* 147569

INTERFERON-GAMMA RECEPTOR 2; IFNGR2


Alternative titles; symbols

IFGR2
INTERFERON-GAMMA TRANSDUCER 1; IFNGT1
INTERFERON-GAMMA RECEPTOR, ACCESSORY FACTOR FOR


HGNC Approved Gene Symbol: IFNGR2

Cytogenetic location: 21q22.11     Genomic coordinates (GRCh38): 21:33,402,882-33,437,516 (from NCBI)


Gene-Phenotype Relationships
Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
21q22.11 Immunodeficiency 28, mycobacteriosis 614889 AR 3

TEXT

Gene Structure

Rhee et al. (1996) found that the IFNGR2 gene spans over 33 kb of DNA and contains 7 exons. A signal peptide is encoded by exons 1 and 2, the extracellular domain by exons 2, 3, 4, 5, and part of 6. Exon 6 also encodes the entire transmembrane domain and part of the intracellular domain. Exon 7 encodes the remainder of the intracellular domain and contains the 3-prime untranslated region. No TATA or CAAT boxes were found in the promoter region. Consistent with the lack of a TATA box, analysis of mRNAs by primer extension showed multiple transcription start sites.


Biochemical Features

Crystal Structure

Mendoza et al. (2019) engineered an affinity-enhanced variant of the ligand-binding chain of the IFN-gamma receptor IFNGR1 (107470), 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 IFNG 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 IFNG variants to tune IFNG receptor signaling output.


Mapping

For the cellular response of somatic cell hybrids (from fibroblasts) to gamma-interferon (IFNG; 147570), the gamma-interferon receptor on 6q and a factor on chromosome 21q are necessary (Jung et al., 1987). Langer et al. (1990) demonstrated that the factor encoded by chromosome 21 is separate from the alpha and beta interferon receptors (see 107450) but maps to the same region. In hamster-human somatic cell hybrids, the presence of the IFN-gamma receptor-related factor mediating cellular responsiveness was determined by HLA induction in hybrid cells containing the IFN-gamma receptor on 6q, a transfected copy of the human HLA-B7 gene, and various portions of chromosome 21. In all hybrids, the IFNGT1 gene cosegregated with the IFNAR gene. (Presumably this is the same as the IFNGR2 gene, which previously, probably incorrectly, was thought to be located on chromosome 18; see 107470.) Bono et al. (1991) likewise mapped this gene to chromosome 21 by study of somatic cell hybrids.

Soh et al. (1993) identified a small region of chromosome 21 that is responsible for encoding accessory factor(s) by study of hamster-human somatic cell hybrids carrying an irradiation-reduced fragment of human chromosome 21. To localize the genes further, 10 different YAC clones from 6 different loci in the region were fused to a human-hamster hybrid cell line that contained 6q (supplying the interferon-gamma receptor) and the human HLA-B7 gene. These transformed cells were assayed for induction of class I HLA antigens upon treatment with gamma-interferon.

Soh et al. (1993) described a 540-kb YAC that could substitute for chromosome 21 in functioning as the accessory factor. The factor encoded by the YAC did not confer antiviral protection against the encephalomyocarditis virus, however, demonstrating that an additional factor encoded on human chromosome 21 is required for the antiviral activity.

Mariano et al. (1996) mapped the Ifgr2 gene to the distal end of mouse chromosome 16 by the study of interspecies backcrosses.


Molecular Genetics

Mutations in the IFN-gamma receptor ligand-binding chain (IFNGR1; 107470) have been shown to confer susceptibility to severe infection with nontuberculous mycobacteria (IMD27A; 209950). Dorman and Holland (1998) described a child with disseminated Mycobacterium fortuitum and M. avium complex infections associated with absent IFN-gamma signaling (IMD28; 614889) due to a mutation in the extracellular domain of IFNGR2 (147569.0001). The patient was a male who had 2 episodes of otitis media and 1 episode of thrush, all of which responded promptly to standard treatment. He received prescribed childhood immunizations but did not receive BCG vaccine. At 20 months of age, he developed a cough with pulmonary infiltrates that did not resolve with antibiotics. At 2 years of age, he developed lymphadenopathy, hepatosplenomegaly, and fevers. Biopsy of an axillary lymph node showed capsular fibrosis and histiocytic infiltration without abscesses or granulomata. Acid-fast bacilli were present on staining, and cultures grew the 2 forms of mycobacterium mentioned. Intensive therapy failed to eliminate the infection. The mother was of English descent and the father of English and Portuguese descent; they were not known to be related. A maternal aunt had been diagnosed with tuberculosis at age 3 years and subsequently developed cervical lymphadenopathy; she died at the age of 26 years of chronic aggressive hepatitis. In vitro cytokine production by the patient's peripheral blood mononuclear cells showed 75% less PHA-induced interferon-gamma production than in normal cells, while the patient's PHA-induced TNF-alpha production was normal.

Mutations involving gains of glycosylation had been considered rare, and the pathogenic role of the new carbohydrate chains had not been formally established. Vogt et al. (2005) identified 3 children with mendelian susceptibility to mycobacterial disease who were homozygous for a missense mutation in the IFNGR2 gene (147569.0002), creating a new N-glycosylation site in the IFNGR2 chain. The resulting additional carbohydrate moiety was both necessary and sufficient to abolish the cellular response to IFN-gamma. Vogt et al. (2005) then searched the Human Gene Mutation Database maintained at Cardiff University for potential gain-of-N-glycosylation missense mutations; of 10,047 mutations in 577 genes encoding proteins trafficked through the secretory pathway, they identified 142 candidate mutations (approximately 1.4%) in 77 genes (approximately 13.3%). Six mutant proteins bore new N-linked carbohydrate moieties. Thus, an unexpectedly high proportion of mutations that cause human genetic disease might lead to the creation of new N-glycosylation sites. Their pathogenic effects may be a direct consequence of the addition of N-linked carbohydrate.

Vogt et al. (2008) reported a child with M. avium disease due to complete IFNGR2 deficiency who was homozygous for an in-frame 6-bp duplication in IFNGR2, resulting in duplication thr128 and met129 (147569.0004). They found that the mutant protein was mostly retained within the cell and not expressed on the cell surface. Surface-expressed mutant IFNGR2 was abnormally folded, high in molecular mass, and N-glycosylated, but it was resistant to endoglycosidase H. The mutation created no known consensus sites for posttranslational modifications, including N-glycosylation. Treating cells expressing the mutant protein with 13 of 29 compounds affecting protein maturation by N-glycosylation reduced the molecular mass of surface-expressed mutant IFNGR2 and restored cellular responsiveness to IFNG. Vogt et al. (2008) proposed that modifiers of N-glycosylation, some of which are available for clinical use, may complement human cells carrying in-frame and misfolding mutations in genes encoding proteins subject to trafficking via the secretory pathway.

In 2 sibs from a consanguineous Turkish family and a boy from a consanguineous Indian family with IMD28, Oleaga-Quintas et al. (2018) identified homozygous mutations in the IFNGR2 gene (M1V, 147569.0005 and c.4delC, 147569.0006, respectively). The mutations, which were identified by whole-exome sequencing and confirmed by Sanger sequencing, were present in heterozygous state in the parents. Overexpression of each mutant IFNGR2 cDNA in HEK293-T cells resulted in reduced levels of full-length protein. Oleaga-Quintas et al. (2018) showed that the full-length IFNGR2 proteins resulting from the mutant cDNAs were due to initiation of translation by non-AUG codons located between codons 2 and 9 in the 21-amino acid signal peptide. Expression of IFNGR2 with either mutation in SV40F cells resulted in an impaired, but not absent, response to IFNG stimulation.


ALLELIC VARIANTS ( 7 Selected Examples):

.0001 IMMUNODEFICIENCY 28

IFNGR2, 2-BP DEL, 278AG
  
RCV000015847

In a male child with disseminated infection with Mycobacterium fortuitum and M. avium complex (IMD28; 614889), Dorman and Holland (1998) found a homozygous dinucleotide deletion (AG) involving nucleotides 278 and 279 in exon 3 of the IFNGR2 gene. The deletion caused a frameshift and a premature stop codon (TGA).


.0002 IMMUNODEFICIENCY 28

IFNGR2, THR168ASN
  
RCV000015848

In 3 children with mendelian susceptibility to mycobacterial disease (IMD28; 614889), 1 Iranian and 2 Saudi Arabian, all from consanguineous parents, Vogt et al. (2005) found a homozygous 503C-A transversion in the IFNGR2 gene resulting in a thr168-to-asn (T168N) amino acid substitution. The healthy parents were heterozygous for the mutation. The T168N mutation in IFNGR2 was said to be the first reported germline mutation for which a causal relationship was unequivocally established between the gain of glycosylation and the loss of function. The mutation results in a protein carrying an N-linked carbohydrate moiety attached at asn168. This polysaccharide was both necessary and sufficient to account for the pathologic effect of the T168N mutation.

Mendoza et al. (2019) determined the crystal structure of the IFNG-IFNGR1-IFNGR2 signaling complex and proposed that the additional steric bulk introduced by the T168N substitution, directly at the site 3 interface, prevents the IFNGR2(T168N) protein from docking to the high affinity 2:2 IFNG-IFNGR1 intermediate to complete the signaling complex.


.0003 IMMUNODEFICIENCY 28

IFNGR2, 7-BP DEL, NT663
  
RCV000015849

In an Austrian child of consanguineous parents with mendelian susceptibility to mycobacterial disease (IMD28; 614889), Vogt et al. (2005) found a novel homozygous in-frame 27-bp microdeletion of nucleotides 663-689 of the IFNGR2 gene (663del27), predicted to lead to the deletion of amino acids 222-230. Both parents, heterozygous for the mutation, were healthy.


.0004 IMMUNODEFICIENCY 28

IFNGR2, 6-BP DUP, NT382
  
RCV000030825

Vogt et al. (2008) reported a child of consanguineous parents with mycobacterial disease (IMD28; 614889) due to a homozygous in-frame duplication of nucleotides 382 to 387 in the IFNGR2 gene, resulting in a duplication of thr128 and met129. Both parents and 1 of 2 sibs were heterozygous for the mutation, but they did not develop disease. The affected child died at age 5 years of disseminated M. avium disease in spite of treatment with multiple antimycobacterial drugs. The mutant IFNGR2 protein was predominantly retained intracellularly, and the fraction expressed on the surface had a high molecular mass, was abnormally folded, and did not respond to IFNG (147570).


.0005 IMMUNODEFICIENCY 28

IFNGR2, MET1VAL
  
RCV001268955

In 2 Turkish sibs (P1 and P2), born to consanguineous parents, with susceptibility to mycobacterial disease (IMD28; 614889), Oleaga-Quintas et al. (2018) identified a homozygous c.1A-G transition in the IFNGR2 gene, resulting in a met1-to-val (M1V) substitution. The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the parents. The variant was reported once in heterozygous state in the gnomAD database. Elevated levels of IFNG (147570) were detected in plasma from the sibs compared to controls, and elevated levels of IFNG were also detected in whole blood from both sibs after stimulation with BCG and IL12 (see 161560). Overexpression of the mutant IFNGR2 cDNA in HEK293-T cells resulted in a reduced amount of full-length protein. Expression of IFNGR2 with the M1V mutation in SV40F cells resulted in an impaired, but not absent, response to IFNG stimulation.


.0006 IMMUNODEFICIENCY 28

IFNGR2, 1-BP DEL, 4C
  
RCV001269033

In an Indian boy, born to consanguineous parents, with susceptibility to mycobacterial disease (IMD28; 614889), Oleaga-Quintas et al. (2018) identified a homozygous 1-bp deletion (c.4delC) in the IFNGR2 gene, predicted to cause early termination 22 residues downstream of the start codon. The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the parents. The mutation was not present in the gnomAD database. Elevated levels of IFNG (147570) were detected in plasma from the patient compared to controls. Overexpression of the mutant IFNGR2 cDNA in HEK293-T cells resulted in a reduced amount of full-length protein. Expression of IFNGR2 with the c.4delC mutation in SV40F cells resulted in an impaired, but not absent, response to IFNG stimulation.


.0007 IMMUNODEFICIENCY 28

IFNGR2, 1-BP DEL, 798T
  
RCV001728186

In a boy, born of consanguineous Saudi parents, with immunodeficiency-28 (IMD28; 614889), Hoyos-Bachiloglu et al. (2017) identified a homozygous 1-bp deletion (c.798delT, NM_005534) in the IFNGR2 gene, resulting in a frameshift and premature termination (Cys266fs) upstream of the residues essential for JAK2 (147796). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. Patient cells showed decreased mRNA levels compared to controls, suggesting that the mutation triggered nonsense-mediated mRNA decay. Transfection of the mutation into HEK293 cells confirmed that the mutant protein has a shorter half-life than wildtype and is degraded by endoplasmic reticulum-associated protein degradation (ERAD). In vitro functional expression studies using patient-derived fibroblasts showed impaired response to stimulation with gamma-IFN as manifest by failure of STAT1 phosphorylation and upregulation of HLA-DR after exposure. The findings, which indicated a defect in the type II interferon pathway resulting from autosomal recessive complete IFNGR2 deficiency, were consistent with the patient's early-onset disseminated mycobacterial disease. In addition to mycobacterial infection, the patient developed cytomegalovirus (CMV) viremia. Whole-exome sequencing identified a homozygous loss-of-function variant in the IFNAR1 gene (107450.0004). Sanger sequencing confirmed that each parent was heterozygous for this variant. Additional in vitro functional expression studies showed impaired downstream IFNAR signaling after stimulation with alpha-IFN, indicating a defect in the IFN type I signaling pathway that may have resulted from the IFNAR1 variant. These findings of likely digenic inheritance were consistent with the patient's atypical presentation for IMD28, which comprised defects in both type I and type II IFN signaling.


See Also:

REFERENCES

  1. Bono, M. R., Alcaide-Loridan, C., Couillin, P., Letouze, B., Grisard, M. C., Jouin, H., Fellous, M. Human chromosome 16 encodes a factor involved in induction of class II major histocompatibility antigens by interferon gamma. Proc. Nat. Acad. Sci. 88: 6077-6081, 1991. [PubMed: 1906174, related citations] [Full Text]

  2. Bono, R., Hatat, D., Couillin, P., Grisard, M. C., Van Cong, N., Fisher, D., Fellous, M. Receptor for human gamma interferon is specified by human chromosomes 6 and 21. (Abstract) Cytogenet. Cell Genet. 46: 584, 1987.

  3. Dorman, S. E., Holland, S. M. Mutation in the signal-transducing chain of the interferon-gamma receptor and susceptibility to mycobacterial infection. J. Clin. Invest. 101: 2364-2369, 1998. [PubMed: 9616207, related citations] [Full Text]

  4. Hoyos-Bachiloglu, R., Chou J., Sodroski, C. N., Beano, A., Bainter, W., Angelova, M., Al Idrissi, E., Habazi, M. K., Alghamdi, H. A., Almanjomi, F., Al Shehri, M., Elsidig, N., Eldin, M. A., Knipe, D. M., AlZahrani, M., Geha, R. S. A digenic human immunodeficiency characterized by IFNAR1 and IFNGR2 mutations. J. Clin. Invest. 127: 4415-4420, 2017. [PubMed: 29106381, images, related citations] [Full Text]

  5. Jung, V., Rashidbaigi, A., Jones, C., Tischfield, J. A., Shows, T. B., Pestka, S. Human chromosomes 6 and 21 are required for sensitivity to human interferon gamma. Proc. Nat. Acad. Sci. 84: 4151-4155, 1987. [PubMed: 2954164, related citations] [Full Text]

  6. Langer, J. A., Rashidbaigi, A., Lai, L.-W., Patterson, D., Jones, C. Sublocalization on chromosome 21 of human interferon-alpha receptor gene and the gene for an interferon-gamma response protein. Somat. Cell Molec. Genet. 16: 231-240, 1990. [PubMed: 2141727, related citations] [Full Text]

  7. Mariano, T. M., Muthukumaran, G., Donnelly, R. J., Wang, N., Adamson, M. C., Pestka, S., Kozak, C. A. Genetic mapping of the gene for the mouse interferon-gamma receptor signaling subunit to the distal end of chromosome 16. Mammalian Genome 7: 321-322, 1996. [PubMed: 8661709, related citations] [Full Text]

  8. Mendoza, J. L., Escalante, N. K., Jude, K. M., Sotolongo Bellon, J., Su, L., Horton, T. M., Tsutsumi, N., Berardinelli, S. J., Haltiwanger, R. S., Piehler, J., Engleman, E. G., Garcia, K. C. Structure of the IFN-gamma receptor complex guides design of biased agonists. Nature 567: 56-60, 2019. [PubMed: 30814731, images, related citations] [Full Text]

  9. Oleaga-Quintas, C., Deswarte, C., Moncada-Velez, M., Metin, A., Rao, I. K., Kanik-Yuksek, S., Nieto-Patlan, A., Guerin, A., Gulhan, B., Murthy, S., Ozkaya-Parlakay, A., Abel, L., Martinez-Barricarte, R., Perez de Diego, R., Boisson-Dupuis, S., Kong, X.-F., Casanova, J.-L., Bustamante, J. A purely quantitative form of partial recessive IFN-gamma-R2 deficiency caused by mutations of the initiation or second codon. Hum. Molec. Genet. 27: 3919-3935, 2018. Note: Erratum: Hum. Molec. Genet. 28: 524 only, 2019. [PubMed: 31222290, images, related citations] [Full Text]

  10. Rhee, S., Ebensperger, C., Dembic, Z., Pestka, S. The structure of the gene for the second chain of the human interferon-gamma receptor. J. Biol. Chem. 271: 28947-28952, 1996. [PubMed: 8910544, related citations] [Full Text]

  11. Soh, J., Donnelly, R. J., Mariano, T. M., Cook, J. R., Schwartz, B., Pestka, S. Identification of a yeast artificial chromosome clone encoding an accessory factor for the human interferon gamma receptor: evidence for multiple accessory factors. Proc. Nat. Acad. Sci. 90: 8737-8741, 1993. [PubMed: 8378357, related citations] [Full Text]

  12. Vogt, G., Bustamante, J., Chapgier, A., Feinberg, J., Boisson Dupuis, S., Picard, C., Mahlaoui, N., Gineau, L., Alcais, A., Lamaze, C., Puck, J. M., de Saint Basile, G., Khayat, C. D., Mikhael, R., Casanova, J.-L. Complementation of a pathogenic IFNGR2 misfolding mutation with modifiers of N-glycosylation. J. Exp. Med. 205: 1729-1737, 2008. [PubMed: 18625743, images, related citations] [Full Text]

  13. Vogt, G., Chapgier, A., Yang, K., Chuzhanova, N., Feinberg, J., Fieschi, C., Boisson-Dupuis, S., Alcais, A., Filipe-Santos, O., Bustamante, J., de Beaucoudrey, L., Al-Mohsen, I., and 20 others. Gains of glycosylation comprise an unexpectedly large group of pathogenic mutations. Nature Genet. 37: 692-700, 2005. [PubMed: 15924140, related citations] [Full Text]


Cassandra L. Kniffin - updated : 10/06/2021
Hilary J. Vernon - updated : 11/30/2020
Ada Hamosh - updated : 10/07/2019
Matthew B. Gross - updated : 9/4/2014
Paul J. Converse - updated : 10/2/2012
Victor A. McKusick - updated : 6/3/2005
Victor A. McKusick - updated : 6/26/1998
Victor A. McKusick - updated : 3/16/1998
Creation Date:
Victor A. McKusick : 9/27/1990
carol : 10/08/2021
carol : 10/07/2021
ckniffin : 10/06/2021
alopez : 02/12/2021
carol : 12/01/2020
carol : 11/30/2020
carol : 07/17/2020
alopez : 10/07/2019
carol : 01/11/2016
carol : 5/14/2015
mgross : 9/4/2014
mgross : 2/12/2013
mgross : 10/8/2012
terry : 10/2/2012
alopez : 7/5/2005
alopez : 6/15/2005
alopez : 6/14/2005
terry : 6/3/2005
carol : 3/3/2004
terry : 3/1/2004
carol : 11/1/2000
carol : 6/29/2000
carol : 6/30/1998
terry : 6/26/1998
alopez : 6/19/1998
alopez : 3/16/1998
terry : 2/25/1998
terry : 1/17/1997
terry : 6/3/1996
terry : 5/28/1996
carol : 7/29/1994
terry : 5/10/1994
carol : 12/6/1993
supermim : 3/16/1992
carol : 8/12/1991
supermim : 9/28/1990

* 147569

INTERFERON-GAMMA RECEPTOR 2; IFNGR2


Alternative titles; symbols

IFGR2
INTERFERON-GAMMA TRANSDUCER 1; IFNGT1
INTERFERON-GAMMA RECEPTOR, ACCESSORY FACTOR FOR


HGNC Approved Gene Symbol: IFNGR2

Cytogenetic location: 21q22.11     Genomic coordinates (GRCh38): 21:33,402,882-33,437,516 (from NCBI)


Gene-Phenotype Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
21q22.11 Immunodeficiency 28, mycobacteriosis 614889 Autosomal recessive 3

TEXT

Gene Structure

Rhee et al. (1996) found that the IFNGR2 gene spans over 33 kb of DNA and contains 7 exons. A signal peptide is encoded by exons 1 and 2, the extracellular domain by exons 2, 3, 4, 5, and part of 6. Exon 6 also encodes the entire transmembrane domain and part of the intracellular domain. Exon 7 encodes the remainder of the intracellular domain and contains the 3-prime untranslated region. No TATA or CAAT boxes were found in the promoter region. Consistent with the lack of a TATA box, analysis of mRNAs by primer extension showed multiple transcription start sites.


Biochemical Features

Crystal Structure

Mendoza et al. (2019) engineered an affinity-enhanced variant of the ligand-binding chain of the IFN-gamma receptor IFNGR1 (107470), 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 IFNG 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 IFNG variants to tune IFNG receptor signaling output.


Mapping

For the cellular response of somatic cell hybrids (from fibroblasts) to gamma-interferon (IFNG; 147570), the gamma-interferon receptor on 6q and a factor on chromosome 21q are necessary (Jung et al., 1987). Langer et al. (1990) demonstrated that the factor encoded by chromosome 21 is separate from the alpha and beta interferon receptors (see 107450) but maps to the same region. In hamster-human somatic cell hybrids, the presence of the IFN-gamma receptor-related factor mediating cellular responsiveness was determined by HLA induction in hybrid cells containing the IFN-gamma receptor on 6q, a transfected copy of the human HLA-B7 gene, and various portions of chromosome 21. In all hybrids, the IFNGT1 gene cosegregated with the IFNAR gene. (Presumably this is the same as the IFNGR2 gene, which previously, probably incorrectly, was thought to be located on chromosome 18; see 107470.) Bono et al. (1991) likewise mapped this gene to chromosome 21 by study of somatic cell hybrids.

Soh et al. (1993) identified a small region of chromosome 21 that is responsible for encoding accessory factor(s) by study of hamster-human somatic cell hybrids carrying an irradiation-reduced fragment of human chromosome 21. To localize the genes further, 10 different YAC clones from 6 different loci in the region were fused to a human-hamster hybrid cell line that contained 6q (supplying the interferon-gamma receptor) and the human HLA-B7 gene. These transformed cells were assayed for induction of class I HLA antigens upon treatment with gamma-interferon.

Soh et al. (1993) described a 540-kb YAC that could substitute for chromosome 21 in functioning as the accessory factor. The factor encoded by the YAC did not confer antiviral protection against the encephalomyocarditis virus, however, demonstrating that an additional factor encoded on human chromosome 21 is required for the antiviral activity.

Mariano et al. (1996) mapped the Ifgr2 gene to the distal end of mouse chromosome 16 by the study of interspecies backcrosses.


Molecular Genetics

Mutations in the IFN-gamma receptor ligand-binding chain (IFNGR1; 107470) have been shown to confer susceptibility to severe infection with nontuberculous mycobacteria (IMD27A; 209950). Dorman and Holland (1998) described a child with disseminated Mycobacterium fortuitum and M. avium complex infections associated with absent IFN-gamma signaling (IMD28; 614889) due to a mutation in the extracellular domain of IFNGR2 (147569.0001). The patient was a male who had 2 episodes of otitis media and 1 episode of thrush, all of which responded promptly to standard treatment. He received prescribed childhood immunizations but did not receive BCG vaccine. At 20 months of age, he developed a cough with pulmonary infiltrates that did not resolve with antibiotics. At 2 years of age, he developed lymphadenopathy, hepatosplenomegaly, and fevers. Biopsy of an axillary lymph node showed capsular fibrosis and histiocytic infiltration without abscesses or granulomata. Acid-fast bacilli were present on staining, and cultures grew the 2 forms of mycobacterium mentioned. Intensive therapy failed to eliminate the infection. The mother was of English descent and the father of English and Portuguese descent; they were not known to be related. A maternal aunt had been diagnosed with tuberculosis at age 3 years and subsequently developed cervical lymphadenopathy; she died at the age of 26 years of chronic aggressive hepatitis. In vitro cytokine production by the patient's peripheral blood mononuclear cells showed 75% less PHA-induced interferon-gamma production than in normal cells, while the patient's PHA-induced TNF-alpha production was normal.

Mutations involving gains of glycosylation had been considered rare, and the pathogenic role of the new carbohydrate chains had not been formally established. Vogt et al. (2005) identified 3 children with mendelian susceptibility to mycobacterial disease who were homozygous for a missense mutation in the IFNGR2 gene (147569.0002), creating a new N-glycosylation site in the IFNGR2 chain. The resulting additional carbohydrate moiety was both necessary and sufficient to abolish the cellular response to IFN-gamma. Vogt et al. (2005) then searched the Human Gene Mutation Database maintained at Cardiff University for potential gain-of-N-glycosylation missense mutations; of 10,047 mutations in 577 genes encoding proteins trafficked through the secretory pathway, they identified 142 candidate mutations (approximately 1.4%) in 77 genes (approximately 13.3%). Six mutant proteins bore new N-linked carbohydrate moieties. Thus, an unexpectedly high proportion of mutations that cause human genetic disease might lead to the creation of new N-glycosylation sites. Their pathogenic effects may be a direct consequence of the addition of N-linked carbohydrate.

Vogt et al. (2008) reported a child with M. avium disease due to complete IFNGR2 deficiency who was homozygous for an in-frame 6-bp duplication in IFNGR2, resulting in duplication thr128 and met129 (147569.0004). They found that the mutant protein was mostly retained within the cell and not expressed on the cell surface. Surface-expressed mutant IFNGR2 was abnormally folded, high in molecular mass, and N-glycosylated, but it was resistant to endoglycosidase H. The mutation created no known consensus sites for posttranslational modifications, including N-glycosylation. Treating cells expressing the mutant protein with 13 of 29 compounds affecting protein maturation by N-glycosylation reduced the molecular mass of surface-expressed mutant IFNGR2 and restored cellular responsiveness to IFNG. Vogt et al. (2008) proposed that modifiers of N-glycosylation, some of which are available for clinical use, may complement human cells carrying in-frame and misfolding mutations in genes encoding proteins subject to trafficking via the secretory pathway.

In 2 sibs from a consanguineous Turkish family and a boy from a consanguineous Indian family with IMD28, Oleaga-Quintas et al. (2018) identified homozygous mutations in the IFNGR2 gene (M1V, 147569.0005 and c.4delC, 147569.0006, respectively). The mutations, which were identified by whole-exome sequencing and confirmed by Sanger sequencing, were present in heterozygous state in the parents. Overexpression of each mutant IFNGR2 cDNA in HEK293-T cells resulted in reduced levels of full-length protein. Oleaga-Quintas et al. (2018) showed that the full-length IFNGR2 proteins resulting from the mutant cDNAs were due to initiation of translation by non-AUG codons located between codons 2 and 9 in the 21-amino acid signal peptide. Expression of IFNGR2 with either mutation in SV40F cells resulted in an impaired, but not absent, response to IFNG stimulation.


ALLELIC VARIANTS 7 Selected Examples):

.0001   IMMUNODEFICIENCY 28

IFNGR2, 2-BP DEL, 278AG
SNP: rs587776822, ClinVar: RCV000015847

In a male child with disseminated infection with Mycobacterium fortuitum and M. avium complex (IMD28; 614889), Dorman and Holland (1998) found a homozygous dinucleotide deletion (AG) involving nucleotides 278 and 279 in exon 3 of the IFNGR2 gene. The deletion caused a frameshift and a premature stop codon (TGA).


.0002   IMMUNODEFICIENCY 28

IFNGR2, THR168ASN
SNP: rs74315444, ClinVar: RCV000015848

In 3 children with mendelian susceptibility to mycobacterial disease (IMD28; 614889), 1 Iranian and 2 Saudi Arabian, all from consanguineous parents, Vogt et al. (2005) found a homozygous 503C-A transversion in the IFNGR2 gene resulting in a thr168-to-asn (T168N) amino acid substitution. The healthy parents were heterozygous for the mutation. The T168N mutation in IFNGR2 was said to be the first reported germline mutation for which a causal relationship was unequivocally established between the gain of glycosylation and the loss of function. The mutation results in a protein carrying an N-linked carbohydrate moiety attached at asn168. This polysaccharide was both necessary and sufficient to account for the pathologic effect of the T168N mutation.

Mendoza et al. (2019) determined the crystal structure of the IFNG-IFNGR1-IFNGR2 signaling complex and proposed that the additional steric bulk introduced by the T168N substitution, directly at the site 3 interface, prevents the IFNGR2(T168N) protein from docking to the high affinity 2:2 IFNG-IFNGR1 intermediate to complete the signaling complex.


.0003   IMMUNODEFICIENCY 28

IFNGR2, 7-BP DEL, NT663
SNP: rs587776823, ClinVar: RCV000015849

In an Austrian child of consanguineous parents with mendelian susceptibility to mycobacterial disease (IMD28; 614889), Vogt et al. (2005) found a novel homozygous in-frame 27-bp microdeletion of nucleotides 663-689 of the IFNGR2 gene (663del27), predicted to lead to the deletion of amino acids 222-230. Both parents, heterozygous for the mutation, were healthy.


.0004   IMMUNODEFICIENCY 28

IFNGR2, 6-BP DUP, NT382
SNP: rs398122890, ClinVar: RCV000030825

Vogt et al. (2008) reported a child of consanguineous parents with mycobacterial disease (IMD28; 614889) due to a homozygous in-frame duplication of nucleotides 382 to 387 in the IFNGR2 gene, resulting in a duplication of thr128 and met129. Both parents and 1 of 2 sibs were heterozygous for the mutation, but they did not develop disease. The affected child died at age 5 years of disseminated M. avium disease in spite of treatment with multiple antimycobacterial drugs. The mutant IFNGR2 protein was predominantly retained intracellularly, and the fraction expressed on the surface had a high molecular mass, was abnormally folded, and did not respond to IFNG (147570).


.0005   IMMUNODEFICIENCY 28

IFNGR2, MET1VAL
SNP: rs1316638883, gnomAD: rs1316638883, ClinVar: RCV001268955

In 2 Turkish sibs (P1 and P2), born to consanguineous parents, with susceptibility to mycobacterial disease (IMD28; 614889), Oleaga-Quintas et al. (2018) identified a homozygous c.1A-G transition in the IFNGR2 gene, resulting in a met1-to-val (M1V) substitution. The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the parents. The variant was reported once in heterozygous state in the gnomAD database. Elevated levels of IFNG (147570) were detected in plasma from the sibs compared to controls, and elevated levels of IFNG were also detected in whole blood from both sibs after stimulation with BCG and IL12 (see 161560). Overexpression of the mutant IFNGR2 cDNA in HEK293-T cells resulted in a reduced amount of full-length protein. Expression of IFNGR2 with the M1V mutation in SV40F cells resulted in an impaired, but not absent, response to IFNG stimulation.


.0006   IMMUNODEFICIENCY 28

IFNGR2, 1-BP DEL, 4C
SNP: rs2083655919, ClinVar: RCV001269033

In an Indian boy, born to consanguineous parents, with susceptibility to mycobacterial disease (IMD28; 614889), Oleaga-Quintas et al. (2018) identified a homozygous 1-bp deletion (c.4delC) in the IFNGR2 gene, predicted to cause early termination 22 residues downstream of the start codon. The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the parents. The mutation was not present in the gnomAD database. Elevated levels of IFNG (147570) were detected in plasma from the patient compared to controls. Overexpression of the mutant IFNGR2 cDNA in HEK293-T cells resulted in a reduced amount of full-length protein. Expression of IFNGR2 with the c.4delC mutation in SV40F cells resulted in an impaired, but not absent, response to IFNG stimulation.


.0007   IMMUNODEFICIENCY 28

IFNGR2, 1-BP DEL, 798T
SNP: rs2123370265, ClinVar: RCV001728186

In a boy, born of consanguineous Saudi parents, with immunodeficiency-28 (IMD28; 614889), Hoyos-Bachiloglu et al. (2017) identified a homozygous 1-bp deletion (c.798delT, NM_005534) in the IFNGR2 gene, resulting in a frameshift and premature termination (Cys266fs) upstream of the residues essential for JAK2 (147796). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. Patient cells showed decreased mRNA levels compared to controls, suggesting that the mutation triggered nonsense-mediated mRNA decay. Transfection of the mutation into HEK293 cells confirmed that the mutant protein has a shorter half-life than wildtype and is degraded by endoplasmic reticulum-associated protein degradation (ERAD). In vitro functional expression studies using patient-derived fibroblasts showed impaired response to stimulation with gamma-IFN as manifest by failure of STAT1 phosphorylation and upregulation of HLA-DR after exposure. The findings, which indicated a defect in the type II interferon pathway resulting from autosomal recessive complete IFNGR2 deficiency, were consistent with the patient's early-onset disseminated mycobacterial disease. In addition to mycobacterial infection, the patient developed cytomegalovirus (CMV) viremia. Whole-exome sequencing identified a homozygous loss-of-function variant in the IFNAR1 gene (107450.0004). Sanger sequencing confirmed that each parent was heterozygous for this variant. Additional in vitro functional expression studies showed impaired downstream IFNAR signaling after stimulation with alpha-IFN, indicating a defect in the IFN type I signaling pathway that may have resulted from the IFNAR1 variant. These findings of likely digenic inheritance were consistent with the patient's atypical presentation for IMD28, which comprised defects in both type I and type II IFN signaling.


See Also:

Bono et al. (1987)

REFERENCES

  1. Bono, M. R., Alcaide-Loridan, C., Couillin, P., Letouze, B., Grisard, M. C., Jouin, H., Fellous, M. Human chromosome 16 encodes a factor involved in induction of class II major histocompatibility antigens by interferon gamma. Proc. Nat. Acad. Sci. 88: 6077-6081, 1991. [PubMed: 1906174] [Full Text: https://doi.org/10.1073/pnas.88.14.6077]

  2. Bono, R., Hatat, D., Couillin, P., Grisard, M. C., Van Cong, N., Fisher, D., Fellous, M. Receptor for human gamma interferon is specified by human chromosomes 6 and 21. (Abstract) Cytogenet. Cell Genet. 46: 584, 1987.

  3. Dorman, S. E., Holland, S. M. Mutation in the signal-transducing chain of the interferon-gamma receptor and susceptibility to mycobacterial infection. J. Clin. Invest. 101: 2364-2369, 1998. [PubMed: 9616207] [Full Text: https://doi.org/10.1172/JCI2901]

  4. Hoyos-Bachiloglu, R., Chou J., Sodroski, C. N., Beano, A., Bainter, W., Angelova, M., Al Idrissi, E., Habazi, M. K., Alghamdi, H. A., Almanjomi, F., Al Shehri, M., Elsidig, N., Eldin, M. A., Knipe, D. M., AlZahrani, M., Geha, R. S. A digenic human immunodeficiency characterized by IFNAR1 and IFNGR2 mutations. J. Clin. Invest. 127: 4415-4420, 2017. [PubMed: 29106381] [Full Text: https://doi.org/10.1172/JCI93486]

  5. Jung, V., Rashidbaigi, A., Jones, C., Tischfield, J. A., Shows, T. B., Pestka, S. Human chromosomes 6 and 21 are required for sensitivity to human interferon gamma. Proc. Nat. Acad. Sci. 84: 4151-4155, 1987. [PubMed: 2954164] [Full Text: https://doi.org/10.1073/pnas.84.12.4151]

  6. Langer, J. A., Rashidbaigi, A., Lai, L.-W., Patterson, D., Jones, C. Sublocalization on chromosome 21 of human interferon-alpha receptor gene and the gene for an interferon-gamma response protein. Somat. Cell Molec. Genet. 16: 231-240, 1990. [PubMed: 2141727] [Full Text: https://doi.org/10.1007/BF01233359]

  7. Mariano, T. M., Muthukumaran, G., Donnelly, R. J., Wang, N., Adamson, M. C., Pestka, S., Kozak, C. A. Genetic mapping of the gene for the mouse interferon-gamma receptor signaling subunit to the distal end of chromosome 16. Mammalian Genome 7: 321-322, 1996. [PubMed: 8661709] [Full Text: https://doi.org/10.1007/s003359900093]

  8. Mendoza, J. L., Escalante, N. K., Jude, K. M., Sotolongo Bellon, J., Su, L., Horton, T. M., Tsutsumi, N., Berardinelli, S. J., Haltiwanger, R. S., Piehler, J., Engleman, E. G., Garcia, K. C. Structure of the IFN-gamma receptor complex guides design of biased agonists. Nature 567: 56-60, 2019. [PubMed: 30814731] [Full Text: https://doi.org/10.1038/s41586-019-0988-7]

  9. Oleaga-Quintas, C., Deswarte, C., Moncada-Velez, M., Metin, A., Rao, I. K., Kanik-Yuksek, S., Nieto-Patlan, A., Guerin, A., Gulhan, B., Murthy, S., Ozkaya-Parlakay, A., Abel, L., Martinez-Barricarte, R., Perez de Diego, R., Boisson-Dupuis, S., Kong, X.-F., Casanova, J.-L., Bustamante, J. A purely quantitative form of partial recessive IFN-gamma-R2 deficiency caused by mutations of the initiation or second codon. Hum. Molec. Genet. 27: 3919-3935, 2018. Note: Erratum: Hum. Molec. Genet. 28: 524 only, 2019. [PubMed: 31222290] [Full Text: https://doi.org/10.1093/hmg/ddy275]

  10. Rhee, S., Ebensperger, C., Dembic, Z., Pestka, S. The structure of the gene for the second chain of the human interferon-gamma receptor. J. Biol. Chem. 271: 28947-28952, 1996. [PubMed: 8910544] [Full Text: https://doi.org/10.1074/jbc.271.46.28947]

  11. Soh, J., Donnelly, R. J., Mariano, T. M., Cook, J. R., Schwartz, B., Pestka, S. Identification of a yeast artificial chromosome clone encoding an accessory factor for the human interferon gamma receptor: evidence for multiple accessory factors. Proc. Nat. Acad. Sci. 90: 8737-8741, 1993. [PubMed: 8378357] [Full Text: https://doi.org/10.1073/pnas.90.18.8737]

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  13. Vogt, G., Chapgier, A., Yang, K., Chuzhanova, N., Feinberg, J., Fieschi, C., Boisson-Dupuis, S., Alcais, A., Filipe-Santos, O., Bustamante, J., de Beaucoudrey, L., Al-Mohsen, I., and 20 others. Gains of glycosylation comprise an unexpectedly large group of pathogenic mutations. Nature Genet. 37: 692-700, 2005. [PubMed: 15924140] [Full Text: https://doi.org/10.1038/ng1581]


Contributors:
Cassandra L. Kniffin - updated : 10/06/2021
Hilary J. Vernon - updated : 11/30/2020
Ada Hamosh - updated : 10/07/2019
Matthew B. Gross - updated : 9/4/2014
Paul J. Converse - updated : 10/2/2012
Victor A. McKusick - updated : 6/3/2005
Victor A. McKusick - updated : 6/26/1998
Victor A. McKusick - updated : 3/16/1998

Creation Date:
Victor A. McKusick : 9/27/1990

Edit History:
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carol : 7/29/1994
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supermim : 3/16/1992
carol : 8/12/1991
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