Alternative titles; symbols
HGNC Approved Gene Symbol: IFNGR1
SNOMEDCT: 718230004;
Cytogenetic location: 6q23.3 Genomic coordinates (GRCh38): 6:137,197,484-137,219,385 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6q23.3 | {H. pylori infection, susceptibility to} | 600263 | 3 | |
| {Hepatitis B virus infection, susceptibility to} | 610424 | 3 | ||
| {Tuberculosis infection, protection against} | 607948 | 3 | ||
| {Tuberculosis, susceptibility to} | 607948 | 3 | ||
| Immunodeficiency 27A, mycobacteriosis, AR | 209950 | Autosomal recessive | 3 | |
| Immunodeficiency 27B, mycobacteriosis, AD | 615978 | Autosomal dominant | 3 |
Interferons may be regarded as polypeptide hormones because of their role in communicating from cell to cell a specific set of instructions that lead to a wide variety of effects. Viruses induce type I interferon, subdivided into alpha-interferon (IFNA1; 147660), produced by leukocytes or lymphoblastoid cells, and beta-interferon (IFNB1; 147640), produced by fibroblasts. Mitogens and antigenic stimuli induce in lymphocytes type II, immune, or gamma-interferon (IFNG; 147570). The biologic effects of human interferons, including increment of histocompatibility antigens, are mediated through species-specific receptors. Human interferons are not active, for example, in mouse cells. The human interferon-gamma receptor is a heterodimer of IFNGR1 and IFNGR2 (147569). IFNGR1 is the ligand-binding subunit.
Branca and Baglioni (1981) concluded that types I and II interferons have different receptors. Celada et al. (1985) demonstrated and partially characterized the interferon-gamma receptor on macrophages. Interferon-gamma has an important role in activating macrophages in host defenses.
Novick et al. (1987) purified and characterized the gamma-interferon receptor. They referred to their work (Orchansky et al., 1986) suggesting that human cells of hematopoietic origin may have an IFNG receptor that is structurally and functionally different from the receptor in cells of nonhematopoietic origin. Rettig et al. (1988) reported results with a panel of 22 monoclonal antibodies recognizing 21 distinct human cell surface antigens. The genes responsible for these were mapped to multiple sites. According to the human gene mapping nomenclature, the genes were designated by the name of the laboratory, Sloan-Kettering. For example, MSK28 mapped to chromosome 6 in the same vicinity as that of immune interferon receptor and may indeed be the same antigen.
Using a polyclonal anti-IFNGR1 antibody to screen a Raji cell cDNA expression library, Aguet et al. (1988) isolated a cDNA encoding IFNGR1. Sequence analysis predicted that the 489-amino acid protein contains an N-terminal signal peptide, 7 potential N-linked glycosylation sites, several ser- and thr-rich regions indicative of potential O-linked glycosylation sites, a transmembrane domain, and an approximately 223-residue cytoplasmic portion. Northern blot analysis revealed expression of a 2.3-kb transcript in monocytes, lymphocytes, placenta, and a colon carcinoma cell line. Immunoblot analysis showed expression of ligand-binding 90- and 50-kD proteins, with the latter likely a proteolytic degradation product that lacks the intracellular region.
Aguet et al. (1988) found that expression of IFNGR1 in mouse cells insensitive to human IFNG demonstrated high-affinity binding of IFNG.
Using confocal microscopy, Maldonado et al. (2004) found a random distribution of Tcrb (see 186930), Il4r (147781), and Ifngr1 in fixed and permeabilized mouse naive T-helper lymphocytes (Thp) conjugated with mouse mature splenic dendritic cells (DCs). In cells fixed and permeabilized 30 minutes after conjugation of Thp and antigen-loaded DCs, the authors observed a calcium- and Ifng-dependent colocalization of Tcrb and Ifngr1, but not Il4r, at the Thp-DC interface. This observation was more apparent in the Th1-prone C57Bl/6 mouse strain than in the Th2-prone BALB/c strain. In the presence of Il4 (147780), but not Il10 (124092), Ifngr1 migration and copolarization was completely inhibited. In mice lacking the Il4r signaling molecule, Stat6 (601512), prevention of Tcrb/Ifngr1 copolarization was abolished. Maldonado et al. (2004) proposed that strong TCR signaling leads to accentuated IFNGR copolarization and the assembly of a Th1 signalosome, which is further stabilized by secretion of IFNG, unless an inhibitory signal, such as IL4 secretion and STAT6 activation, occurs and leads to the assembly of a Th2 signalosome. They concluded that the immunologic synapse may be involved in the control of cell fate decisions.
Crystal Structure
Mendoza et al. (2019) engineered an affinity-enhanced variant of the ligand-binding chain of the IFN-gamma receptor IFNGR1, which enabled the determination of the crystal structure of the complete hexameric (2:2:2) IFNG (147570)-IFNGR1-IFNGR2 signaling complex at 3.25-angstrom resolution. The structure revealed the mechanism underlying deficits in IFN-gamma responsiveness in mycobacterial disease syndrome resulting from a T168N mutation in IFNGR2 (147569.0002), which impairs assembly of the full signaling complex. The topology of the hexameric complex offers a blueprint for engineering IFN-gamma variants to tune IFN-gamma receptor signaling output.
By studies in man-mouse somatic cell hybrids, Fellous et al. (1985) suggested that chromosome 18 carries the gene for gamma-interferon receptor. They examined the capacity of human interferons to induce mouse H-2 antigens in these hybrid cells. Human 18 was required for action of human gamma-interferon. On the other hand, Rashidbaigi et al. (1986) concluded that the IFNG receptor or its binding subunit is coded by a gene on 6q. They identified a complex with a molecular weight of about 117,000 daltons when (32)P-labeled human recombinant DNA was crosslinked to human cells with disuccinimidyl suberate. Formation of the complex was inhibited when the binding was performed in the presence of an excess of human IFNG. Mouse and Chinese hamster ovary cells did not show complex formation. In studies of hamster-human and mouse-human hybrid cells, they showed that human 6q is necessary and sufficient for formation of complexes. Fellous (1986) reported that he had exchanged somatic cell hybrids with Rashidbaigi and concluded that indeed chromosome 6 is involved in the genetic control of human gamma-interferon receptor, but that chromosome 18 was also necessary. Jung et al. (1987) found that the presence of chromosome 6 in hamster-human hybrids was by itself insufficient to confer sensitivity to human immune interferon as measured by the induction of human HLA. Human chromosome 21 was found to be the second chromosome essential for HLA inducibility. Similar results were found with mouse-human somatic cell hybrids. Thus, at least 2 steps are involved in the action of gamma-interferon: the binding of gamma-interferon to its receptor coded by chromosome 6 and the coupling of this binding event through a factor coded by chromosome 21 to trigger biologic action. Both of these steps were shown to be species-specific. The finding of a receptor element on chromosome 18 must be considered inconsistent (Fellous et al., 1985).
By radiation hybrid analysis, Aguet et al. (1988) mapped the IFNGR1 gene to chromosome 6q. Southern blot analysis suggested that IFNGR1 is a single-copy gene. Le Coniat et al. (1989) confirmed the assignment to chromosome 6 and regionalized the gene to 6q23-q24 by in situ hybridization. By fluorescence in situ hybridization, Papanicolaou et al. (1997) refined the assignment of IFNGR1 to 6q24.1-q24.2.
Gross (2014) mapped the IFNGR1 gene to chromosome 6q23.3 based on an alignment of the IFNGR1 sequence (GenBank AF056979) with the genomic sequence (GRCh38).
Mariano et al. (1987) demonstrated that the mouse immune interferon receptor gene (Ifgr) maps to chromosome 10. Mouse chromosome 10 also carries the gene for gamma-interferon, which in man is coded by chromosome 12.
Associations Pending Confirmation
Lethal disease due to hepatic periportal fibrosis occurs in 2 to 10% of subjects infected by Schistosoma mansoni in endemic regions such as Sudan. Schistosoma mansoni infection levels have been shown to be controlled by a locus (SM1; 181460) on 5q31-q33. To investigate the genetic control of severe hepatic fibrosis (assessed by ultrasound examination) causing portal hypertension, Dessein et al. (1999) performed a segregation analysis in 65 Sudanese pedigrees from the same village. Results provided evidence for a codominant major gene, with 0.16 as the estimated allele A frequency predisposing to advanced periportal fibrosis. For AA males, AA females, and Aa males, a 50% penetrance was reached after, respectively, 9, 14, and 19 years of residency in the area, whereas for other subjects the penetrance remained less than 0.02 after 20 years of exposure. Linkage analysis performed in 4 candidate regions showed that this major locus maps to 6q22-q23 and that it is closely linked (multipoint lod score = 3.12) to the IFNGR1 gene, which encodes the receptor of the strongly antifibrogenic cytokine interferon-gamma. The results showed that infection levels and advanced hepatic fibrosis in schistosomiasis are controlled by distinct loci; they suggested that polymorphisms within the IFNGR1 gene may determine severe hepatic disease due to S. mansoni infection and that the IFNGR1 gene is a strong candidate for the control of abnormal fibrosis observed in other diseases.
Immunodeficiency 27A
Levin et al. (1995) described a group of related children from a village in Malta who appeared to have an autosomal recessive familial immunologic defect predisposing them to infection with a range of mycobacteria (IMD27A; 209950). Despite intensive treatment, 3 of the 4 affected patients died and the survivor had persistent infection. Immunologic studies showed that the affected children had defective production of tumor necrosis factor-alpha (TNF; 191160) in response to endotoxin and a failure to upregulate this cytokine in response to interferon-gamma. Newport et al. (1996) performed a genomewide search using microsatellite markers to identify a region on 6q in which the affected children were all homozygous for 8 markers. This finding led to focus on the gene for interferon-gamma receptor-1, which maps to 6q23-q24. Sequence analysis of cDNA for the gene revealed a point mutation at nucleotide 395 that introduced a stop codon and resulted in a truncated protein that lacked the transmembrane and cytoplasmic domains (107470.0001).
The attenuated strain of Mycobacterium bovis bacille Calmette-Guerin (BCG) is the vaccine most widely used worldwide. Jouanguy et al. (1996) noted that in most children, inoculation of live BCG vaccine is harmless, although it occasionally leads to a benign regional adenitis. In rare cases, however, vaccination causes disseminated BCG infection, which may be lethal. Most of these children have had severe combined immunodeficiency and some have had chronic granulomatous disease. Rare cases of BCG infection have also been reported in association with AIDS. However, a specific immunodeficiency can be identified in only about half the cases of disseminated BCG infection. Such idiopathic cases have been reported from many countries with a prevalence in France of at least 0.50 case per 1 million children vaccinated with BCG. Jouanguy et al. (1996) stated that a high rate of consanguinity (30%) and familial forms (17%) and the equal sex distribution support the hypothesis of a new type of primary immune defect with an autosomal recessive pattern of inheritance. Pathologic features and clinical outcome suggest 2 distinct forms of idiopathic BCG infection. Well-circumscribed and well-differentiated tuberculoid granulomas with few visible acid-fast rods are associated with a good prognosis. In contrast, ill-defined and poorly differentiated, leproma-like granulomas with many visible bacilli are associated with a fatal outcome, despite antimycobacterial therapy. The second form appears to represent a defect affecting an obligatory and relatively specific step in the formation of a bactericidal BCG granuloma. In mice in which the Ifngr1 gene or interferon-gamma regulatory factor 1 (IRF1; 147575) has been deleted, there is failure to control BCG growth (Dalton et al., 1993). Mice treated with antibodies against tumor necrosis factor-alpha are susceptible to BCG infection, with defective granuloma structure and a fatal outcome. Jouanguy et al. (1996) examined these genes in an infant with fatal idiopathic disseminated BCG infection and found a mutation in the IFNGR1 gene (131delC; 107470.0002). The girl was born of Tunisian parents who were first cousins (patient 16 of Casanova et al., 1995). The patient was vaccinated with BCG at the age of 1 month and was healthy until age 2.5 months. She died at the age of 10 months from BCG infection with multiorgan failure. Jouanguy et al. (1996) stated that intrafamilial segregation of microsatellites which would be expected to show homozygosity for genes closely linked to the affected locus pointed to the IFNGR1 locus as a probable site of the mutation.
Jouanguy et al. (1997) described a kindred with partial IFN-gamma receptor-1 deficiency: 1 child was afflicted by disseminated BCG infection with tuberculoid granulomas, and a sib, who had not been inoculated previously with BCG, had clinical tuberculosis. Both responded to antimicrobials and remained well without prophylactic therapy. Impaired response to IFN-gamma was documented in B cells by signal transducer and activator of transcription 1 nuclear translocation, in fibroblasts by cell surface HLA class II induction, and in monocytes by cell surface CD64 induction and TNF-alpha secretion. Whereas cells from healthy children responded to even low TNF-gamma concentrations, and cells from a child with complete IFN-gamma receptor deficiency did not respond to even high IFN-gamma concentrations, cells from the 2 sibs did not respond to low or intermediate concentrations, yet responded to high IFN-gamma concentrations. Jouanguy et al. (1997) identified a homozygous missense mutation (I87T; 107470.0003) in the IFNGR1 gene. Its pathogenic role was ascertained by molecular complementation. Thus, whereas complete deficiency of the receptor in previously identified kindreds caused fatal lepromatoid BCG infection and disseminated nontuberculosis mycobacterial infections, partial deficiency in this kindred caused curable tuberculoid BCG infection and clinical tuberculosis. In keeping with the observation that only a minority of individuals infected with M. tuberculosis developed clinical disease, it is tempting to speculate that clinical tuberculosis in otherwise healthy individuals in the general population may be associated with partial deficiency of the interferon-gamma receptor. As pointed out by Jouanguy et al. (1997), a range of different mutations in the IFNGR1 gene had been identified, causing a range from complete absence of expression to subtle alterations in the function of the receptor. Homozygosity or compound heterozygosity for mutations causing mild functional impairment of the receptor may be prevalent in different ethnic populations and may help to explain variation in susceptibility to tuberculosis within the general population.
Jouanguy et al. (2000) described 4 patients from 3 unrelated families with pathogenic mutations in the IFNGR1 gene that did not affect cell surface expression of IFNGR1 but impaired its binding to IFNG, resulting in susceptibility to either BCG or nontuberculous mycobacteria. Flow cytometric analysis demonstrated abnormal binding to a panel of 8 monoclonal anti-IFNGR1 antibodies in 3 of the 4 patients. Binding analysis with radiolabeled IFNG showed an absence of binding by the patients' cells. EMSA analysis detected no GAS motif-binding proteins or STAT1 translocation in the patients' cells, even with high concentrations of IFNG. FACS analysis also revealed a lack of HLA-DR upregulation in response to IFNG. Jouanguy et al. (2000) concluded that the patients had complete IFNGR1 deficiency with normal surface expression of the protein.
Immunodeficiency 27B
Jouanguy et al. (1999) described 18 patients with sporadic or dominantly inherited susceptibility to infections caused by poorly virulent mycobacteria (IMD27B; 615978). The patients, including 9 from 3 unrelated families and 9 sporadic cases, were heterozygous for either a 1-bp (1 case) or 4-bp (all others) deletion (107470.0006) at nucleotide 818 of IFNGR1. There were 12 independent mutational events at a single mutation site, defining a small deletion hotspot. Neighboring sequence analysis, which shows 2 direct repeats in close vicinity (808-812 and 817-821), favors a small deletion model of slipped mispairing events during replication. The mutant alleles resulted in stable mRNA which encoded cell surface interferon-gamma receptors that lacked the intracytoplasmic domain.
In a review of immunodeficiency diseases caused by defects in phagocytes, Lekstrom-Himes and Gallin (2000) pointed out that late-onset osteomyelitis is associated with autosomal dominant interferon-gamma receptor defects (see their Table 1 and 107470.0006).
Janssen et al. (2002) studied macrophage and T-cell function in 8 patients from 3 unrelated families with partial IFNGR1 deficiency due to heterozygosity for the 818del4 mutation. They found that, in response to IFNG stimulation, TNF production was normal, but IL12 (see 161560) production and CD64 (FCGR1A; 146760) upregulation were strongly reduced, and macrophage killing of Salmonella typhimurium or Toxoplasma gondii was completely abrogated. Clinically, the patients suffered from infections with nontuberculous mycobacteria and Salmonella, but not T. gondii, even though 6 of 8 patients had serologic evidence of exposure to T. gondii. Further studies in control and patient macrophages revealed that IFNG-induced killing of T. gondii was partially mediated by TNF, whereas IFNG-induced killing of S. typhimurium appeared to be independent of TNF. Janssen et al. (2002) proposed that the divergent role of TNF in IFNG-induced killing of the intracellular pathogens T. gondii, S. typhimurium, and nontuberculous mycobacteria may explain the selective susceptibility of patients with partial IFNGR1 deficiency to these organisms.
Storgaard et al. (2006) reported on a man they first described in 1981 as a 10-year-old boy with Mycobacterium intracellulare-associated osteomyelitis and depressed monocyte cytotoxicity. Thirty months of antituberculosis treatment resolved the condition until age 30 years, when he was diagnosed with disseminated (spleen and lymph node) M. avium abscesses. Eight months of antituberculosis treatment provided complete recovery. The man was HIV negative. Flow cytometric analysis showed that he had upregulated IFNGR1 expression on lymphocytes, monocytes, and granulocytes, but production of phosphorylated STAT1 after stimulation with IFNG was impaired. Storgaard et al. (2006) identified a heterozygous point mutation (794delT; 107470.0013) in the man and his daughter, who developed nontuberculous mycobacterial osteomyelitis at the age of 7 years. They noted that it was possible to make the genetic diagnosis 25 years after the first disease episode and 1 year before clinical manifestations in the daughter.
Other Associations
Helicobacter pylori is considered the most prevalent infectious agent of humans (see 600263), and it causes gastric inflammation, gastroduodenal ulcers, and a risk of gastric cancer. Thye et al. (2003) performed a genomewide linkage analysis of Senegalese sibs phenotyped for H. pylori-reactive serum immunoglobulin G. A multipoint lod score of 3.1 was obtained at IFNGR1. Sequencing of IFNGR1 revealed 3 variants which were found to be associated with high antibody concentrations, including a -56C-T transition (107470.0012). The inclusion of these in the linkage analysis raised the lod score to 4.2. The variants were more prevalent in Africans than in whites. The findings indicated that interferon-gamma signaling plays an essential role in human H. pylori infection and contributed to an explanation of the observation of high prevalences and relatively low pathogenicity of H. pylori in Africa.
In a case-control study of 682 tuberculosis (TB; see 607948) patients and 619 controls from 3 West African countries (Gambia, Guinea-Bissau, and Guinea-Conakry), Cooke et al. (2006) found that the -56CC genotype of the IFNGR1 promoter -56C-T SNP was associated with protection from TB. Cooke et al. (2006) concluded that variation in the IFNGR1 promoter plays a role in the pathogenesis of TB.
As a follow-up to their studies examining TNF levels in response to M. tuberculosis culture filtrate antigen as an intermediate phenotype model for TB susceptibility in a Ugandan population, Stein et al. (2007) studied genes related to TNF regulation by positional candidate linkage followed by family-based SNP association analysis. They found that the IL10, IFNGR1, and TNFR1 (191190) genes were linked and associated to both TB and TNF. These associations were with active TB rather than susceptibility to latent infection.
Zhou et al. (2009) investigated SNPs in the IFNGR1 gene and their associations with susceptibility to hepatitis B virus (HBV; 610424) in a Chinese population. Using PCR and RFLP analysis, they identified 7 SNPs in the IFNGR1 gene. Comparison of 361 chronic hepatitis B patients, 256 individuals who spontaneously recovered from HBV infection, and 366 healthy controls showed that the -56C and -56T alleles of a promoter polymorphism (107470.0012) were associated with viral clearance and viral persistence, respectively (P = 0.014). Luciferase reporter analysis showed that the -56C variant exhibited a higher transcription level than the -56T variant in a liver cell line. Zhou et al. (2009) concluded that the -56C/T SNP in the IFNGR1 promoter is associated with the clinical outcome of HBV infection in Chinese adults.
Dorman et al. (2004) compared the clinical features of recessive and dominant IFNGR1 deficiencies using a worldwide cohort of patients. They assessed the patients by medical histories and genetic and immunologic studies. Recessive deficiency, which Dorman et al. (2004) identified in 22 patients, results in complete loss of cellular response to IFNG and absence of surface IFNGR1 expression. Dominant deficiency, which they identified in 38 patients, is typically due to cytoplasmic domain truncations resulting in accumulation of nonfunctional IFNGR1 proteins that may impede the function of molecules encoded by the wildtype allele, thereby leading to diminished but not absent responsiveness to IFNG. Although the clinical phenotypes are related, Dorman et al. (2004) found that patients with the recessive form had an earlier age of onset (3 vs 13 years), more mycobacterial disease episodes (19 vs 8 per 100 person years of observation), more severe mycobacterial disease (involvement of 4 vs 2 organs), shorter mean disease-free intervals (1.6 vs 7.2 years), and lower Kaplan-Meier survival probability. Recessive patients also had more frequent disease from rapidly growing mycobacteria. Patients with a dominant mutation, however, were more likely to have M. avium complex osteomyelitis, and only dominant patients had osteomyelitis without other organ involvement. Dorman et al. (2004) concluded that there is a strong correlation between the IFNGR1 genotype, clinical disease features, and the cellular responsiveness to IFNG. They suggested that subtle defects in IFNG production, signaling, or related pathways may predispose to diseases caused by virulent mycobacteria, including M. tuberculosis.
Shankaran et al. (2001) found that mice lacking the lymphocyte-specific Rag2 gene (179616), the Ifn receptor signal transcription factor Stat1 (600555), Ifngr1, or both Rag2 and Stat1, are significantly more susceptible to chemically induced tumor formation than wildtype mice, suggesting that T, NKT, and/or B cells are essential to suppress development of chemically induced tumors. Spontaneous malignant tumors did not occur in wildtype mice, occurred late in half of mice lacking either Rag2 or Stat1, but occurred early in 82% of mice lacking both genes. Transplanted chemically induced tumors from lymphocyte-deficient mice (Shankaran et al., 2001) or from Ifng-unresponsive mice (Kaplan et al., 1998), but not tumors from immunocompetent hosts, were rejected by wildtype mice, indicating that the tumors from immunodeficient mice are more immunogenic and that lymphocytes and the IFNG/STAT1 signaling pathway collaborate to shape the immunogenic phenotype of tumors that eventually form in immunocompetent hosts. Shankaran et al. (2001) proposed that tumors are imprinted by the immunologic environment in which they form and that 'cancer immunoediting' rather than 'immunosurveillance' best describes the protective and sculpting actions of the immune response on developing tumors.
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.
Tissues of the nervous system are shielded from plasma proteins, such as antibodies, by the blood-brain and blood-nerve barriers. Iijima and Iwasaki (2016) examined the mechanisms by which circulating antibodies access neuronal tissues in a mouse model of genital herpes (HSV-2) infection. (Converse (2016) noted that others, such as Svensson et al. (2005) (see TBX21, 604895), have explored additional requirements for immune protection against HSV-2.) Iijima and Iwasaki (2016) found that memory Cd4 (186940)-positive T cells migrated to dorsal root ganglia (DRG) harboring latent HSV-2 and released Ifng, leading to a local increase in vascular permeability that enabled antibody to access the DRG and control the virus. Mice lacking Ifngr1 were also more susceptible to intravaginal HSV-2 challenge. Depletion of Cd4 cells, but not Cd8 (see 186910) or natural killer cells, rendered mice unable to resist HSV-2 challenge or to respond effectively after intranasal vaccination. Iijima and Iwasaki (2016) concluded that the efficacy of circulating antibody-mediated protection requires CD4 T cells and IFNG.
In 4 children with familial disseminated atypical mycobacterial infection (IMD27A; 209950) in Malta, Newport et al. (1996) demonstrated homozygosity for a C-to-A transversion at nucleotide 395, which resulted in a stop codon: a change from TCA (ser) to TAA (stop). The codon number was not provided.
Jouanguy et al. (1996) identified a mutation in exon 2 of the IFNGR1 gene in a Tunisian patient with fatal BCG infection (IMD27A; 209950). A single nucleotide deletion (131delC) created a frameshift and led to a premature stop codon (TAA) at nucleotides 187-189 of the coding region of the IFNGR1 gene. Both the deletion and the stop codon were located in the region that codes for the N-terminal portion of the extracellular domain of the receptor. The affected child was homozygous; both parents and 2 healthy brothers were heterozygous.
In a family in which 1 sib had disseminated BCG infection (IMD27A; 209950) with tuberculoid granulomas and a second sib, who had not been inoculated previously with BCG, had clinical tuberculosis (see 607948), Jouanguy et al. (1997) identified an ile87-to-thr (I187T) missense mutation in the IFNGR1 gene. The amino acid substitution resulted from a T-to-C transition at nucleotide 260.
Altare et al. (1998) investigated an Italian child, born to nonconsanguineous parents, who presented at 3 years of age with disseminated infection due to Mycobacterium smegmatis (IMD27A; 209950) (Pierre-Audigier et al., 1997). The child was not vaccinated with BCG and died at 8 years of age of a progressive mycobacterial disease, despite intensive antimycobacterial therapy. Four older sibs had received the BCG vaccine in infancy with no adverse effect and were healthy. Sequencing of the 7 IFNGR1 exons and associated intronic consensus splice sites demonstrated a 4-bp insertion, designated 107ins4, within exon 2 of the IFNGR1 gene on 1 chromosome in the child and in the father. The 4 inserted nucleotides, TTAC, were found to duplicate flanking nucleotides 104-107. The frameshift was expected to produce premature termination of translation before the transmembrane segment, because of a stop codon at nucleotides 115 to 117. A substitution of the first base of the consensus splice-donor site of IFNGR1 intron 3 was found at the other locus in the child and in the mother, designated 200+1G-A (107470.0005). This mutation was expected to cause exon 2 skipping and/or cryptic splice site usage. The affected child was the only member of the family carrying both mutant alleles.
For discussion of the splice site mutation (200+1G-A) in the IFNGR1 gene that was found in compound heterozygous state in a patient with immunodeficiency-27A (IMD27A; 209950) by Altare et al. (1998), see 107470.0004.
Jouanguy et al. (1999) described 3 families and 8 sporadic cases with immunodeficiency-27B (IMD27B; 615978) who had a 4-bp deletion in exon 6 of the IFNGR1 gene. The deletion was either AATT at nucleotide 816, ATTA at nucleotide 817, TTAA at nucleotide 818, or TAAT at nucleotide 819 of the IFNGR1 ORF and was arbitrarily designated 818del4. The 818del4 mutation caused a frameshift that led to a premature stop codon at position 827 to 829, downstream of the segment encoding the transmembrane domain, and a predicted truncation of the cytoplasmic domain of the mutant receptor. The truncated protein was stable and exerted a dominant-negative effect through impaired recycling, abrogated signaling, and normal binding to interferon-gamma. Patients were at risk of disseminated infection from poorly virulent mycobacteria and bacille Calmette-Guerin. Two of the families were from Ireland and 1, originally reported by Heyne (1976), was from Germany. Of the 2 affected members of the German family, 1 was dead at age 27 and the other alive at age 30.
Holland et al. (2017) reported autosomal dominant heterozygous IFNGR1 deficiency and disseminated M. genavense infection in a 13-month-old girl and her 33-year-old mother. The mother also had progressive osteomyelitis. Exome sequencing revealed a heterozygous 818del4 mutation, specifically of TAAT at nucleotide 819, in the IFNGR1 gene of both the child and mother.
Jouanguy et al. (2000) reported an only child of first-cousin Algerian parents living in France who had atypical mycobacterial infection (IMD27A; 209950). The patient was homozygous for an in-frame 12-bp deletion at nucleotide 295 in exon 3 of the IFNGR1 gene, resulting in the deletion of amino acids 99 to 102 (trp-val-arg-val). She had been BCG vaccinated at age 1 year. Three months after a successful 1-year antimycobacterial drug treatment was discontinued, M. avium infection was diagnosed. Antibiotic treatment was partially successful. An HLA-identical bone marrow transplant from an uncle engrafted but was followed in 2 months by a fatal disseminated granulomatous reaction. The patient's cells expressed IFNGR1 but were unresponsive to IFNG (147570).
Jouanguy et al. (2000) reported 2 sibs, a boy and a girl, born to consanguineous Turkish parents who had atypical mycobacterial infections (IMD27A; 209950). The patients were homozygous for a G-to-A transition at nucleotide 230 near the 5-prime end of exon 3 of the IFNGR1 gene, resulting in a cys77-to-tyr (C77Y) substitution. The girl had recurrent BCG infection that was poorly responsive to antibiotic treatment. At age 10 years, she was diagnosed with M. fortuitum infection. One year later, she remained ill despite antibiotic treatment. The boy had recurrent BCG infection until 8 years of age, when disseminated M. fortuitum was also diagnosed. At age 9 years he was in partial remission with multiple antibiotic treatments. Two other sibs died at age 3 years of acute leukemia and typhoid fever, while 3 others were healthy, BCG-vaccinated adults. The patients' cells expressed IFNGR1 but were unresponsive to IFNG (147570).
Jouanguy et al. (2000) reported a child of a French mother and a Portuguese father living in France who had atypical mycobacterial infection (IMD27A; 209950). The patient was compound heterozygous for a T-to-A transversion at nucleotide 182 near the 3-prime end of exon 2 of the IFNGR1 gene, resulting in a val61-to-gln (V61Q) substitution, and an in-frame 3-bp deletion (107470.0010) in exon 5 of the IFNGR1 gene, resulting in the deletion of glu218 in the extracellular portion of the receptor. Disseminated BCG infection responded well to antimycobacterial drugs. At 2 years of age, the patient was undergoing a maternal HLA-haploidentical bone marrow transplant. Her older brother (5 years of age) was healthy and BCG vaccinated. The patient's cells expressed IFNGR1 but were unresponsive to IFNG (147570).
For discussion of the 3-bp deletion in the IFNGR1 gene that was found in compound heterozygous state in a patient with immunodeficiency-27A (IMD27A; 209950) by Jouanguy et al. (2000), see 107470.0009.
Jouanguy et al. (1999) reported an Italian family in which a single case of atypical mycobacterial infection (bacille Calmette-Guerin and Mycobacterium avium) (IMD27B; 615978), with episodes at ages 1 and 6 years, carried a deletion of a single nucleotide (T) in exon 6 at position 818 or 819, arbitrarily designated as 818delT, in the IFNGR1 gene. Note that 818del4 (107470.0006) is the most common cause of autosomal dominant atypical mycobacterial infection. The parents in the Italian family, and those of the other sporadic cases of this disorder carrying the 818del4 mutation, were free of the deletion found in the proband.
Thye et al. (2003) performed a genomewide linkage analysis of 111 sibs from 35 Senegalese nuclear families, comprising 143 sib pairs, for H. pylori (see 600263)-reactive serum immunoglobulin G. They identified a -56C-T transition in the IFNGR1 gene in approximately half of all chromosomes. Twenty-nine homozygous and 55 heterozygous carriers of the variant had higher levels of anti-H. pylori immunoglobulin G than did the remaining 27 wildtype sibs. Thye et al. (2003) concluded that the -56C-T variant was associated with high susceptibility to H. pylori infection.
In a case-control study of 682 tuberculosis (TB; see 607948) patients and 619 controls from 3 West African countries (Gambia, Guinea-Bissau, and Guinea-Conakry), Cooke et al. (2006) found that the -56CC genotype of the IFNGR1 promoter -56C-T SNP was associated with protection from TB. Cooke et al. (2006) concluded that variation in the IFNGR1 promoter plays a role in the pathogenesis of TB.
By studying 361 chronic hepatitis B patients, 256 spontaneously recovered individuals, and 366 healthy control subjects in 4 Chinese hospitals, Zhou et al. (2009) reported that the -56C and -56T promoter alleles are associated with viral clearance and persistence, respectively.
By studying 983 Chinese individuals, including 361 chronic hepatitis B patients (see 610424), 256 individuals who spontaneously recovered from HBV infection, and 366 healthy controls, Zhou et al. (2009) showed that the -56C and -56T alleles of the IFNGR1 promoter polymorphism were associated with viral clearance and viral persistence, respectively (P = 0.014). Luciferase reporter analysis showed that the -56C variant exhibited a higher transcription level than the -56T variant in a liver cell line. Zhou et al. (2009) concluded that the -56C/T SNP in the IFNGR1 promoter is associated with the clinical outcome of HBV infection in Chinese adults.
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