR Orphanet; 88; Idiopathic aplastic anemia.
DR PharmGKB; PA29674; -.
DR eggNOG; NOG45353; -.
DR HOGENOM; HOG000254784; -.
DR HOVERGEN; HBG056912; -.
DR InParanoid; P01579; -.
DR KO; K04687; -.
DR OMA; KEYFNAS; -.
DR OrthoDB; EOG7VHSZM; -.
DR PhylomeDB; P01579; -.
DR Reactome; REACT_6900; Immune System.
DR SignaLink; P01579; -.
DR EvolutionaryTrace; P01579; -.
DR GeneWiki; Interferon-gamma; -.
DR GenomeRNAi; 3458; -.
DR NextBio; 13624; -.
DR PMAP-CutDB; P01579; -.
DR PRO; PR:P01579; -.
DR ArrayExpress; P01579; -.
DR Bgee; P01579; -.
DR CleanEx; HS_IFNG; -.
DR Genevestigator; P01579; -.
DR GO; GO:0009897; C:external side of plasma membrane; IEA:Ensembl.
DR GO; GO:0005576; C:extracellular region; IDA:BHF-UCL.
DR GO; GO:0005615; C:extracellular space; IEA:UniProtKB-KW.
DR GO; GO:0005133; F:interferon-gamma receptor binding; TAS:ProtInc.
DR GO; GO:0002250; P:adaptive immune response; IEA:Ensembl.
DR GO; GO:0019882; P:antigen processing and presentation; IEA:Ensembl.
DR GO; GO:0002302; P:CD8-positive, alpha-beta T cell differentiation involved in immune response; IEA:Ensembl.
DR GO; GO:0007050; P:cell cycle arrest; IDA:BHF-UCL.
DR GO; GO:0006928; P:cellular component movement; TAS:ProtInc.
DR GO; GO:0071351; P:cellular response to interleukin-18; IEA:Ensembl.
DR GO; GO:0071222; P:cellular response to lipopolysaccharide; IEA:Ensembl.
DR GO; GO:0042742; P:defense response to bacterium; IEA:Ensembl.
DR GO; GO:0042832; P:defense response to protozoan; IEA:Ensembl.
DR GO; GO:0051607; P:defense response to virus; IEA:UniProtKB-KW.
DR GO; GO:0030968; P:endoplasmic reticulum unfolded protein response; IEA:Ensembl.
DR GO; GO:0097191; P:extrinsic apoptotic signaling pathway; IDA:BHF-UCL.
DR GO; GO:0006959; P:humoral immune response; IEA:Ensembl.
DR GO; GO:0060333; P:interferon-gamma-mediated signaling pathway; TAS:Reactome.
DR GO; GO:0044130; P:negative regulation of growth of symbiont in host; IEA:Ensembl.
DR GO; GO:0032700; P:negative regulation of interleukin-17 production; IDA:BHF-UCL.
DR GO; GO:0003340; P:negative regulation of mesenchymal to epithelial transition involved in metanephros morphogenesis; ISS:BHF-UCL.
DR GO; GO:0072308; P:negative regulation of metanephric nephron tubule epithelial cell differentiation; ISS:BHF-UCL.
DR GO; GO:0031642; P:negative regulation of myelination; IEA:Ensembl.
DR GO; GO:0048662; P:negative regulation of smooth muscle cell proliferation; IDA:BHF-UCL.
DR GO; GO:0000122; P:negative regulation of transcription from RNA polymerase II promoter; ISS:BHF-UCL.
DR GO; GO:0001781; P:neutrophil apoptotic process; IEA:Ensembl.
DR GO; GO:0030593; P:neutrophil chemotaxis; IEA:Ensembl.
DR GO; GO:0060559; P:positive regulation of calcidiol 1-monooxygenase activity; IDA:BHF-UCL.
DR GO; GO:0045785; P:positive regulation of cell adhesion; IEA:Ensembl.
DR GO; GO:0045080; P:positive regulation of chemokine biosynthetic process; IEA:Ensembl.
DR GO; GO:0060550; P:positive regulation of fructose 1,6-bisphosphate 1-phosphatase activity; IDA:BHF-UCL.
DR GO; GO:0060552; P:positive regulation of fructose 1,6-bisphosphate metabolic process; IDA:BHF-UCL.
DR GO; GO:0050718; P:positive regulation of interleukin-1 beta secretion; IEA:Ensembl.
DR GO; GO:0045084; P:positive regulation of interleukin-12 biosynthetic process; IEA:Ensembl.
DR GO; GO:0032735; P:positive regulation of interleukin-12 production; IDA:UniProtKB.
DR GO; GO:0032747; P:positive regulation of interleukin-23 production; IDA:BHF-UCL.
DR GO; GO:0045410; P:positive regulation of interleukin-6 biosynthetic process; IEA:Ensembl.
DR GO; GO:0048304; P:positive regulation of isotype switching to IgG isotypes; IEA:Ensembl.
DR GO; GO:0051712; P:positive regulation of killing of cells of other organism; IDA:BHF-UCL.
DR GO; GO:0051044; P:positive regulation of membrane protein ectodomain proteolysis; IDA:BHF-UCL.
DR GO; GO:0002053; P:positive regulation of mesenchymal cell proliferation; ISS:BHF-UCL.
DR GO; GO:0045348; P:positive regulation of MHC class II biosynthetic process; IEA:Ensembl.
DR GO; GO:0045666; P:positive regulation of neuron differentiation; IEA:Ensembl.
DR GO; GO:0045429; P:positive regulation of nitric oxide biosynthetic process; IDA:BHF-UCL.
DR GO; GO:0045672; P:positive regulation of osteoclast differentiation; IDA:BHF-UCL.
DR GO; GO:0033141; P:positive regulation of peptidyl-serine phosphorylation of STAT protein; NAS:BHF-UCL.
DR GO; GO:0034393; P:positive regulation of smooth muscle cell apoptotic process; IDA:BHF-UCL.
DR GO; GO:0032224; P:positive regulation of synaptic transmission, cholinergic; IEA:Ensembl.
DR GO; GO:0042102; P:positive regulation of T cell proliferation; IEA:Ensembl.
DR GO; GO:0045944; P:positive regulation of transcription from RNA polymerase II promoter; IEA:Ensembl.
DR GO; GO:2000309; P:positive regulation of tumor necrosis factor (ligand) superfamily member 11 production; IDA:BHF-UCL.
DR GO; GO:0032760; P:positive regulation of tumor necrosis factor production; IEA:Ensembl.
DR GO; GO:0042511; P:positive regulation of tyrosine phosphorylation of Stat1 protein; IDA:BHF-UCL.
DR GO; GO:0060557; P:positive regulation of vitamin D biosynthetic process; IDA:BHF-UCL.
DR GO; GO:0000060; P:protein import into nucleus, translocation; IDA:UniProtKB.
DR GO; GO:0050796; P:regulation of insulin secretion; IDA:BHF-UCL.
DR GO; GO:0060334; P:regulation of interferon-gamma-mediated signaling pathway; TAS:Reactome.
DR GO; GO:0002026; P:regulation of the force of heart contraction; IEA:Ensembl.
DR GO; GO:0042493; P:response to drug; IEA:Ensembl.
DR GO; GO:0009615; P:response to virus; IDA:MGI.
DR Gene3D; 1.20.1250.10; -; 1.
DR InterPro; IPR009079; 4_helix_cytokine-like_core.
DR InterPro; IPR012351; 4_helix_cytokine_core.
DR InterPro; IPR002069; Interferon_gamma.
DR PANTHER; PTHR11419; PTHR11419; 1.
DR Pfam; PF00714; IFN-gamma; 1.
DR PIRSF; PIRSF001936; IFN-gamma; 1.
DR ProDom; PD002435; Interferon_gamma; 1.
DR SUPFAM; SSF47266; SSF47266; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Antiviral defense; Cleavage on pair of basic residues;
KW Complete proteome; Cytokine; Direct protein sequencing; Glycoprotein;
KW Growth regulation; Pharmaceutical; Polymorphism;
KW Pyrrolidone carboxylic acid; Reference proteome; Secreted; Signal.
FT SIGNAL 1 23
FT CHAIN 24 161 Interferon gamma.
FT /FTId=PRO_0000016444.
FT PROPEP 162 166
FT /FTId=PRO_0000259481.
FT MOD_RES 24 24 Pyrrolidone carboxylic acid.
FT CARBOHYD 48 48 N-linked (GlcNAc...).
FT CARBOHYD 120 120 N-linked (GlcNAc...); in dimeric form.
FT VARIANT 29 29 K -> Q.
FT /FTId=VAR_004017.
FT VARIANT 160 160 R -> Q.
FT /FTId=VAR_004018.
FT HELIX 28 38
FT HELIX 43 46
FT HELIX 53 58
FT HELIX 62 81
FT TURN 82 85
FT TURN 87 89
FT HELIX 90 104
FT HELIX 109 119
FT HELIX 126 140
FT HELIX 146 148
SQ SEQUENCE 166 AA; 19348 MW; 1514E8F785FD81AA CRC64;
MKYTSYILAF QLCIVLGSLG CYCQDPYVKE AENLKKYFNA GHSDVADNGT LFLGILKNWK
EESDRKIMQS QIVSFYFKLF KNFKDDQSIQ KSVETIKEDM NVKFFNSNKK KRDDFEKLTN
YSVTDLNVQR KAIHELIQVM AELSPAAKTG KRKRSQMLFR GRRASQ
//

MIM 147570
*RECORD*
*FIELD* NO
147570
*FIELD* TI
*147570 INTERFERON, GAMMA; IFNG
;;IFG;;
IFN, IMMUNE; IFI
*FIELD* TX

DESCRIPTION

Interferon-gamma (IFNG), or type II interferon, is a cytokine critical
read morefor innate and adaptive immunity against viral and intracellular
bacterial infections and for tumor control. Aberrant IFNG expression is
associated with a number of autoinflammatory and autoimmune diseases.
The importance of IFNG in the immune system stems in part from its
ability to inhibit viral replication directly, but most importantly
derives from its immunostimulatory and immunomodulatory effects. IFNG is
produced predominantly by natural killer (NK) and natural killer T (NKT)
cells as part of the innate immune response, and by CD4 (186940) and CD8
(see 186910) cytotoxic T lymphocyte (CTL) effector T cells once
antigen-specific immunity develops (Schoenborn and Wilson, 2007).

CLONING

Naylor et al. (1983) determined that the 146-amino acid sequence of
mature gamma-interferon, deduced from the nucleotide sequence of cloned
cDNA, is unrelated to the sequences of other interferons.

GENE STRUCTURE

Gray and Goeddel (1982) found that the immune interferon gene contains 4
exons, a repetitive DNA element, and a low order of polymorphism. There
appeared to be a single gene; resolution of gamma-interferon into 2
components (Yip et al., 1982) probably reflects posttranslational
processing. Naylor et al. (1983) noted that gamma-interferon differs
from the alpha- and beta-interferons (which are on 9p and have no
introns) by the presence of 3 introns.

MAPPING

Naylor et al. (1983) found that the gamma-interferon gene is on
chromosome 12. By in situ hybridization, Trent et al. (1982) assigned
the IFI gene to chromosome 12q24.1. On both the physical and the genetic
maps of chromosome 12, Bureau et al. (1995) mapped the IFG gene close to
the D12S335 and D12S313 microsatellites. They also physically mapped it
close to the locus of the MDM2 oncogene (164875) on 12q15, a
localization proximal to that arrived at earlier. By FISH, Zimonjic et
al. (1995) mapped the IFNG gene to chromosome 12q14. This correction of
the previous localization resolved the discrepancy between the syntenic
maps of human chromosome 12 and mouse 10.

Justice et al. (1990) showed that the mouse Ifng gene is located on
chromosome 10. Using RFLVs in multipoint backcrosses, Shimizu et al.
(1992) determined the map position of the Ifng gene in relation to other
genes on mouse chromosome 10. Bureau et al. (1995) described the
organization of the Ifng, Myf6, Mdm1 (613813), and Mdm2 loci on mouse
chromosome 10 in a region with homology of synteny to human 12q15.

GENE FUNCTION

Luster et al. (1985) showed that gamma-interferon regulates the INP10
gene (147310), which encodes a protein with amino acid homology to
platelet factor-4 (PF4; 173460) and beta-thromboglobulin (see PPBP;
121010).

Tzoneva et al. (1988) found failure of phytohemagglutinin-induced
gamma-IFN synthesis in lymphocyte cultures in a Bulgarian brother and
sister, aged 18 and 16 years, respectively. Both had had recurrent
infections and showed selective IgA deficiency and reduced blast
transformation index under PHA stimulation. Recurrent 'flu' was
complicated at times in both of them by a painless swelling of the
carotid gland on one or both sides. Both had had 'butterfly rubella' in
early childhood and an appendectomy. Furthermore, both had oxalate renal
stones.

Expression of HLA-DR antigen (see 142860) and intracellular adhesion
molecule-1 (ICAM1; 147840) in human conjunctival epithelium is
upregulated in patients with dry eyes associated with Sjogren syndrome
(270150). Tsubota et al. (1999) reported that this upregulation in
Sjogren syndrome patients may be controlled by interferon-gamma through
the activation of transcription factor NFKB (nuclear factor kappa-B; see
164011).

Diefenbach et al. (1999) studied the relationship of IL12 (see 161561)
and nitric oxide synthase-2 (NOS2A; 163730), also known as inducible NOS
(iNOS), to innate immunity to the parasite Leishmania in mice. In the
absence of iNOS activity, IL12 was unable to prevent spreading of
Leishmania parasites, did not stimulate natural killer cells for
cytotoxicity or interferon-gamma release, and failed to activate TYK2
(176941) and to tyrosine-phosphorylate STAT4, the central signal
transducer of IL12, in NK cells. Activation of TYK2 in NK cells by
IFN-alpha/beta (type I interferon) also required iNOS. Thus,
iNOS-derived NO is a prerequisite for cytokine signaling and function in
innate immunity.

Takayanagi et al. (2000) demonstrated that T-cell production of IFNG
strongly suppresses osteoclastogenesis by interfering with the RANKL
(602642)-RANK (603499) signaling pathway. IFNG induces rapid degradation
of the RANK adaptor protein, TRAF6 (602355), resulting in strong
inhibition of the RANKL-induced activation of the transcription factor
NFKB and JNK (601158). This inhibition of osteoclastogenesis could be
rescued by overexpressing TRAF6 in precursor cells, indicating that
TRAF6 is the target critical for the IFNG action. Furthermore,
Takayanagi et al. (2000) provided evidence that the accelerated
degradation of TRAF6 requires both its ubiquitination, which is
initiated by RANKL, and IFNG-induced activation of the
ubiquitin-proteasome system. Takayanagi et al. (2000) concluded that
there is crosstalk between the tumor necrosis factor (TNF; 191160) and
IFN families of cytokines, through which IFNG provides a negative link
between T-cell activation and bone resorption.

Cryptosporidiosis presents as a self-limited diarrhea after infection
with the protozoan C. parvum in healthy hosts. In immunocompromised
individuals, however, infection leads to a chronic and often fatal
illness for which there is no direct treatment. In studies with
experimentally infected healthy volunteers, White et al. (2000) detected
IFNG expression predominantly in previously exposed individuals, with
serum IgG specific for C. parvum in lamina propria lymphocytes after
reinfection. IFNG expression was not detected in AIDS patients. IFNG
expression in the healthy individuals occurred early after infection,
and stronger expression was associated with greater resistance to
symptomatic infection and reduced oocyst excretion. White et al. (2000)
concluded that IFNG expression in the intestinal mucosa is important in
controlling parasite burden and preventing chronic disease.

Zohlnhofer et al. (2001) investigated the expression of 2,435 genes in
atherectomy specimens and blood cells of patients with restenosis,
normal coronary artery specimens, and cultured human smooth muscle cells
(SMCs). Of the 223 differentially expressed genes, 37 genes indicated
activation of IFNG signaling in neointimal SMCs. In cultured SMCs, IFNG
inhibited apoptosis. Genetic disruption of Ifng signaling in a mouse
model of restenosis significantly reduced the vascular proliferative
response.

Binder and Griffin (2001) observed that antibody-deficient mice could
recover from alphaviral (Sindbis virus) encephalomyelitis by using Ifng,
but not Tnfa (191160), secreted by CD4-positive and CD8-positive T
cells. They found that Ifng mediated noncytolytic viral clearance from
spinal cord and brainstem, and at least reduced the amount of virus in
brain, indicating that neurons are heterogeneous in their responses to
Ifng.

Tbet is a member of the T-box family of transcription factors that
appears to regulate lineage commitment in CD4 T helper cells in part by
activating the hallmark T(H)1 cytokine, IFNG. IFNG is also produced by
NK cells and most prominently by CD8 cytotoxic T cells, and is vital for
the control of microbial pathogens. Although Tbet is expressed in all
these cell types, Szabo et al. (2002) demonstrated that it is required
for control of IFNG production in CD4 and NK cells, but not in CD8
cells. This difference is also apparent in the function of these cell
subsets. Thus, Szabo et al. (2002) concluded that the regulation of a
single cytokine, IFNG, is controlled by distinct transcriptional
mechanisms within the T cell lineage. Szabo et al. (2002) studied mice
deficient in Tbet and established that Tbet is a transcription factor
required for T(H)1 lineage commitment.

PKR (176871), an interferon-inducible protein kinase activated by
double-stranded RNA, inhibits translation by phosphorylating eIF2-alpha
(603907). Ben-Asouli et al. (2002) showed that human IFNG mRNA uses
local activation of PKR in the cell to control its own translation
yield. IFNG mRNA was found to activate PKR through a pseudoknot in its
5-prime untranslated region. Mutations that impaired pseudoknot
stability reduced the ability to activate PKR and strongly increased the
translation efficiency of IFNG mRNA. Nonphosphorylatable mutant
eIF2-alpha, knockout of PKR, and the PKR inhibitors 2-aminopurine,
transdominant-negative PKR, or vaccinia E3L correspondingly enhanced
translation of IFNG mRNA. The potential to form the pseudoknot was found
to be phylogenetically conserved. Ben-Asouli et al. (2002) proposed that
the RNA pseudoknot acts to adjust translation of IFNG mRNA to the PKR
level expressed in the cell.

Fields et al. (2002) noted that high levels of histone acetylation at
particular loci correlate with transcriptional activity, whereas reduced
levels correlate with silencing. Using chromatin immunoprecipitation
(ChIP), PCR, and green fluorescent protein analysis, they demonstrated
that histones in the cytokine loci (IFNG; IL4, 147780) of naive T cells
are unacetylated, but upon TCR stimulation, the loci are rapidly and
progressively acetylated on histones H3 and H4. The acetylation at the
IL4 locus occurs early, regardless of Th1/Th2 polarizing conditions,
correlating with early transcription. The maintenance of acetylation
depends on cytokine and STAT4 (600558) and STAT6 (601512) signaling and
also on the transactivator activity of TBET (604895) and GATA3 (131320),
the putative 'master regulators' of Th lineage determination.

Messi et al. (2003) showed that under conditions priming CD4-positive T
cells to become either Th1 cells preferentially expressing a subset of
cytokines, particularly IFNG, or Th2 cells expressing a different subset
of cytokines, particularly interleukin-4 (IL4; 147780), naive and
effector memory T cells acquire polarized cytokine gene acetylation
patterns. They stated that commitment of T cells to either the Th1 or
Th2 lineage requires upregulation of the fate-determining transcription
factors TBET and GATA3, respectively. Whereas histone hyperacetylation
of IFNG and IL4 promoters in Th1 and Th2 cells, respectively, was
stable, central memory T cells had hypoacetylated cytokine genes that
became hyperacetylated upon polarization after appropriate stimulation.
However, all Th1 and most Th2 cells tested could express the alternative
cytokine when stimulated under opposite Th conditions. Messi et al.
(2003) concluded that most human CD4-positive T cells retain both memory
and flexibility of cytokine gene expression.

The T helper cell 1 and 2 (T(H)1 and T(H)2) pathways, defined by
cytokines IFN-gamma and IL4, respectively, comprise 2 alternative CD4+
T-cell fates, with functional consequences for the host immune system.
These cytokine genes are encoded on different chromosomes. The T(H)2
locus control region (LCR) coordinately regulates the T(H)2 cytokine
genes by participating in a complex between the LCR and promoters of the
cytokine genes IL4, IL5 (147850), and IL13 (147683). Although they are
spread over 120 kb, these elements are closely juxtaposed in the nucleus
in a poised chromatin conformation. In addition to these
intrachromosomal interactions, Spilianakis et al. (2005) described
interchromosomal interactions between the promoter region of the
IFN-gamma gene on chromosome 10 and the regulatory regions of the T(H)2
cytokine locus on chromosome 11. DNase I hypersensitive sites that
comprise the T(H)2 LCR developmentally regulate these interchromosomal
interactions. Furthermore, there seems to be a cell type-specific
dynamic interaction between interacting chromatin partners whereby
interchromosomal interactions are apparently lost in favor of
intrachromosomal ones upon gene activation. Thus, Spilianakis et al.
(2005) provided an example of eukaryotic genes located on separate
chromosomes associating physically in the nucleus via interactions that
may have a function in coordinating gene expression.

Chang and Aune (2005) compared long-range histone hyperacetylation
patterns across the Ifng gene in mouse T cells and NK cells in the
resting state and after induction of Ifng gene transcription by
stimulation with Il12 (see 161560) and/or Il18 (600953). In T cells,
long-range histone acetylation depended on stimulation that drove both
Th1 differentiation and active transcription, and it depended on the
presence of Stat4 and Tbet, transcription factors required for Th1
lineage commitment. Binding of these factors was not observed in Th2
cells. In NK cells, similar histone hyperacetylated domains were found
in the absence of stimulation and active transcription, and additional
proximal domains were hyperacetylated after transcription stimulation.
Chang and Aune (2005) proposed that formation of extended histone
hyperacetylated domains across the Ifng region marks this gene for cell-
or stimulus-specific transcription.

Bai et al. (2008) investigated the effects of IFNG on vascular smooth
muscle cells (VSMCs) through interactions involving STAT proteins. They
found that IFNG stimulation phosphorylated both STAT1 (600555) and STAT3
(102582) in human VSMCs, but not in mouse VSMCs or human endothelial
cells. Activation by IFNG induced STAT3 translocation to the nucleus.
Microarray analysis identified signaling candidates that were inducible
by IFNG and dependent on STAT3, and RT-PCR and immunoblot analyses
verified roles for XAF1 (606717) and NOXA (PMAIP1; 604959). STAT3
activation sensitized VSMCs to apoptosis triggered by both death
receptor- and mitochondria-mediated pathways. Knockdown of XAF1 and NOXA
expression inhibited priming of VSMCs to apoptotic stimuli by IFNG.
Immunodeficient mice with human coronary artery grafts were susceptible
to the proapoptotic effects of XAF1 and NOXA induced by IFNG. Bai et al.
(2008) concluded that STAT1-independent signaling by IFNG via STAT3
promotes death of VSMCs.

Zaidi et al. (2011) introduced a mouse model permitting
fluorescence-aided melanocyte imaging and isolation following in vivo UV
irradiation. They used expression profiling to show that activated
neonatal skin melanocytes isolated following a melanomagenic UVB dose
bear a distinct, persistent interferon response signature, including
genes associated with immunoevasion. UVB-induced melanocyte activation,
characterized by aberrant growth and migration, was abolished by
antibody-mediated systemic blockade of IFN-gamma, but not type I
interferons. IFN-gamma was produced by macrophages recruited to neonatal
skin by UVB-induced ligands to the chemokine receptor Ccr2 (601267).
Admixed recruited skin macrophages enhanced transplanted melanoma growth
by inhibiting apoptosis; notably, IFN-gamma blockade abolished
macrophage-enhanced melanoma growth and survival. IFN-gamma-producing
macrophages were also identified in 70% of human melanomas examined.
Zaidi et al. (2011) concluded that their data revealed an unanticipated
role for IFN-gamma in promoting melanocytic cell survival/immunoevasion,
identifying a novel candidate therapeutic target for a subset of
melanoma patients.

Using an approach that combined the in vitro priming of naive T cells
with the ex vivo analysis of memory T cells, Zielinski et al. (2012)
described 2 types of human TH17 cells with distinct effector function
and differentiation requirements. Candida albicans-specific TH17 cells
produced IL17 (603149) and IFN-gamma but no IL10 (124092), whereas
Staphylococcus aureus-specific TH17 cells produced IL17 and could
produce IL10 upon restimulation. IL6 (147620), IL23 (see 605580), and
IL1-beta (147720) contributed to TH17 differentiation induced by both
pathogens, but IL1-beta was essential in C. albicans-induced TH17
differentiation to counteract the inhibitory activity of IL12 (see
161561) and to prime IL17/IFN-gamma double-producing cells. In addition,
IL1-beta inhibited IL10 production in differentiating and in memory TH17
cells, whereas blockade of IL1-beta in vivo led to increased IL10
production by memory TH17 cells. Zielinski et al. (2012) showed that,
after restimulation, TH17 cells transiently downregulated IL17
production through a mechanism that involved IL2 (147680)-induced
activation of STAT5 (601511) and decreased expression of ROR-gamma-t
(see 602943). Zielinski et al. (2012) concluded that, taken together,
their findings demonstrated that by eliciting different cytokines, C.
albicans and S. aureus prime TH17 cells that produce either IFN-gamma or
IL10, and identified IL1-beta and IL2 as pro- and antiinflammatory
regulators of TH17 cells both at priming and in the effector phase.

Braumuller et al. (2013) showed that the combined action of the T
helper-1-cell cytokines IFNG and tumor necrosis factor (TNF; 191160)
directly induces permanent growth arrest in cancers. To safely separate
senescence induced by tumor immunity from oncogene-induced senescence,
Braumuller et al. (2013) used a mouse model in which the Simian virus-40
large T antigen (Tag) expressed under the control of the rat insulin
promoter creates tumors by attenuating p53 (191170)- and Rb
(614041)-mediated cell cycle control. When combined, Ifng and Tnf drive
Tag-expressing cancers into senescence by inducing permanent growth
arrest in G1/G0, activation of p16Ink4a (CDKN2A; 600160), and downstream
Rb hypophosphorylation at ser795. This cytokine-induced senescence
strictly requires Stat1 and Tnfr1 (TNFRSF1A; 191190) signaling in
addition to p16Ink4a. In vivo, Tag-specific T-helper-1 cells permanently
arrest Tag-expressing cancers by inducing Ifng- and Tnfr1-dependent
senescence. Conversely, Tnfr1-null Tag-expressing cancers resist
cytokine-induced senescence and grow aggressively, even in
Tnfr1-expressing hosts. Braumuller et al. (2013) concluded that as IFNG
and TNF induce senescence in numerous murine and human cancers, this may
be a general mechanism for arresting cancer progression.

Using RT-PCR and immunohistochemistry, Teles et al. (2013) demonstrated
increased expression of the type I interferon IFNB (IFNB1; 147640) in
lesions of lepromatous leprosy (i.e., multibacillary, or L-lep) patients
compared with tuberculoid leprosy (i.e., paucibacillary, or T-lep)
patients (see 609888). Expression of an IFNB receptor, IFNAR1 (107450),
was also increased in L-lep lesions. Increased expression of IFNB was
associated with increased expression of IL10, and IFNB alone induced
IL10 expression in mononuclear cells in vitro. There was an inverse
correlation between IL10 expression and expression of the antimicrobial
peptides CAMP (600474) and DEFB4 (DEFB4A; 602215). Measurement of
uncultivable Mycobacterium leprae viability based on the ratio of M.
leprae 16S rRNA to M. leprae repetitive element DNA indicated that IFNG
induced antimicrobial activity against M. leprae in monocytes by about
35%, which was abrogated by the addition of either IFNB or IL10. Teles
et al. (2013) concluded that the type I interferon gene expression
program prominently expressed in L-lep lesions inhibits the IFNG-induced
antimicrobial response against M. leprae through an intermediary, IL10.

- Reviews of IFNG Function

Schoenborn and Wilson (2007) reviewed the regulation of IFNG during
innate and adaptive immune responses.

MOLECULAR GENETICS

The first intron of the IFNG gene contains a CA microsatellite repeat
that is highly polymorphic, with up to 6 alleles (variable number of CA
dinucleotide repeats at position 1349; VNDR 1349). Allele 2, with 12 CA
repeats (147470.0001), is associated with high levels of
interferon-gamma production in vitro (Pravica et al., 1999), which may
be due to its association with a nearby SNP within a putative NFKB
(164011) binding site. This allele has been associated with higher or
lower risk of a variety of diseases, including rheumatoid arthritis (RA;
180300) (Khani-Hanjani et al., 2000), allograft fibrosis in lung
transplant recipients (Awad et al., 1999), and acute graft-versus-host
disease (GVHD; see 614395) (Cavet et al., 2001) in bone marrow
transplant recipients.

Dabora et al. (2002) found that the frequency of the intron 1 allele 2,
with 12 CA repeats, of the IFNG gene in patients with tuberous sclerosis
(613254) with mutations in the TSC2 gene (191092) was significantly
higher in those without kidney angiomyolipomas than in those with kidney
angiomyolipomas.

Interferon-gamma mediates the final damage of the stem cell compartment
in aplastic anemia (609135). Dufour et al. (2004) studied the
distribution of the VNDR 1349 polymorphism of IFNG in 67 Caucasian
patients with aplastic anemia and in normal controls. Homozygosity for
allele 2 (12 repeats on each chromosome) or the 12 repeats on only 1
chromosome were significantly more frequent (p = 0.005 and 0.004,
respectively) in patients versus controls. The polymorphism was equally
distributed in aplastic anemia patients regardless of their response to
immunosuppression. Dufour et al. (2004) concluded that homozygosity for
12 CA repeats at position 1349 of the IFNG gene is strongly associated
with the risk of aplastic anemia in Caucasian subjects.

To test the hypothesis that a polymorphism in IFNG is associated with
susceptibility to tuberculosis (TB), Rossouw et al. (2003) conducted 2
independent studies. In a case-control study of 313 tuberculosis cases,
they noted a significant association between a polymorphism (+874A-T;
147570.0002) in IFNG and protection against tuberculosis (607948) in a
South African population (p = 0.0055). This finding was replicated in a
family-based study, in which the transmission disequilibrium test was
used in 131 families (p = 0.005). The transcription factor NF-kappa-B
(NFKB1; 164011) binds preferentially to the +874T allele, which was
overrepresented in controls, suggesting that genetically-determined
variability in IFNG and expression might be important for the
development of tuberculosis.

In a case-control study of 682 TB patients and 619 controls from 3 West
African countries (Gambia, Guinea-Bissau, and Guinea-Conakry), Cooke et
al. (2006) observed the IFNG +874AA genotype more frequently in TB
patients than controls, but the trend was not statistically significant.
However, the +874A-T SNP was in strong linkage disequilibrium with 2
other SNPs, -1616G-A and +3234T-C, and both the -1616GG and +3234TT
genotypes were significantly associated with TB. Haplotype analysis in a
smaller Gambian population sample showed that the 3 alleles putatively
associated with TB were all found on the most common West African
haplotype, which, although overtransmitted, was not significantly
associated with disease in this smaller population. Cooke et al. (2006)
concluded that there is a significant role for genetic variation in IFNG
in susceptibility to TB.

Huang et al. (2007) genotyped 8 SNPs spanning the entire 5.4-kb IFNG
gene in 2 large cohorts of hepatitis C virus (HCV; see 609532)-positive
patients, one consisting of IFNA (147660)-treated patients, and the
other consisting of intravenous drug users who had spontaneously cleared
HCV infection or who had chronic HCV infection. One SNP, a C-to-G change
at position -764 (147570.0004; dbSNP rs2069707) in the proximal promoter
region next to the binding motif for HSF1 (140580), was significantly
associated with sustained virologic response to IFNA therapy in the
first cohort and with spontaneous recovery in the second cohort.
Luciferase reporter and EMSA analyses showed that the -764G allele had
2- to 3-fold higher promoter activity and stronger binding affinity for
HSF1 than the -764C allele. Huang et al. (2007) concluded that the
-764C-G SNP is functionally important in determining viral clearance and
treatment response in HCV-infected patients.

NOMENCLATURE

Diaz et al. (1993), with the approval of the Nomenclature Committee of
the International Society of Interferon Research, tabulated the
nomenclature for the human interferon genes.

ANIMAL MODEL

Badovinac et al. (2000) showed that Ifng knockout mice failed to
eliminate Listeria monocytogenes as rapidly as wildtype mice but had a
higher number of antigen-specific cytotoxic CD8 cells due to the higher
number of cells responding to relatively nonimmunodominant antigens, as
measured by intracellular cytokine or MHC class I tetramer staining. In
addition, there was little CD8-positive T-cell death after clearance of
infection, as seen in wildtype mice. In mice that also had a disruption
of the Prf1 gene (170280), there was a greater expansion of cytotoxic T
cells, an equivalence of cells responding to dominant antigens, and an
attenuated rate of T-cell death compared to wildtype. In contrast to
Prf1 knockout mice, Badovinac et al. (2000) found that Ifng knockout
mice cleared lymphocytic choriomeningitis virus as well as wildtype
mice. Again, there was little CD8-positive T-cell death after clearance
of infection. The authors proposed a number of hypotheses to test the
basis of altered immunodominance, a poorly understood phenomenon, and
reduced T-cell death in animals lacking Ifng. Badovinac et al. (2000)
also proposed that their findings may suggest strategies for enhancing
T-cell memory in response to vaccination.

In immunodeficient mice inoculated with human peripheral blood
mononuclear cells, Koh et al. (2004) examined transplanted human
arteries for endothelial cell and vascular smooth muscle cell
dysfunction. Within 7 to 9 days, transplanted arteries developed
endothelial cell dysfunction but remained sensitive to exogenous nitric
oxide. By 2 weeks, the grafts developed signs of vascular smooth muscle
cell dysfunction, including impaired contractility and desensitization
to NO. These T-cell dependent changes correlated with loss of
endothelial nitric oxide synthase (eNOS; 163729) and expression of iNOS.
Neutralizing IFN-gamma completely prevented both vascular dysfunction
and changes in NOS expression; neutralizing TNF reduced IFN-gamma
production and partially prevented dysfunction. Inhibiting iNOS
partially preserved responses to NO at 2 weeks and reduced graft intimal
expansion after 4 weeks in vivo. Koh et al. (2004) concluded that
IFN-gamma is a central mediator of vascular dysfunction through
dysregulation of NO production.

Barton et al. (2007) showed that herpesvirus latency, always presumed to
be parasitic as it leaves the host at risk for subsequent viral
reactivation and disease, actually confers a surprising benefit to the
host. Mice latently infected with either murine gammaherpesvirus-68 or
murine cytomegalovirus, which are genetically highly similar to the
human pathogens Epstein-Barr virus and human cytomegalovirus,
respectively, were resistant to infection with the bacterial pathogens
Listeria monocytogenes and Yersinia pestis. Latency-induced protection
was not antigen-specific but involved prolonged production of the
antiviral cytokine interferon-gamma and systemic activation of
macrophages. Latency thereby upregulates the basal activation state of
innate immunity against subsequent infections. Barton et al. (2007)
speculated that herpesvirus latency may also sculpt the immune response
to self and environmental antigens through establishment of a polarized
cytokine environment. Thus, Barton et al. (2007) concluded that whereas
the immune evasion capabilities and lifelong persistence of
herpesviruses were commonly viewed as solely pathogenic, their data
suggested that latency is a symbiotic relationship with immune benefits
for the host.

Kosaka et al. (2008) used cecal cauterization to develop a unique
experimental mouse model of intestinal adhesion. Mice developed severe
intestinal adhesion after this treatment. Adhesion development depended
upon the IFNG and STAT1 system. Natural killer T (NKT) cell-deficient
mice developed adhesion poorly, whereas they developed severe adhesion
after reconstitution with NKT cells from wildtype mice, suggesting that
NKT cell IFNG production is indispensable for adhesion formation. This
response does not depend on STAT4 (605989), STAT6 (601512), IL12 (see
161560), IL18 (600953), TNF-alpha, TLR4 (603030), or MYD88
(602170)-mediated signals. Wildtype mice increased the ratio of
plasminogen activator inhibitor type-1 (PAI1; 173360) to tPA (173370)
after cecal cauterization, whereas Ifng-null or Stat1-null mice did not,
suggesting that IFNG has a crucial role in the differential regulation
of PAI1 and tPA. Additionally, hepatocyte growth factor (HGF; 142409), a
potent mitogenic factor for hepatocytes, strongly inhibited intestinal
adhesion by diminishing IFNG production, providing a potential new way
to prevent postoperative adhesions.

Using Ifng-deficient mice and Cxcl10-deficient mice, King et al. (2009)
showed that the Ifng-Cxcl10 pathway inhibited abdominal aneurysm
formation and promoted plaque formation. They proposed that cellular
immunity may play different roles in these 2 vascular diseases.

Using mice lacking Ifngr1, Baldridge et al. (2010) showed that Ifng was
required for activation of hemopoietic stem cells and restoration of
hematopoietic stem cells expressing KSL (i.e., Kit (164920) and Sca1)
and Cd150 (SLAMF1; 603492), as well neutrophils and lymphocytes, after
infection with the chronic bacterial disease agent Mycobacterium avium.
Experiments with Ifng -/- hematopoietic stem cells showed that Ifng
stimulated hematopoietic stem cells even in the steady state, and
suggested that baseline Ifng tone may influence hematopoietic stem cell
turnover. Baldridge et al. (2010) concluded that IFNG is a regulator of
hematopoietic stem cells during homeostasis and under conditions of
infectious stress.

*FIELD* AV
.0001
TSC2 ANGIOMYOLIPOMAS, RENAL, MODIFIER OF
APLASTIC ANEMIA, SUSCEPTIBILITY TO, INCLUDED
IFNG, NT1349, 12 CA REPEATS

TSC2 Renal Angiomyolipoma Modifier

Because interferon-gamma is a useful mediator of tumor regression in
animal models of kidney tumors, and because allele 2 of the IFNG gene is
known to be highly expressed in humans, Dabora et al. (2002) examined
the influence of this IFNG genotype on the severity of renal disease in
patients with tuberous sclerosis-2 (613254) who had mutations in the
TSC2 gene (191092). The frequency of allele 2, with 12 CA repeats, was
significantly higher in the patients without kidney angiomyolipomas than
in those with kidney angiomyolipomas.

Susceptibility to Aplastic Anemia

Dufour et al. (2004) studied the distribution of the VNDR 1349
polymorphism of IFNG in 67 Caucasian aplastic anemia (609135) patients
and in normal controls. Homozygosity for allele 2 (12 repeats on each
chromosome) or the 12 repeats on only 1 chromosome were significantly
more frequent (p = 0.005 and 0.004, respectively) in patients versus
controls. The polymorphism was equally distributed in aplastic anemia
patients regardless of their response to immunosuppression. Dufour et
al. (2004) concluded that homozygosity for 12 CA repeats at position
1349 of the IFNG gene is strongly associated with the risk of aplastic
anemia in Caucasian subjects.

.0002
MYCOBACTERIUM TUBERCULOSIS, PROTECTION AGAINST
IFNG, +874A-T

A microsatellite polymorphism in the first intron of IFNG (147570.0001)
has been associated with several autoimmune and chronic inflammatory
conditions (Bream et al., 2000). One particular allele of this
microsatellite (the 12 CA repeat) is associated with increased
production of IFNG in vitro (Pravica et al., 2000), and with allograft
fibrosis in recipients of lung transplant. This association might
reflect a functional role in vivo for either the microsatellite itself
or, perhaps more probably, a functional polymorphism in linkage
disequilibrium with the 12 CA repeat. Directly adjacent to the CA repeat
region in the first intron of IFNG is located a single-nucleotide
polymorphism (+874A-T). The presence of the +874T allele and the 12 CA
repeat allele was absolute (Pravica et al., 2000). The +874A-T
polymorphism lies within a binding site for the transcription factor
NF-kappa-B (164011) and electrophoretic mobility shift assays showed
specific binding of NF-kappa-B to the allelic sequence containing the
+874T allele. Since this transcription factor induces IFNG expression,
the +874T and +874A alleles probably correlate with high and low
interferon gamma expression, respectively. In an association study and
in a family study using the transmission disequilibrium test, Rossouw et
al. (2003) implicated the +874T allele in protection against
tuberculosis (607948).

By meta-analysis of 11 studies using random effects models, Pacheco et
al. (2008) determined that the IFNG +874T allele has a significant
protective effect against tuberculosis.

.0003
ACQUIRED IMMUNODEFICIENCY SYNDROME, RAPID PROGRESSION TO
IFNG, -179G-T

An et al. (2003) reported an association between a SNP in the IFNG
promoter region, a G-to-T change at position -173, and progression to
AIDS (see 609423). In individuals with the rare -179T allele, but not in
those with the -179G allele, IFNG is inducible by TNF (191160). An et
al. (2003) studied 298 African American HIV-1 seroconverters and found
that the -179T allele was associated with accelerated progression to a
CD4 (186940) cell count below 200 and to AIDS. They noted that the SNP
is present in 4% of African Americans and in only 0.02% of European
Americans, and proposed that the increased IFNG production may cause CD4
depletion by apoptosis.

.0004
HEPATITIS C VIRUS INFECTION, RESPONSE TO THERAPY OF
IFNG, -764C-G

Huang et al. (2007) identified a SNP in the IFNG gene, a C-to-G change
at position -764 (dbSNP rs2069707) in the proximal promoter region next
to the binding motif for HSF1 (140580), that was significantly
associated with sustained virologic response to IFNA (147660) therapy in
one cohort of hepatitis C virus (HCV; see 609532)-positive patients and
with spontaneous recovery from HCV infection in another cohort of
HCV-positive patients. Luciferase reporter and EMSA analyses showed that
the -764G allele had 2- to 3-fold higher promoter activity and stronger
binding affinity for HSF1 than the -764C allele. Huang et al. (2007)
concluded that the -764C-G SNP is functionally important in determining
viral clearance and treatment response in HCV-infected patients.

*FIELD* SA
Blalock and Smith (1980); Burke (1977); Creagan et al. (1975); Devos
et al. (1982); Knight (1980); Lipinski et al. (1980); Maeda et al.
(1980); Mantei et al. (1980); Nathan et al. (1983); Zoon et al. (1980)
*FIELD* RF
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Lautenberger, J.; O'Brien, S. J.; Winkler, C. A.: A tumor necrosis
factor-alpha-inducible promoter variant of interferon-gamma accelerates
CD4-positive T cell depletion in human immunodeficiency virus-1-infected
individuals. J. Infect. Dis. 188: 228-231, 2003.

2. Awad, M.; Pravica, V.; Perrey, C.; El Gamel, A.; Yonan, N.; Sinnott,
P. J.; Hutchinson, I. V.: CA repeat allele polymorphism in the first
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31. Kosaka, H.; Yoshimoto, T.; Yoshimoto, T.; Fujimoto, J.; Nakanishi,
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34. Maeda, S.; McCandliss, R.; Gross, M.; Sloma, A.; Familletti, P.
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35. Mantei, N.; Schwarzstein, M.; Streuli, M.; Panem, S.; Nagata,
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36. Messi, M.; Giacchetto, I.; Nagata, K.; Lanzavecchia, A.; Natoli,
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37. Nathan, C. F.; Murray, H. W.; Wiebe, M. E.; Rubin, B. Y.: Identification
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38. Naylor, S. L.; Sakaguchi, A. Y.; Shows, T. B.; Law, M. L.; Goeddel,
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39. Pacheco, A. G.; Cardoso, C. C.; Moraes, M. O.: IFNG +874T/A,
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2008.

40. Pravica, V.; Asderakis, A.; Perrey, C.; Hajeer, A.; Sinnott, P.
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Immunogenet. 26: 1-3, 1999.

41. Pravica, V.; Perrey, C.; Stevens, A.; Lee, J.-H.; Hutchinson,
I. V.: A single nucleotide polymorphism in the first intron of the
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42. Rossouw, M.; Nel, H. J.; Cooke, G. S.; van Helden, P. D.; Hoal,
E. G.: Association between tuberculosis and a polymorphic NF-kappa-B
binding site in the interferon gamma gene. Lancet 361: 1871-1872,
2003.

43. Schoenborn, J. R.; Wilson, C. B.: Regulation of interferon-gamma
during innate and adaptive immune responses. Adv. Immun. 96: 41-101,
2007.

44. Shimizu, A.; Sakai, Y.; Ohno, K.; Masaki, S.; Kuwano, R.; Takahashi,
Y.; Miyashita, N.; Watanabe, T.: A molecular genetic linkage map
of mouse chromosome 10, including the Myb, S100b, Pah, Sl, and Ifg
genes. Biochem. Genet. 30: 529-535, 1992.

45. Spilianakis, C. G.; Lalioti, M. D.; Town, T.; Lee, G. R.; Flavell,
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46. Szabo, S. J.; Sullivan, B. M.; Stemmann, C.; Satoskar, A. R.;
Sleckman, B. P.; Glimcher, L. H.: Distinct effects of T-bet in T(H)1
lineage commitment and IFN-gamma production in CD4 and CD8 T cells. Science 295:
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47. Takayanagi, H.; Ogasawara, K.; Hida, S.; Chiba, T.; Murata, S.;
Sato, K.; Takaoka, A.; Yokochi, T.; Oda, H.; Tanaka, K.; Nakamura,
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48. Teles, R. M. B.; Graeber, T. G.; Krutzik, S. R.; Montoya, D.;
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49. Trent, J. M.; Olson, S.; Lawn, R. M.: Chromosomal localization
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51. Tzoneva, M.; Ganev, V.; Galabov, A.; Georgieva, K.: Selective
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52. White, A. C., Jr.; Robinson, P.; Okhuysen, P. C.; Lewis, D. E.;
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54. Zaidi, M. R.; Davis, S.; Noonan, F. P.; Graff-Cherry, C.; Hawley,
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55. Zielinski, C. E.; Mele, F.; Aschenbrenner, D.; Jarrossay, D.;
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56. Zimonjic, D. B.; Rezanka, L. J.; Evans, C. H.; Polymeropoulos,
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57. Zohlnhofer, D.; Richter, T.; Neumann, F.-J.; Nuhrenberg, T.; Wessely,
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58. Zoon, K. C.; Smith, M. E.; Bridgen, P. J.; Anfinsen, C. B.; Hunkapiller,
M. W.; Hood, L. E.: Amino terminal sequence of the major component
of human lymphoblastoid interferon. Science 207: 527-528, 1980.

*FIELD* CN
Paul J. Converse - updated: 12/20/2013
Paul J. Converse - updated: 5/24/2013
Ada Hamosh - updated: 3/21/2013
Ada Hamosh - updated: 5/4/2012
Ada Hamosh - updated: 5/6/2011
Paul J. Converse - updated: 6/25/2010
Patricia A. Hartz - updated: 3/15/2010
Paul J. Converse - updated: 5/15/2009
Matthew B. Gross - reorganized: 10/15/2008
Matthew B. Gross - updated: 10/15/2008
Paul J. Converse - updated: 10/8/2008
Ada Hamosh - updated: 6/11/2008
Paul J. Converse - updated: 7/2/2007
Ada Hamosh - updated: 5/30/2007
Paul J. Converse - updated: 3/2/2007
Paul J. Converse - updated: 7/6/2005
Ada Hamosh - updated: 6/15/2005
Victor A. McKusick - updated: 12/9/2004
Marla J. F. O'Neill - updated: 10/14/2004
Marla J. F. O'Neill - updated: 3/3/2004
Victor A. McKusick - updated: 12/23/2003
Paul J. Converse - updated: 8/5/2003
Paul J. Converse - updated: 12/16/2002
Victor A. McKusick - updated: 10/29/2002
Stylianos E. Antonarakis - updated: 3/21/2002
Paul J. Converse - updated: 3/8/2002
Ada Hamosh - updated: 1/17/2002
Paul J. Converse - updated: 8/8/2001
Stylianos E. Antonarakis - updated: 8/7/2001
Paul J. Converse - updated: 11/30/2000
Ada Hamosh - updated: 11/29/2000
Jane Kelly - updated: 8/26/1999
Ada Hamosh - updated: 5/5/1999

*FIELD* CD
Victor A. McKusick: 6/23/1986

*FIELD* ED
mgross: 12/20/2013
mgross: 5/24/2013
alopez: 4/2/2013
terry: 3/21/2013
terry: 6/6/2012
alopez: 5/7/2012
terry: 5/4/2012
mgross: 12/16/2011
alopez: 5/9/2011
terry: 5/6/2011
terry: 3/16/2011
mgross: 3/15/2011
mgross: 6/25/2010
mgross: 3/15/2010
carol: 2/18/2010
alopez: 1/13/2010
mgross: 5/18/2009
terry: 5/15/2009
mgross: 10/15/2008
mgross: 10/14/2008
mgross: 10/13/2008
terry: 10/8/2008
terry: 9/24/2008
alopez: 6/13/2008
terry: 6/11/2008
mgross: 7/12/2007
terry: 7/2/2007
alopez: 6/15/2007
terry: 5/30/2007
terry: 5/7/2007
mgross: 3/9/2007
terry: 3/2/2007
terry: 7/26/2006
mgross: 7/6/2005
alopez: 6/15/2005
terry: 6/15/2005
terry: 2/22/2005
carol: 1/4/2005
tkritzer: 12/27/2004
terry: 12/9/2004
carol: 11/5/2004
carol: 10/15/2004
terry: 10/14/2004
terry: 7/27/2004
carol: 3/3/2004
cwells: 12/24/2003
terry: 12/23/2003
cwells: 8/5/2003
alopez: 1/9/2003
mgross: 12/16/2002
carol: 11/18/2002
tkritzer: 10/29/2002
terry: 10/29/2002
mgross: 3/21/2002
mgross: 3/8/2002
alopez: 1/22/2002
terry: 1/17/2002
carol: 9/13/2001
mgross: 8/8/2001
mgross: 8/7/2001
mgross: 11/30/2000
mgross: 11/29/2000
carol: 8/26/1999
alopez: 7/20/1999
alopez: 5/7/1999
terry: 5/5/1999
alopez: 6/26/1997
terry: 3/12/1997
mark: 2/5/1996
terry: 1/29/1996
mark: 8/17/1995
jason: 6/22/1994
carol: 4/12/1994
pfoster: 3/30/1994
carol: 1/5/1993
carol: 12/23/1992

MIM 609135
*RECORD*
*FIELD* NO
609135
*FIELD* TI
#609135 APLASTIC ANEMIA
APLASTIC ANEMIA, SUSCEPTIBILITY TO, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
read moreaplastic anemia can be associated with mutations in the interferon-gamma
gene (IFNG; 147570), the NBS1 gene (602667), the PRF1 gene (170280), or
the SBDS gene (607444).

Aplastic anemia may also result from bone marrow failure in patients
with mutations in the TERT (187270) or the TERC (602322) gene: see
PFBMFT1 (614742) and PFBMFT2 (614743).

DESCRIPTION

Aplastic anemia is a serious disorder of the bone marrow that affects
between 2 and 5 persons per million per year. About 75% of these cases
are classified as idiopathic (Young, 2000). In about 15% of cases a drug
or infection can be identified that precipitates the aplasia, although
why only some individuals are susceptible is unclear. In about 5 to 10%
of patients, the aplastic anemia is constitutional--i.e., is familial or
presents with one or more associated somatic abnormalities.

MOLECULAR GENETICS

Interferon-gamma mediates the final damage of the stem cell compartment
in aplastic anemia. Dufour et al. (2004) studied the distribution of the
VNDR 1349 polymorphism of IFNG (147570.0001) in 67 Caucasian patients
with aplastic anemia and in normal controls. Homozygosity for allele 2
(12 repeats on each chromosome) or the 12 repeats on only 1 chromosome
were significantly more frequent (p = 0.005 and 0.004, respectively) in
patients versus controls. The polymorphism was equally distributed in
aplastic anemia patients regardless of their response to
immunosuppression. Dufour et al. (2004) concluded that homozygosity for
12 CA repeats at position 1349 of the IFNG gene is strongly associated
with the risk of aplastic anemia in Caucasian subjects.

In an 11-year-old Japanese girl with aplastic anemia, Shimada et al.
(2004) identified homozygosity for the I171V mutation in the NBS1 gene
(602667.0007). The patient had no features of NBS (251260). Cytogenetic
analysis of lymphoblastic cell lines from the patient showed a marked
increase in numerical and structural chromosomal aberrations in the
absence of clastogens, suggesting genomic instability.

Solomou et al. (2007) identified mutations in the PRF1 gene
(170280.0011-170280.0013) in 5 unrelated patients with adult-onset
aplastic anemia. Four of the 5 patients showed hemophagocytosis on bone
marrow biopsy, but none had clinical manifestations of the
hemophagocytosis syndrome (FHL2; 603553). Perforin protein levels in
these patients were very low or absent, perforin granules were absent,
and natural killer cell cytotoxicity was significantly decreased.
Solomou et al. (2007) concluded that PRF1 gene alterations may explain
aberrant proliferation and activation of cytotoxic T cells in aplastic
anemia.

Calado et al. (2007) identified a heterozygous mutation in the SBDS gene
(607444.0002) in 4 of 91 unrelated patients with aplastic anemia. These
patients were younger on average (5 to 19 years) compared to other
patients with aplastic anemia. Two mothers tested were carriers of the
mutation; these 2 and another mother who was not tested had histories of
subclinical mild anemia. Heterozygous mutation carriers had partial loss
of SBDS protein expression, indicating haploinsufficiency. Although
telomere shortening was observed in patients' granulocytes, lymphocytes
had normal telomere length. Homozygous or compound heterozygous
mutations in the SBDS gene result in Shwachman-Diamond syndrome (SDS;
260400), but none of the patients with aplastic anemia had pancreatic
exocrine failure or skeletal anomalies as seen in SDS. One of the 4
probands was also heterozygous for a presumed pathogenic variant in the
TERT gene.

*FIELD* RF
1. Calado, R. T.; Graf, S. A.; Wilkerson, K. L.; Kajigaya, S.; Ancliff,
P. J.; Dror, Y.; Chanock, S. J.; Lansdorp, P. M.; Young, N. S.: Mutations
in the SBDS gene in acquired aplastic anemia. Blood 110: 1141-1146,
2007.

2. Dufour, C.; Capasso, M.; Svahn, J.; Marrone, A.; Haupt, R.; Bacigalupo,
A.; Giordani, L.; Longoni, D.; Pillon, M.; Pistorio, A.; Di Michele,
P.; Iori, A. P.; Pongiglione, C.; Lanciotti, M.; Iolascon, A.: Homozygosis
for (12)CA repeats in the first intron of the human IFN-gamma gene
is significantly associated with the risk of aplastic anaemia in Caucasian
population. Brit. J. Haemat. 126: 682-685, 2004.

3. Shimada, H.; Shimizu, K; Mimaki, S.; Sakiyama, T.; Mori, T.; Shimasaki,
N.; Yokota, J.; Nakachi, K.; Ohta, T.; Ohki, M.: First case of aplastic
anemia in a Japanese child with a homozygous missense mutation in
the NBS1 gene (I171V) associated with genomic instability. Hum. Genet. 115:
372-376, 2004.

4. Solomou, E. E.; Gibellini, F.; Stewart, B.; Malide, D.; Berg, M.;
Visconte, V.; Green, S.; Childs, R.; Chanock, S. J.; Young, N. S.
: Perforin gene mutations in patients with acquired aplastic anemia. Blood 109:
5234-5237, 2007.

5. Young, N. S.: The etiology of acquired aplastic anemia. Rev.
Clin. Exp. Hemat. 4: 236-239, 2000.

*FIELD* CN
Cassandra L. Kniffin - updated: 2/25/2008
Cassandra L. Kniffin - updated: 9/20/2007
Marla J. F. O'Neill - updated: 4/29/2005
Victor A. McKusick - updated: 4/11/2005

*FIELD* CD
Victor A. McKusick: 1/4/2005

*FIELD* ED
carol: 08/06/2012
ckniffin: 7/26/2012
wwang: 6/25/2009
mgross: 10/15/2008
wwang: 3/5/2008
ckniffin: 2/25/2008
wwang: 9/25/2007
ckniffin: 9/20/2007
wwang: 4/29/2005
wwang: 4/28/2005
wwang: 4/20/2005
terry: 4/11/2005
tkritzer: 1/4/2005
carol: 1/4/2005