|Mutation Type||critical splice donor site|
|Coordinate||19,601,485 bp (GRCm38)|
|Base Change||T ⇒ C (forward strand)|
|Gene Name||interferon gamma receptor 1|
|Synonym(s)||CD119, Ifgr, IFN-gamma R, Nktar, Ifngr, IFN-gammaR|
|Chromosomal Location||19,591,949-19,610,229 bp (+)|
FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] This gene (IFNGR1) encodes the ligand-binding chain (alpha) of the gamma interferon receptor. Human interferon-gamma receptor is a heterodimer of IFNGR1 and IFNGR2. A genetic variation in IFNGR1 is associated with susceptibility to Helicobacter pylori infection. In addition, defects in IFNGR1 are a cause of mendelian susceptibility to mycobacterial disease, also known as familial disseminated atypical mycobacterial infection. [provided by RefSeq, Jul 2008]
PHENOTYPE: Mice homozygous for a mutant allele exhibit increased susceptibility to viral infection and experimental autoimmune uveoretinitis. [provided by MGI curators]
|Amino Acid Change|
|Institutional Source||Beutler Lab|
|Gene Model||predicted gene model for protein(s): [ENSMUSP00000020188 †] [ENSMUSP00000129309] † probably from a misspliced transcript|
|Predicted Effect||probably null|
|Predicted Effect||probably null|
|Predicted Effect||probably benign|
|Predicted Effect||noncoding transcript|
|Predicted Effect||noncoding transcript|
|Meta Mutation Damage Score||0.9589|
|Is this an essential gene?||Non Essential (E-score: 0.000)|
|Candidate Explorer Status||CE: potential candidate; Verification probability: 0.303; ML prob: 0.334; human score: 0|
Linkage Analysis Data
|Alleles Listed at MGI|
|Mode of Inheritance||Autosomal Recessive|
|Last Updated||2020-07-29 6:45 PM by External Program|
|Record Created||2016-02-28 11:28 AM by Bruce Beutler|
The marigold phenotype was identified among G3 mice of the pedigree R4089, some of which showed an increased frequency of B cells (Figure 1), an increased IgD+ B cell percentage (Figure 2), an increased frequency of IgM+ B cells (Figure 3), and a diminished macrophage frequency (Figure 4), all in the peripheral blood. Some mice also exhibited reduced TNFα secretion from macrophages in response to the Toll-like receptor 3 (TLR3) ligand, poly(I:C), and priming with interferon (IFN)-γ (Figure 5).
|Nature of Mutation|
Whole exome HiSeq sequencing of the G1 grandsire (R4089) identified 50 mutations. All of the above anomalies were linked by continuous variable mapping to a mutation in Ifngr1: a T to C transition at base pair 19,601,485 (v38) on chromosome 10, or base pair 9,528 in the GenBank genomic region NC_000076 within the donor splice site of intron 3 in Ifngr1. The strongest association was found with a recessive model of linkage to the normalized amount of TNFα secretion from macrophages after poly(I:C) + IFN-γ treatment, wherein six variant homozygotes departed phenotypically from eight homozygous reference mice and 24 heterozygous mice with a P value of 2.608 x 10-8 (Figure 6). A substantial semidominant effect was also observed in most of the assays and a dominant effect with seen in the B cell and IgD+ B cell assays.
The effects of the mutation at the cDNA and protein level have not examined, but the mutation could result in skipping of the 164-nucleotide exon 3 (out of 7 total exons). Deletion of exon 3 would result in a frame-shift and coding of 24 aberrant amino acids followed by a premature stop codon after amino acid 100.
Genomic numbering corresponds to NC_000076. The donor splice site of intron 3, which is destroyed by the marigold mutation, is indicated in blue lettering and the mutated nucleotide is indicated in red.
|Illustration of Mutations in
Gene & Protein
Ifngr1 encodes the ligand-binding chain of the IFN-γ receptor (IFN-γR1) that, along with IFN-γR2 (encoded by Ifngr2), forms the type II IFN receptor (IFN-γR). The IFN-γR binds to type II interferon, namely the IFN-γ homodimer (1). IFN-γR1 is a member of the class II cytokine receptor family, which includes IFNAR1, IFNAR2, tissue factor (TF), and interleukin (IL)-10 (2). IFN-γR1 has a single transmembrane domain at amino acids 255-275 (Figure 7). The extracellular ligand-binding regions of these receptors (amino acids 26-254 in IFN-γR1; amino acids 1-25 constitute a signal peptide) all share fibronectin type III (FNIII) domains similar to the constant region of immunoglobin (Ig). Most of these receptors contain two of these domains, each containing ~100 amino acids with seven β-strands and connecting loops.
IFN-γR1 binds IFN-γ in a 1:2 complex (3;4). Subsequently, two copies of IFN-γR2 bind forming a 1:2:2 signaling complex (5). The crystal structure of a single copy of 229 amino acids of the extracellular domain of human IFN-γR1 bound to the monovalent form of IFN-γ has been solved (Figure 8; PDB:1FYH; (6;7)). The IFN-γR monomer folds into six α-helices connected by short loops (6). In the IFN-γR dimer, the first four helices of one monomer (helices A–D) and the last two helices of the second monomer (helices E' and F') form a structural domain. A short linker connects the two FNIII domains in the extracellular domain of IFN-γR1. The β-sandwich formed by each FNIII repeat consists of a three-stranded (A, B, E) and a four-stranded (G, F, C, C') β-sheet. The receptor interface that mediates the interaction with IFN-γ consists of strands C, F, and G, as well as the CC' and EF loops of the first FNIII domain (D1; membrane distal); the short helix (α2) of the interdomain linker; and strand F, as well as the BC, C'E, and FG loops of the second FNIII domain (D2; membrane proximal). Each D domain folds into two β-strands consisting of β-pleated sheets. The D domains are separated by an 11 amino acid linker and are oriented at an angle of 120° relative to one another. The membrane proximal D2 domain is positioned at a 60° angle relative to the cell membrane (4).
The IFN-γR receptor is typical of class II helical cytokine receptors and lacks intrinsic kinase activity. Instead, the intracellular domains of the IFN-γR receptor subunits are associated with Janus activating kinases (JAKs) that phosphorylate receptors and signal transducing molecules (see Background). In particular, IFN-γR1 binds to JAK1 and IFN-γR2 binds to JAK2. Once phosphorylated, JAK1 recruits signal transducer and activator of transcription (STAT)1 (see the records for domino and poison). Tyr441 of IFNAR1 associates with negative regulators of type I IFN signaling such as suppressor of cytokine signaling 1 (SOCS1) (8). Mutation of Tyr441 to phenylalanine (Tyr441Phe) resulted in impaired negative regulation of IFN-γ signaling. IFN-γ-induced STAT1 was prolonged in the Tyr441Phe cells.
A YVSLI motif at amino acids 287-291 is essential for IFN-γ-induced IFN-γR1 internalization (see Expression and Localization) and function (9). IFN-γR1 is N-linked glycosylated at Asn61 and Asn85 within the extracellular domain (10;11).
The marigold mutation is predicted to result in deletion of exon 3. Deletion of exon 3 would result in a frame-shift and coding of 24 aberrant amino acids followed by a premature stop codon after amino acid 100 within the ligand-binding domain. Expression and function of IFNGR1marigold have not been assessed.
IFN-γR1 is constitutively expressed at moderate levels on the surface of most cells. Upon exposure to IFN-γ, IFN-γR1 translocates to the nucleus (12-14). IFN-γ has a nuclear localization sequence at its C-terminus that mediates the translocation of the IFN-γR1/IFN-γ complex to the nucleus via receptor-mediated endocytosis (12). After endocytosis, the C-terminus of IFN-γ interacts with the intracellular domain of IFN-γR1 (amino acids 253-287) (15). IFN-γ, IFN-γR1, and STAT1 all can bind to IFN-γ-activated sequence response (GAS) element in the promoter region of IFN-γ-activated genes (e.g., IRF-1 and indoleamine dioxygenase) (16). Upon binding to the GAS element, IFN-γ and IFN-γR1 enhance transcription. IFN-γR1 does not have a DNA-binding domain, but binding to STAT1 at the GAS element may result in the IFN-γR1-associated increased transcriptional activity.
The IFN-γ-associated signaling pathway is a canonical signaling pathway activating STAT proteins, called the JAK (Janus kinase)-STAT pathway. Upon IFN-γ to the IFN-γR, the IFN-γR associates with JAK1 and JAK2 (17). The JAK tyrosine kinases are normally dephosphorylated and inactive. Receptor stimulation results in dimerization/oligomerization and subsequent apposition of JAK proteins, which are now capable of trans-phosphorylation as they are brought in close proximity (18). This activates JAKs to phosphorylate the receptor cytoplasmic domains, creating phosphotyrosine ligands for the SH2 domains of STAT proteins. In the IFN-γ-associated signaling pathway, the JAK1/JAK2 recruit STAT1. Once recruited to the receptor, STAT proteins are also tyrosine phosphorylated by JAKs, a phosphorylation event which occurs on a single tyrosine residue that is found at around residue 700 of all STATs. Tyrosine phosphorylation of STATs may allow formation and/or conformational reorganization of the activated STAT dimer, involving reciprocal SH2 domain-phosphotyrosine interactions between STAT monomers. In addition to tyrosine phosphorylation, several STATs including STAT1, also require phosphorylation on a serine in the TAD for full activation (19;20). In STAT1, this serine is residue 727, and it exists within a consensus MAPK phosphorylation site (19). Phosphorylated, activated STATs enter the nucleus and accumulate there to promote transcription (21). They do so by facilitated transport involving importin-α5, a subunit of the nucleocytoplasmic transport machinery (22). Termination of transcriptional activation appears to require nuclear dephosphorylation by at least one nuclear phosphatase, TC45 (23). Once dephosphorylated, STAT1 may be exported through the chromosome region maintenance 1 (CRM1) export receptor (24). Additional STAT protein nuclear inhibitors are the PIAS (protein inhibitor of activated STAT) proteins (25). PIAS proteins interact directly with phosphorylated STATs and block DNA binding.
Termination of STAT signaling requires ending both transcriptional activation and cytoplasmic STAT signaling. In the cytoplasm, there are several mechanisms to halt signaling. First, the suppressors of cytokine signaling (SOCS) proteins can directly bind and suppress JAKs or can compete with STATs for receptor binding (26;27). SOCS proteins are induced transcriptionally by cytokine stimulation, and recruited to active receptor complexes to induce inhibition. Second, protein tyrosine phosphatases including SHP1 and SHP2 prevent further cytoplasmic STAT tyrosine phosphorylation (28;29). Third, the β isoforms of some STATs can function as dominant negative inhibitors in certain circumstances. STAT1β apparently activates a distinct set of genes from STAT1α, and STAT1β fails to complement impaired IFN-γ-induced α-specific gene activation in STAT1-deficient cells (30).
IFN-γ has several known functions. IFN-γ mediates host defense against infectious agents and tumors, and is synthesized exclusively by T lymphocytes and natural killer cells upon immune and inflammatory stimuli. Similar to type I IFN, IFN-γ protects cells from viral infection and mediates antiproliferative effects on normal and neoplastic cells. IFN-γ is the primary cytokine that upregulates MHC class I protein expression and induces MHC class II proteins on leukocytes and epithelial cells. IFN-γ also promotes the activation and regulation of mononuclear phagocytes. During humoral immune responses, IFN-γ promotes IgG heavy chain switching. In addition, IFN-γ regulates proinflammatory cytokine production, including IL-12 and TNFα. IFN-γ induces macrophage activation, host defense against intracellular pathogens, and Th1 type cell-associated inflammation (31). IFN-γ signaling in dendritic cells controls T cell expansion. IFN-γ signaling has cell-specific functions. In neutrophils, IFN-γ signaling regulates T cell expansion and inflammation. In non-hematopoietic cells, IFN-γ signaling is proposed to control inflammation. IFN-γ signaling is not necessary for the expansion, contraction, and memory differentiation of CD8+ T cells in response to peptide vaccination (32). However, IFN-γ signaling counterregulates CD8+ T cell responses and the generation of effector memory T cell processes. IFN-γ signaling limits the expansion of naïve CD8+ T cells and their differentiation into effector memory-like T cells.
Ifngr1-deficient (Ifngr1−/−) mice are overtly normal, but exhibit impaired resistance to infection by several microbial pathogens such as Listeria monocytogenes and Leishmania major as well as myocobacteria species, including M. bovis and M. avium (33;34). Ifngr1−/− mice develop normal helper and cytotoxic T cell responses to the pathogens (33;35). Ifngr1−/− mice are able to mount immune responses to many viruses (36). However, Ifngr1−/− mice exposed to murine cytomegalovirus (MCMV) infection exhibit chronic aortic inflammation (37). In addition, the infected Ifngr1−/− mice showed MCMV viral titers in the spleen, peritoneal exudate cells, and salivary gland up to six months after infection, while control mice cleared the infection. Ifngr1−/− mice developed experimental autoimmune uveoretinitis after subcutaneous immunization with Bordetella pertussis toxin (38). Ifngr1−/− mice exhibited an increased resistance to lipopolysaccharide [LPS]-induced shock (39). A separate study found that Ifngr1−/− mice failed to develop IFN-γ-mediated antiviral responses (40). Ifngr1−/− mice exhibited delayed clearance of a neuroadapted strain of sindbis virus from the brain and spinal cord as well as lower levels of TNFα and IL-6 mRNAs than infected wild-type mice (40). In contrast, the Ifngr1−/− mice exhibited more inflammation marked by increased expression of MHCII and IL-17A mRNAs than wild-type mice. Ifngr1−/− mice treated with curprizone, a demyelination inducer, exhibited delayed demyelination compared to wild-type mice (41). After removal of the cuprizone from the diet, the Ifngr1−/− mice exhibited accelerated remyelination in the corpus callosum due to enhanced recruitment of new oligodendrocytes in the demyelinated areas. Taken together, IFN-γ is proposed to regulate the development and resolution of demyelinating syndromes such as multiple sclerosis.
Polymorphisms in human IFNGR1 have been implicated in a number of diseases including autosomal recessive immunodeficiency 27A [OMIM: #209950; (42;43)] and autosomal dominant immunodeficiency 27B [OMIM: #615978; (44;45)]. Immunodeficiences 27A and 27B are predispositions to diseases caused by weakly virulent mycobacteria. Patients with immunodeficiency 27A or 27B are otherwise overtly normal. The mycobacteriosis usually begins in childhood and can cause either localized or disseminated infections upon exposure to mycobacteria. Polymorphisms in IFNGR1 also are linked to increased susceptibility to Helicobacter pylori [OMIM: #600263; (46)], hepatitis B [OMIM: #610424; (47)], and Tuberculosis infections (OMIM: #607948).
The immune phenotypes observed in the marigold mice indicate loss of IFNGR1marigold function.
1) 94°C 2:00
The following sequence of 624 nucleotides is amplified (chromosome 10, + strand):
1 taggggttcc tggactgatt cctgcaccaa catttctgat cattgttgta atatctatga
Primer binding sites are underlined and the sequencing primers are highlighted; the mutated nucleotide is shown in red.
1. Ealick, S. E., Cook, W. J., Vijay-Kumar, S., Carson, M., Nagabhushan, T. L., Trotta, P. P., and Bugg, C. E. (1991) Three-Dimensional Structure of Recombinant Human Interferon-Gamma. Science. 252, 698-702.
2. Bazan, J. F. (1990) Structural Design and Molecular Evolution of a Cytokine Receptor Superfamily. Proc Natl Acad Sci U S A. 87, 6934-6938.
3. Thiel, D. J., le Du, M. H., Walter, R. L., D'Arcy, A., Chene, C., Fountoulakis, M., Garotta, G., Winkler, F. K., and Ealick, S. E. (2000) Observation of an Unexpected Third Receptor Molecule in the Crystal Structure of Human Interferon-Gamma Receptor Complex. Structure. 8, 927-936.
4. Walter, M. R., Windsor, W. T., Nagabhushan, T. L., Lundell, D. J., Lunn, C. A., Zauodny, P. J., and Narula, S. K. (1995) Crystal Structure of a Complex between Interferon-Gamma and its Soluble High-Affinity Receptor. Nature. 376, 230-235.
5. Bach, E. A., Aguet, M., and Schreiber, R. D. (1997) The IFN Gamma Receptor: A Paradigm for Cytokine Receptor Signaling. Annu Rev Immunol. 15, 563-591.
6. Randal, M., and Kossiakoff, A. A. (2001) The Structure and Activity of a Monomeric Interferon-Gamma:Alpha-Chain Receptor Signaling Complex. Structure. 9, 155-163.
7. Randal, M., and Kossiakoff, A. A. (1998) Crystallization and Preliminary X-Ray Analysis of a 1:1 Complex between a Designed Monomeric Interferon-Gamma and its Soluble Receptor. Protein Sci. 7, 1057-1060.
8. Starr, R., Fuchsberger, M., Lau, L. S., Uldrich, A. P., Goradia, A., Willson, T. A., Verhagen, A. M., Alexander, W. S., and Smyth, M. J. (2009) SOCS-1 Binding to Tyrosine 441 of IFN-Gamma Receptor Subunit 1 Contributes to the Attenuation of IFN-Gamma Signaling in Vivo. J Immunol. 183, 4537-4544.
9. Yancoski, J., Sadat, M. A., Aksentijevich, N., Bernasconi, A., Holland, S. M., and Rosenzweig, S. D. (2012) A Novel Internalization Motif Regulates Human IFN-Gamma R1 Endocytosis. J Leukoc Biol. 92, 301-308.
10. Mao, C., Aguet, M., and Merlin, G. (1989) Molecular Characterization of the Human Interferon-Gamma Receptor: Analysis of Polymorphism and Glycosylation. J Interferon Res. 9, 659-669.
11. Hershey, G. K., and Schreiber, R. D. (1989) Biosynthetic Analysis of the Human Interferon-Gamma Receptor. Identification of N-Linked Glycosylation Intermediates. J Biol Chem. 264, 11981-11988.
12. Ahmed, C. M., Burkhart, M. A., Mujtaba, M. G., Subramaniam, P. S., and Johnson, H. M. (2003) The Role of IFNgamma Nuclear Localization Sequence in Intracellular Function. J Cell Sci. 116, 3089-3098.
13. Larkin, J.,3rd, Johnson, H. M., and Subramaniam, P. S. (2000) Differential Nuclear Localization of the IFNGR-1 and IFNGR-2 Subunits of the IFN-Gamma Receptor Complex Following Activation by IFN-Gamma. J Interferon Cytokine Res. 20, 565-576.
14. Subramaniam, P. S., Larkin, J.,3rd, Mujtaba, M. G., Walter, M. R., and Johnson, H. M. (2000) The COOH-Terminal Nuclear Localization Sequence of Interferon Gamma Regulates STAT1 Alpha Nuclear Translocation at an Intracellular Site. J Cell Sci. 113 ( Pt 15), 2771-2781.
15. Subramaniam, P. S., Torres, B. A., and Johnson, H. M. (2001) So Many Ligands, so Few Transcription Factors: A New Paradigm for Signaling through the STAT Transcription Factors. Cytokine. 15, 175-187.
16. Ahmed, C. M., and Johnson, H. M. (2006) IFN-Gamma and its Receptor Subunit IFNGR1 are Recruited to the IFN-Gamma-Activated Sequence Element at the Promoter Site of IFN-Gamma-Activated Genes: Evidence of Transactivational Activity in IFNGR1. J Immunol. 177, 315-321.
17. Kotenko, S. V., Izotova, L. S., Pollack, B. P., Mariano, T. M., Donnelly, R. J., Muthukumaran, G., Cook, J. R., Garotta, G., Silvennoinen, O., and Ihle, J. N. (1995) Interaction between the Components of the Interferon Gamma Receptor Complex. J Biol Chem. 270, 20915-20921.
18. Igarashi, K., Garotta, G., Ozmen, L., Ziemiecki, A., Wilks, A. F., Harpur, A. G., Larner, A. C., and Finbloom, D. S. (1994) Interferon-Gamma Induces Tyrosine Phosphorylation of Interferon-Gamma Receptor and Regulated Association of Protein Tyrosine Kinases, Jak1 and Jak2, with its Receptor. J Biol Chem. 269, 14333-14336.
19. Wen, Z., Zhong, Z., and Darnell, J. E.,Jr. (1995) Maximal Activation of Transcription by Stat1 and Stat3 Requires both Tyrosine and Serine Phosphorylation. Cell. 82, 241-250.
20. Pilz, A., Ramsauer, K., Heidari, H., Leitges, M., Kovarik, P., and Decker, T. (2003) Phosphorylation of the Stat1 Transactivating Domain is Required for the Response to Type I Interferons. EMBO Rep. 4, 368-373.
21. Schindler, C., Shuai, K., Prezioso, V. R., and Darnell, J. E.,Jr. (1992) Interferon-Dependent Tyrosine Phosphorylation of a Latent Cytoplasmic Transcription Factor. Science. 257, 809-813.
22. McBride, K. M., Banninger, G., McDonald, C., and Reich, N. C. (2002) Regulated Nuclear Import of the STAT1 Transcription Factor by Direct Binding of Importin-Alpha. EMBO J. 21, 1754-1763.
23. ten Hoeve, J., de Jesus Ibarra-Sanchez, M., Fu, Y., Zhu, W., Tremblay, M., David, M., and Shuai, K. (2002) Identification of a Nuclear Stat1 Protein Tyrosine Phosphatase. Mol Cell Biol. 22, 5662-5668.
24. McBride, K. M., McDonald, C., and Reich, N. C. (2000) Nuclear Export Signal Located within theDNA-Binding Domain of the STAT1transcription Factor. EMBO J. 19, 6196-6206.
25. Chung, C. D., Liao, J., Liu, B., Rao, X., Jay, P., Berta, P., and Shuai, K. (1997) Specific Inhibition of Stat3 Signal Transduction by PIAS3. Science. 278, 1803-1805.
26. Endo, T. A., Masuhara, M., Yokouchi, M., Suzuki, R., Sakamoto, H., Mitsui, K., Matsumoto, A., Tanimura, S., Ohtsubo, M., Misawa, H., Miyazaki, T., Leonor, N., Taniguchi, T., Fujita, T., Kanakura, Y., Komiya, S., and Yoshimura, A. (1997) A New Protein Containing an SH2 Domain that Inhibits JAK Kinases. Nature. 387, 921-924.
27. Naka, T., Narazaki, M., Hirata, M., Matsumoto, T., Minamoto, S., Aono, A., Nishimoto, N., Kajita, T., Taga, T., Yoshizaki, K., Akira, S., and Kishimoto, T. (1997) Structure and Function of a New STAT-Induced STAT Inhibitor. Nature. 387, 924-929.
28. David, M., Chen, H. E., Goelz, S., Larner, A. C., and Neel, B. G. (1995) Differential Regulation of the alpha/beta Interferon-Stimulated Jak/Stat Pathway by the SH2 Domain-Containing Tyrosine Phosphatase SHPTP1. Mol Cell Biol. 15, 7050-7058.
29. You, M., Yu, D. H., and Feng, G. S. (1999) Shp-2 Tyrosine Phosphatase Functions as a Negative Regulator of the Interferon-Stimulated Jak/STAT Pathway. Mol Cell Biol. 19, 2416-2424.
30. Muller, M., Laxton, C., Briscoe, J., Schindler, C., Improta, T., Darnell, J. E.,Jr., Stark, G. R., and Kerr, I. M. (1993) Complementation of a Mutant Cell Line: Central Role of the 91 kDa Polypeptide of ISGF3 in the Interferon-Alpha and -Gamma Signal Transduction Pathways. EMBO J. 12, 4221-4228.
31. Singh, U. P., Singh, S., Iqbal, N., Weaver, C. T., McGhee, J. R., and Lillard, J. W.,Jr. (2003) IFN-Gamma-Inducible Chemokines Enhance Adaptive Immunity and Colitis. J Interferon Cytokine Res. 23, 591-600.
32. Sercan, O., Stoycheva, D., Hammerling, G. J., Arnold, B., and Schuler, T. (2010) IFN-Gamma Receptor Signaling Regulates Memory CD8+ T Cell Differentiation. J Immunol. 184, 2855-2862.
33. Huang, S., Hendriks, W., Althage, A., Hemmi, S., Bluethmann, H., Kamijo, R., Vilcek, J., Zinkernagel, R. M., and Aguet, M. (1993) Immune Response in Mice that Lack the Interferon-Gamma Receptor. Science. 259, 1742-1745.
34. Dalton, D. K., Pitts-Meek, S., Keshav, S., Figari, I. S., Bradley, A., and Stewart, T. A. (1993) Multiple Defects of Immune Cell Function in Mice with Disrupted Interferon-Gamma Genes. Science. 259, 1739-1742.
35. Kamijo, R., Le, J., Shapiro, D., Havell, E. A., Huang, S., Aguet, M., Bosland, M., and Vilcek, J. (1993) Mice that Lack the Interferon-Gamma Receptor have Profoundly Altered Responses to Infection with Bacillus Calmette-Guerin and Subsequent Challenge with Lipopolysaccharide. J Exp Med. 178, 1435-1440.
36. Muller, U., Steinhoff, U., Reis, L. F., Hemmi, S., Pavlovic, J., Zinkernagel, R. M., and Aguet, M. (1994) Functional Role of Type I and Type II Interferons in Antiviral Defense. Science. 264, 1918-1921.
37. Presti, R. M., Pollock, J. L., Dal Canto, A. J., O'Guin, A. K., and Virgin, H. W.,4th. (1998) Interferon Gamma Regulates Acute and Latent Murine Cytomegalovirus Infection and Chronic Disease of the Great Vessels. J Exp Med. 188, 577-588.
38. Fukushima, A., Yamaguchi, T., Ishida, W., Fukata, K., Udaka, K., and Ueno, H. (2005) Mice Lacking the IFN-Gamma Receptor Or Fyn Develop Severe Experimental Autoimmune Uveoretinitis Characterized by Different Immune Responses. Immunogenetics. 57, 337-343.
39. Car, B. D., Eng, V. M., Schnyder, B., Ozmen, L., Huang, S., Gallay, P., Heumann, D., Aguet, M., and Ryffel, B. (1994) Interferon Gamma Receptor Deficient Mice are Resistant to Endotoxic Shock. J Exp Med. 179, 1437-1444.
40. Lee, E. Y., Schultz, K. L., and Griffin, D. E. (2013) Mice Deficient in Interferon-Gamma Or Interferon-Gamma Receptor 1 have Distinct Inflammatory Responses to Acute Viral Encephalomyelitis. PLoS One. 8, e76412.
41. Mana, P., Linares, D., Fordham, S., Staykova, M., and Willenborg, D. (2006) Deleterious Role of IFNgamma in a Toxic Model of Central Nervous System Demyelination. Am J Pathol. 168, 1464-1473.
42. Jouanguy, E., Altare, F., Lamhamedi, S., Revy, P., Emile, J. F., Newport, M., Levin, M., Blanche, S., Seboun, E., Fischer, A., and Casanova, J. L. (1996) Interferon-Gamma-Receptor Deficiency in an Infant with Fatal Bacille Calmette-Guerin Infection. N Engl J Med. 335, 1956-1961.
43. Newport, M. J., Huxley, C. M., Huston, S., Hawrylowicz, C. M., Oostra, B. A., Williamson, R., and Levin, M. (1996) A Mutation in the Interferon-Gamma-Receptor Gene and Susceptibility to Mycobacterial Infection. N Engl J Med. 335, 1941-1949.
44. Storgaard, M., Varming, K., Herlin, T., and Obel, N. (2006) Novel Mutation in the Interferon-Gamma-Receptor Gene and Susceptibility to Mycobacterial Infections. Scand J Immunol. 64, 137-139.
45. Dorman, S. E., Picard, C., Lammas, D., Heyne, K., van Dissel, J. T., Baretto, R., Rosenzweig, S. D., Newport, M., Levin, M., Roesler, J., Kumararatne, D., Casanova, J. L., and Holland, S. M. (2004) Clinical Features of Dominant and Recessive Interferon Gamma Receptor 1 Deficiencies. Lancet. 364, 2113-2121.
46. Thye, T., Burchard, G. D., Nilius, M., Muller-Myhsok, B., and Horstmann, R. D. (2003) Genomewide Linkage Analysis Identifies Polymorphism in the Human Interferon-Gamma Receptor Affecting Helicobacter Pylori Infection. Am J Hum Genet. 72, 448-453.
|Science Writers||Anne Murray|
|Authors||Lei Sun, Ying Wang, Bruce Beutler|