RBCC

Full text data of IFNGR1

IFNGR1 [Confidence: high (a blood group or CD marker)]
Interferon gamma receptor 1; IFN-gamma receptor 1; IFN-gamma-R1 (CDw119; CD119; Flags: Precursor)

UniProt P15260
ID INGR1_HUMAN Reviewed; 489 AA.
AC P15260; E1P587; Q53Y96;
DT 01-APR-1990, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-APR-1990, sequence version 1.
DT 22-JAN-2014, entry version 162.
DE RecName: Full=Interferon gamma receptor 1;
DE Short=IFN-gamma receptor 1;
DE Short=IFN-gamma-R1;
DE AltName: Full=CDw119;
DE AltName: CD_antigen=CD119;
DE Flags: Precursor;
GN Name=IFNGR1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=2971451; DOI=10.1016/0092-8674(88)90050-5;
RA Aguet M., Dembic Z., Merlin G.;
RT "Molecular cloning and expression of the human interferon-gamma
RT receptor.";
RL Cell 55:273-280(1988).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS ILE-61; PRO-335 AND
RP PRO-467.
RG SeattleSNPs variation discovery resource;
RL Submitted (APR-2004) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor
RT vector.";
RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=14574404; DOI=10.1038/nature02055;
RA Mungall A.J., Palmer S.A., Sims S.K., Edwards C.A., Ashurst J.L.,
RA Wilming L., Jones M.C., Horton R., Hunt S.E., Scott C.E.,
RA Gilbert J.G.R., Clamp M.E., Bethel G., Milne S., Ainscough R.,
RA Almeida J.P., Ambrose K.D., Andrews T.D., Ashwell R.I.S.,
RA Babbage A.K., Bagguley C.L., Bailey J., Banerjee R., Barker D.J.,
RA Barlow K.F., Bates K., Beare D.M., Beasley H., Beasley O., Bird C.P.,
RA Blakey S.E., Bray-Allen S., Brook J., Brown A.J., Brown J.Y.,
RA Burford D.C., Burrill W., Burton J., Carder C., Carter N.P.,
RA Chapman J.C., Clark S.Y., Clark G., Clee C.M., Clegg S., Cobley V.,
RA Collier R.E., Collins J.E., Colman L.K., Corby N.R., Coville G.J.,
RA Culley K.M., Dhami P., Davies J., Dunn M., Earthrowl M.E.,
RA Ellington A.E., Evans K.A., Faulkner L., Francis M.D., Frankish A.,
RA Frankland J., French L., Garner P., Garnett J., Ghori M.J.,
RA Gilby L.M., Gillson C.J., Glithero R.J., Grafham D.V., Grant M.,
RA Gribble S., Griffiths C., Griffiths M.N.D., Hall R., Halls K.S.,
RA Hammond S., Harley J.L., Hart E.A., Heath P.D., Heathcott R.,
RA Holmes S.J., Howden P.J., Howe K.L., Howell G.R., Huckle E.,
RA Humphray S.J., Humphries M.D., Hunt A.R., Johnson C.M., Joy A.A.,
RA Kay M., Keenan S.J., Kimberley A.M., King A., Laird G.K., Langford C.,
RA Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C.R., Lloyd D.M.,
RA Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M.,
RA Maslen G.L., Matthews L., McCann O.T., McLaren S.J., McLay K.,
RA McMurray A., Moore M.J.F., Mullikin J.C., Niblett D., Nickerson T.,
RA Novik K.L., Oliver K., Overton-Larty E.K., Parker A., Patel R.,
RA Pearce A.V., Peck A.I., Phillimore B.J.C.T., Phillips S., Plumb R.W.,
RA Porter K.M., Ramsey Y., Ranby S.A., Rice C.M., Ross M.T., Searle S.M.,
RA Sehra H.K., Sheridan E., Skuce C.D., Smith S., Smith M., Spraggon L.,
RA Squares S.L., Steward C.A., Sycamore N., Tamlyn-Hall G., Tester J.,
RA Theaker A.J., Thomas D.W., Thorpe A., Tracey A., Tromans A., Tubby B.,
RA Wall M., Wallis J.M., West A.P., White S.S., Whitehead S.L.,
RA Whittaker H., Wild A., Willey D.J., Wilmer T.E., Wood J.M., Wray P.W.,
RA Wyatt J.C., Young L., Younger R.M., Bentley D.R., Coulson A.,
RA Durbin R.M., Hubbard T., Sulston J.E., Dunham I., Rogers J., Beck S.;
RT "The DNA sequence and analysis of human chromosome 6.";
RL Nature 425:805-811(2003).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Prostate;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [7]
RP DISULFIDE BONDS, PARTIAL PROTEIN SEQUENCE, AND MUTAGENESIS.
RX PubMed=8443182; DOI=10.1021/bi00060a038;
RA Stueber D., Friedlein A., Fountoulakis M., Lahm H.-W., Garotta G.;
RT "Alignment of disulfide bonds of the extracellular domain of the
RT interferon gamma receptor and investigation of their role in
RT biological activity.";
RL Biochemistry 32:2423-2430(1993).
RN [8]
RP X-RAY CRYSTALLOGRAPHY (2.9 ANGSTROMS) OF 26-248.
RX PubMed=7617032; DOI=10.1038/376230a0;
RA Walter M.R., Windsor W.T., Nagabhushan T.L., Lundell D.J., Lunn C.A.,
RA Zauodny P.J., Narula S.K.;
RT "Crystal structure of a complex between interferon-gamma and its
RT soluble high-affinity receptor.";
RL Nature 376:230-235(1995).
RN [9]
RP X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 28-122 IN COMPLEX WITH
RP ANTIBODY.
RX PubMed=9367779; DOI=10.1006/jmbi.1997.1336;
RA Sogabe S., Stuart F., Henke C., Bridges A., Williams G., Birch A.,
RA Winkler F.K., Robinson J.A.;
RT "Neutralizing epitopes on the extracellular interferon gamma receptor
RT (IFNgammaR) alpha-chain characterized by homolog scanning mutagenesis
RT and X-ray crystal structure of the A6 fab-IFNgammaR1-108 complex.";
RL J. Mol. Biol. 273:882-897(1997).
RN [10]
RP X-RAY CRYSTALLOGRAPHY (2.9 ANGSTROMS) OF COMPLEX WITH ING.
RX PubMed=10986460; DOI=10.1016/S0969-2126(00)00184-2;
RA Thiel D.J., le Du M.-H., Walter R.L., D'Arcy A., Chene C.,
RA Fountoulakis M., Garotta G., Winkler F.K., Ealick S.E.;
RT "Observation of an unexpected third receptor molecule in the crystal
RT structure of human interferon-gamma receptor complex.";
RL Structure 8:927-936(2000).
RN [11]
RP VARIANT MSMD THR-87.
RX PubMed=9389728; DOI=10.1172/JCI119810;
RA Jouanguy E., Lamhamedi-Cherradi S.-E., Altare F., Fondaneche M.-C.,
RA Tuerlinckx D., Blanche S., Emile J.-F., Gaillard J.-L., Schreiber R.,
RA Levin M., Fischer A., Hivroz C., Casanova J.-L.;
RT "Partial interferon-gamma receptor 1 deficiency in a child with
RT tuberculoid bacillus Calmette-Guerin infection and a sibling with
RT clinical tuberculosis.";
RL J. Clin. Invest. 100:2658-2664(1997).
RN [12]
RP VARIANTS MSMD TYR-77 AND 99-TRP--VAL-102 DEL.
RX PubMed=10811850; DOI=10.1172/JCI9166;
RA Jouanguy E., Dupuis S., Pallier A., Doffinger R., Fondaneche M.-C.,
RA Fieschi C., Lamhamedi-Cherradi S., Altare F., Emile J.-F., Lutz P.,
RA Bordigoni P., Cokugras H., Akcakaya N., Landman-Parker J.,
RA Donnadieu J., Camcioglu Y., Casanova J.-L.;
RT "In a novel form of IFN-gamma receptor 1 deficiency, cell surface
RT receptors fail to bind IFN-gamma.";
RL J. Clin. Invest. 105:1429-1436(2000).
RN [13]
RP INVOLVEMENT IN SUSCEPTIBILITY TO HELICOBACTER PYLORI INFECTION, AND
RP VARIANTS PRO-335 AND PRO-467.
RX PubMed=12516030; DOI=10.1086/367714;
RA Thye T., Burchard G.D., Nilius M., Mueller-Myhsok B., Horstmann R.D.;
RT "Genomewide linkage analysis identifies polymorphism in the human
RT interferon-gamma receptor affecting Helicobacter pylori infection.";
RL Am. J. Hum. Genet. 72:448-453(2003).
CC -!- FUNCTION: Receptor for interferon gamma. Two receptors bind one
CC interferon gamma dimer.
CC -!- SUBUNIT: Monomer.
CC -!- INTERACTION:
CC P42224:STAT1; NbExp=5; IntAct=EBI-1030755, EBI-1057697;
CC -!- SUBCELLULAR LOCATION: Membrane; Single-pass type I membrane
CC protein.
CC -!- PTM: Phosphorylated at Ser/Thr residues.
CC -!- POLYMORPHISM: A genetic variation in the IFNGR1 gene is associated
CC with susceptibility to Helicobacter pylori infection [MIM:600263].
CC -!- DISEASE: Mendelian susceptibility to mycobacterial disease (MSMD)
CC [MIM:209950]: This rare condition confers predisposition to
CC illness caused by moderately virulent mycobacterial species, such
CC as Bacillus Calmette-Guerin (BCG) vaccine and environmental non-
CC tuberculous mycobacteria, and by the more virulent Mycobacterium
CC tuberculosis. Other microorganisms rarely cause severe clinical
CC disease in individuals with susceptibility to mycobacterial
CC infections, with the exception of Salmonella which infects less
CC than 50% of these individuals. The pathogenic mechanism underlying
CC MSMD is the impairment of interferon-gamma mediated immunity,
CC whose severity determines the clinical outcome. Some patients die
CC of overwhelming mycobacterial disease with lepromatous-like
CC lesions in early childhood, whereas others develop, later in life,
CC disseminated but curable infections with tuberculoid granulomas.
CC MSMD is a genetically heterogeneous disease with autosomal
CC recessive, autosomal dominant or X-linked inheritance. Note=The
CC disease is caused by mutations affecting the gene represented in
CC this entry.
CC -!- SIMILARITY: Belongs to the type II cytokine receptor family.
CC -!- SIMILARITY: Contains 2 fibronectin type-III domains.
CC -!- SIMILARITY: Contains 2 Ig-like C2-type (immunoglobulin-like)
CC domains.
CC -!- WEB RESOURCE: Name=IFNGR1base; Note=IFNGR1 mutation db;
CC URL="http://bioinf.uta.fi/IFNGR1base/";
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/IFNGR1";
CC -!- WEB RESOURCE: Name=SeattleSNPs;
CC URL="http://pga.gs.washington.edu/data/ifngr1/";
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; J03143; AAA52731.1; -; mRNA.
DR EMBL; AY594694; AAS89302.1; -; Genomic_DNA.
DR EMBL; BT006814; AAP35460.1; -; mRNA.
DR EMBL; AL050337; CAB53062.1; -; Genomic_DNA.
DR EMBL; CH471051; EAW47931.1; -; Genomic_DNA.
DR EMBL; CH471051; EAW47932.1; -; Genomic_DNA.
DR EMBL; BC005333; AAH05333.1; -; mRNA.
DR PIR; A31555; A31555.
DR RefSeq; NP_000407.1; NM_000416.2.
DR UniGene; Hs.520414; -.
DR PDB; 1FG9; X-ray; 2.90 A; C/D/E=18-262.
DR PDB; 1FYH; X-ray; 2.04 A; B/E=18-246.
DR PDB; 1JRH; X-ray; 2.80 A; I=18-125.
DR PDBsum; 1FG9; -.
DR PDBsum; 1FYH; -.
DR PDBsum; 1JRH; -.
DR ProteinModelPortal; P15260; -.
DR SMR; P15260; 28-241.
DR DIP; DIP-47N; -.
DR IntAct; P15260; 6.
DR MINT; MINT-8013365; -.
DR STRING; 9606.ENSP00000356713; -.
DR ChEMBL; CHEMBL2364171; -.
DR DrugBank; DB00033; Interferon gamma-1b.
DR PhosphoSite; P15260; -.
DR UniCarbKB; P15260; -.
DR DMDM; 124474; -.
DR PaxDb; P15260; -.
DR PRIDE; P15260; -.
DR DNASU; 3459; -.
DR Ensembl; ENST00000367739; ENSP00000356713; ENSG00000027697.
DR GeneID; 3459; -.
DR KEGG; hsa:3459; -.
DR UCSC; uc003qho.2; human.
DR CTD; 3459; -.
DR GeneCards; GC06M137518; -.
DR HGNC; HGNC:5439; IFNGR1.
DR HPA; CAB004444; -.
DR HPA; HPA029213; -.
DR MIM; 107470; gene.
DR MIM; 209950; phenotype.
DR MIM; 600263; phenotype.
DR neXtProt; NX_P15260; -.
DR Orphanet; 319581; Autosomal dominant mendelian susceptibility to mycobacterial diseases due to partial IFNgammaR1 deficiency.
DR Orphanet; 319569; Autosomal recessive mendelian susceptibility to mycobacterial diseases due to partial IFNgammaR1 deficiency.
DR Orphanet; 99898; Mendelian susceptibility to mycobacterial diseases due to complete IFNgammaR1 deficiency.
DR PharmGKB; PA29675; -.
DR eggNOG; NOG45077; -.
DR HOGENOM; HOG000113074; -.
DR HOVERGEN; HBG052128; -.
DR InParanoid; P15260; -.
DR KO; K05132; -.
DR OMA; NSYHSRN; -.
DR PhylomeDB; P15260; -.
DR Reactome; REACT_6900; Immune System.
DR SignaLink; P15260; -.
DR ChiTaRS; IFNGR1; human.
DR EvolutionaryTrace; P15260; -.
DR GeneWiki; Interferon_gamma_receptor_1; -.
DR GenomeRNAi; 3459; -.
DR NextBio; 13628; -.
DR PRO; PR:P15260; -.
DR ArrayExpress; P15260; -.
DR Bgee; P15260; -.
DR CleanEx; HS_IFNGR1; -.
DR Genevestigator; P15260; -.
DR GO; GO:0005887; C:integral to plasma membrane; TAS:ProtInc.
DR GO; GO:0004906; F:interferon-gamma receptor activity; TAS:ProtInc.
DR GO; GO:0060334; P:regulation of interferon-gamma-mediated signaling pathway; TAS:Reactome.
DR GO; GO:0009615; P:response to virus; TAS:ProtInc.
DR Gene3D; 2.60.40.10; -; 2.
DR InterPro; IPR003961; Fibronectin_type3.
DR InterPro; IPR013783; Ig-like_fold.
DR InterPro; IPR021126; Interferon_gamma_pox/mammal.
DR InterPro; IPR008355; Interferon_gamma_rcpt_asu.
DR PANTHER; PTHR20859:SF5; PTHR20859:SF5; 1.
DR Pfam; PF07140; IFNGR1; 1.
DR PRINTS; PR01777; INTERFERONGR.
DR SUPFAM; SSF49265; SSF49265; 2.
DR PROSITE; PS50853; FN3; FALSE_NEG.
PE 1: Evidence at protein level;
KW 3D-structure; Complete proteome; Direct protein sequencing;
KW Disease mutation; Disulfide bond; Glycoprotein; Immunoglobulin domain;
KW Membrane; Phosphoprotein; Polymorphism; Receptor; Reference proteome;
KW Signal; Transmembrane; Transmembrane helix.
FT SIGNAL 1 17
FT CHAIN 18 489 Interferon gamma receptor 1.
FT /FTId=PRO_0000011009.
FT TOPO_DOM 18 245 Extracellular (Potential).
FT TRANSMEM 246 266 Helical; (Potential).
FT TOPO_DOM 267 489 Cytoplasmic (Potential).
FT MOD_RES 369 369 Phosphoserine (By similarity).
FT CARBOHYD 34 34 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 79 79 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 86 86 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 179 179 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 240 240 N-linked (GlcNAc...) (Potential).
FT DISULFID 77 85
FT DISULFID 122 167
FT DISULFID 195 200
FT DISULFID 214 235
FT VARIANT 61 61 V -> I (in dbSNP:rs17175322).
FT /FTId=VAR_019281.
FT VARIANT 77 77 C -> Y (in MSMD; fails to bind IFN-
FT gamma).
FT /FTId=VAR_017577.
FT VARIANT 87 87 I -> T (in MSMD; impaired response to
FT IFN-gamma).
FT /FTId=VAR_017578.
FT VARIANT 99 102 Missing (in MSMD; fails to bind IFN-
FT gamma).
FT /FTId=VAR_017579.
FT VARIANT 335 335 H -> P (in dbSNP:rs17175350).
FT /FTId=VAR_019282.
FT VARIANT 467 467 L -> P (in dbSNP:rs1887415).
FT /FTId=VAR_019283.
FT STRAND 33 38
FT STRAND 40 42
FT STRAND 45 49
FT STRAND 58 65
FT STRAND 69 71
FT STRAND 74 86
FT HELIX 88 90
FT STRAND 98 106
FT HELIX 121 124
FT STRAND 131 136
FT STRAND 138 146
FT HELIX 149 151
FT STRAND 168 178
FT STRAND 181 191
FT STRAND 197 205
FT STRAND 212 221
FT TURN 222 224
FT STRAND 234 237
SQ SEQUENCE 489 AA; 54405 MW; DCF9E574D8F47400 CRC64;
MALLFLLPLV MQGVSRAEMG TADLGPSSVP TPTNVTIESY NMNPIVYWEY QIMPQVPVFT
VEVKNYGVKN SEWIDACINI SHHYCNISDH VGDPSNSLWV RVKARVGQKE SAYAKSEEFA
VCRDGKIGPP KLDIRKEEKQ IMIDIFHPSV FVNGDEQEVD YDPETTCYIR VYNVYVRMNG
SEIQYKILTQ KEDDCDEIQC QLAIPVSSLN SQYCVSAEGV LHVWGVTTEK SKEVCITIFN
SSIKGSLWIP VVAALLLFLV LSLVFICFYI KKINPLKEKS IILPKSLISV VRSATLETKP
ESKYVSLITS YQPFSLEKEV VCEEPLSPAT VPGMHTEDNP GKVEHTEELS SITEVVTTEE
NIPDVVPGSH LTPIERESSS PLSSNQSEPG SIALNSYHSR NCSESDHSRN GFDTDSSCLE
SHSSLSDSEF PPNNKGEIKT EGQELITVIK APTSFGYDKP HVLVDLLVDD SGKESLIGYR
PTEDSKEFS
//

MIM 107470
*RECORD*
*FIELD* NO
107470
*FIELD* TI
*107470 INTERFERON-GAMMA RECEPTOR 1; IFNGR1
;;AVP, TYPE II;;
ANTIVIRAL PROTEIN, TYPE II;;
read moreIMMUNE INTERFERON RECEPTOR 1;;
CD119 ANTIGEN; CD119
*FIELD* TX

DESCRIPTION

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 (147660), produced by
leukocytes or lymphoblastoid cells, and beta-interferon (147640),
produced by fibroblasts. Mitogens and antigenic stimuli induce in
lymphocytes type II, immune, or gamma-interferon (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.

CLONING

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.

GENE FUNCTION

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.

MAPPING

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.

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.

MOLECULAR GENETICS

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 (see 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 (147475) 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
(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. Deletion of
nucleotide 131 in the coding region was found. Deletion of C at this
position caused a frameshift and led to a premature stop codon (TAA) at
nucleotides 187-189 of their sequence. 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.

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 (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. (1999) described 18 patients with sporadic or dominantly
inherited susceptibility to infections caused by poorly virulent
mycobacteria. 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 INFGR1. 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.

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 did impair 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.

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.

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).

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.

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 antituberculsosis 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.

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 (see 607948), 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.

GENOTYPE/PHENOTYPE CORRELATIONS

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.

ANIMAL MODEL

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.

*FIELD* AV
.0001
ATYPICAL MYCOBACTERIAL INFECTION, FAMILIAL DISSEMINATED
IFNGR1, 395C-A, SER-TER

In 4 children with familial disseminated atypical mycobacterial
infection (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).

.0002
BCG INFECTION, GENERALIZED FAMILIAL
IFNGR1, 1-BP DEL

Jouanguy et al. (1996) identified a mutation in the IFNGR1 gene in a
Tunisian patient with fatal BCG infection (209950). A single nucleotide
deletion, designated 131delC by them, created a frameshift and led to a
premature stop codon (TAA) at nucleotides 187-189 of the coding region
of the IFNGR1 gene. The mutation was located in exon 2. The affected
child was homozygous; both parents and 2 healthy brothers were
heterozygous.

.0003
BCG INFECTION, TUBERCULOID, ANTIBIOTIC-RESPONSIVE
MYCOBACTERIUM TUBERCULOSIS, SUSCEPTIBILITY TO INFECTION BY
IFNGR1, ILE87THR

In a family in which 1 sib had disseminated BCG infection (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.

.0004
ATYPICAL MYCOBACTERIAL INFECTION, FAMILIAL DISSEMINATED
IFNGR1, 4-BP INS, 107TTAC

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 (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. 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.

.0005
ATYPICAL MYCOBACTERIAL INFECTION, FAMILIAL DISSEMINATED
IFNGR1, IVS3DS, G-A, +1

See 107470.0004 and Altare et al. (1998).

.0006
BCG INFECTION, GENERALIZED FAMILIAL SEMIBENIGN
IFNGR1, 4-BP DEL, NT818

Jouanguy et al. (1999) described 3 families and 9 sporadic cases with a
4-bp deletion, referred to as 818del4, at nucleotide 818 of the INFGR1
gene. 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
(BCG; see 209950). 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 at the time of the report.

.0007
ATYPICAL MYCOBACTERIAL INFECTION, DISSEMINATED
IFNGR1, 12-BP DEL, NT295

Jouanguy et al. (2000) reported an only child of first-cousin Algerian
parents living in France who had atypical mycobacterial infection
(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).

.0008
ATYPICAL MYCOBACTERIAL INFECTION, DISSEMINATED FAMILIAL
IFNGR1, CYS77TYR

Jouanguy et al. (2000) reported 2 sibs, a boy and a girl, born to
consanguineous Turkish parents who had atypical mycobacterial infections
(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 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).

.0009
ATYPICAL MYCOBACTERIAL INFECTION, DISSEMINATED
IFNGR1, VAL61GLN

Jouanguy et al. (2000) reported a child of a French mother and a
Portuguese father living in France who had atypical mycobacterial
infection (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 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).

.0010
ATYPICAL MYCOBACTERIAL INFECTION, DISSEMINATED
IFNGR1, 3-BP DEL, 652GAA or 653AAG

See 107470.0009 and Jouanguy et al. (2000).

.0011
ATYPICAL MYCOBACTERIAL INFECTION, AUTOSOMAL DOMINANT
IFNGR1, 818 DEL

Jouanguy et al. (1999) reported an Italian family in which a single case
of atypical mycobacterial infection (bacille Calmette-Guerin and
Mycobacterium avium; 209950), 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.

.0012
HELICOBACTER PYLORI INFECTION, SUSCEPTIBILITY TO
MYCOBACTERIUM TUBERCULOSIS, PROTECTION AGAINST, INCLUDED;;
HEPATITIS B VIRUS, SUSCEPTIBILITY TO
IFNGR1, -56C-T

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.

.0013
ATYPICAL MYCOBACTERIAL INFECTION, DISSEMINATED
IFNGR1, 1-BP DEL, 794T

Storgaard et al. (2006) reported a man with disseminated mycobacterial
infection (209950) who had increased IFNGR1 expression but reduced
IFNGR1 function. They identified a 1-bp deletion at nucleotide 794 (T)
in exon 6 of the IFNGR1 gene, resulting in a frameshift at codon 265 and
a premature stop at codon 276. The mutation was not present in the man's
biologic parents, who had normal flow cytometric measurements. The
mutation was present in the patient's 6-year-old daughter, who later
developed mycobacterial osteomyelitis.

.0014
ATYPICAL MYCOBACTERIAL INFECTION, DISSEMINATED
IFNGR1, MET1LYS

Kong et al. (2010) reported a 9-year-old Finnish girl, born to
consanguineous parents, who presented with lymphadenitis after a BCG
vaccination as a newborn and severe Mycobacterium avium infections in
childhood. Elevated plasma levels of interferon-gamma prompted
investigation of IFNGR1 as a candidate gene. The patient was homozygous
for a T-to-A transversion in the initiation codon, leading to a
met1-to-lys (M1K) substitution. No detectable expression or function of
IFNGR1 was found in the patient's fibroblasts. Weak expression in
EBV-transformed B cells was attributed to leaky translation initiation
at both non-AUG codons and the third AUG codon at position 19, resulting
in residual expression of IFNGR1 protein of normal molecular weight and
function.

*FIELD* SA
Alcaide-Loridan et al. (1989)
*FIELD* RF
1. Aguet, M.; Dembic, Z.; Merlin, G.: Molecular cloning and expression
of the human interferon-gamma receptor. Cell 55: 273-280, 1988.

2. Alcaide-Loridan, C.; Le Coniat, M.; Bono, R.; Benech, P.; Couillin,
P.; Van Cong, N.; Fisher, D. N.; Berger, R.; Fellous, M.: Mapping
of the human interferon gamma response. (Abstract) Cytogenet. Cell
Genet. 51: 949 only, 1989.

3. Altare, F.; Jouanguy, E.; Lamhamedi-Cherradi, S.; Fondaneche, M.-C.;
Fizame, C.; Ribierre, F.; Merlin, G.; Dembic, Z.; Schreiber, R.; Lisowska-Grospierre,
B.; Fischer, A.; Seboun, E.; Casanova, J.-L.: A causative relationship
between mutant IFNgR1 alleles and impaired cellular response to IFN-gamma
in a compound heterozygous child. (Letter) Am. J. Hum. Genet. 62:
723-726, 1998.

4. Baldridge, M. T.; King, K. Y.; Boles, N. C.; Weksberg, D. C.; Goodell,
M. A.: Quiescent haematopoietic stem cells are activated by IFN-gamma
in response to chronic infection. Nature 465: 793-797, 2010.

5. Branca, A. A.; Baglioni, C.: Evidence that types I and II interferons
have different receptors. Nature 294: 768-770, 1981.

6. Casanova, J.-L.; Jouanguy, E.; Lamhamedi, S.; Blanche, S.; Fischer,
A.: Immunological conditions of children with BCG disseminated infection.
(Letter) Lancet 346: 581 only, 1995.

7. Celada, A.; Allen, R.; Esparza, I.; Gray, P. W.; Schreiber, R.
D.: Demonstration and partial characterization of the interferon-gamma
receptor on human mononuclear phagocytes. J. Clin. Invest. 76: 2196-2205,
1985.

8. Cooke, G. S.; Campbell, S. J.; Sillah, J.; Gustafson, P.; Bah,
B.; Sirugo, G.; Bennett, S.; McAdam, K. P. W. J.; Sow, O.; Lienhardt,
C.; Hill, A. V. S.: Polymorphism within the interferon-gamma/receptor
complex is associated with pulmonary tuberculosis. Am. J. Resp. Crit.
Care Med. 174: 339-343, 2006.

9. Dalton, D. K.; Pitts-Meek, S.; Keshav, S.; Figari, I. S.; Bradley,
A.; Stewart, T. A.: Multiple defects of immune cell function in mice
with disrupted interferon-gamma genes. Science 259: 1739-1742, 1993.

10. Dessein, A. J.; Hillaire, D.; Elwali, N. E. M. A.; Marquet, S.;
Mohamed-Ali, Q.; Mirghani, A.; Henri, S.; Abdelhameed, A. A.; Saeed,
O. K.; Magzoub, M. M. A.; Abel, L.: Severe hepatic fibrosis in Schistosoma
mansoni infection is controlled by a major locus that is closely linked
to the interferon-gamma receptor gene. Am. J. Hum. Genet. 65: 709-721,
1999.

11. 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.; Holland, S. M.: Clinical features
of dominant and recessive interferon-gamma receptor 1 deficiencies. Lancet 364:
2113-2121, 2004.

12. Fellous, M.: Personal Communication. Paris, France 10/24/1986.

13. Fellous, M.; Couillin, P.; Rosa, F.; Metezeau, P.; Foubert, C.;
Gross, M. S.; Frezal, J.; Van Cong, N.: Receptor for human gamma
interferon is specified by human chromosome 18. (Abstract) Cytogenet.
Cell Genet. 40: 627-628, 1985.

14. Heyne, K.: Generalisatio BCG familiaris semibenigna, Osteomyelitis
salmonellosa und Pseudotuberculosis intestinalis--folgen eines familiaeren
Makrophagendefektes? Europ. J. Pediat. 121: 179-189, 1976.

15. Jouanguy, E.; Altare, F.; Lamhamedi, S.; Revy, P.; Emile, J.-F.;
Newport, M.; Levin, M.; Blanche, S.; Seboun, E.; Fischer, A.; Casanova,
J.-L.: Interferon-gamma-receptor deficiency in an infant with fatal
bacille Calmette-Guerin infection. New Eng. J. Med. 335: 1956-1961,
1996.

16. Jouanguy, E.; Dupuis, S.; Pallier, A.; Doffinger, R.; Fondaneche,
M.-C.; Fieschi, C.; Lamhamedi-Cherradi, S.; Altare, F.; Emile, J.-F.;
Lutz, P.; Bordigoni, P.; Cokugras, H.; Akcakaya, N.; Landman-Parker,
J.; Donnadieu, J.; Camcioglu, Y.; Casanova, J.-L.: In a novel form
of IFN-gamma receptor 1 deficiency, cell surface receptors fail to
bind IFN-gamma. J. Clin. Invest. 105: 1429-1436, 2000.

17. Jouanguy, E.; Lamhamedi-Cherradi, S.; Altare, F.; Fondaneche,
M.-C.; Tuerlinckx, D.; Blanche, S.; Emile, J.-F.; Gaillard, J.-L.;
Schreiber, R.; Levin, M.; Fischer, A.; Hivroz, C.; Casanova, J.-L.
: Partial interferon-gamma receptor 1 deficiency in a child with tuberculoid
bacillus Calmette-Guerin infection and a sibling with clinical tuberculosis. J.
Clin. Invest. 100: 2658-2664, 1997.

18. Jouanguy, E.; Lamhamedi-Cherradi, S.; Lammas, D.; Dorman, S. E.;
Fondaneche, M.-C.; Dupuis, S.; Doffinger, R.; Altare, F.; Girdlestone,
J.; Emile, J.-F.; Ducoulombier, H.; Edgar, D.; and 10 others: A
human IFNGR1 small deletion hotspot associated with dominant susceptibility
to mycobacterial infection. Nature Genet. 21: 370-378, 1999.

19. 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.

20. Kaplan, D. H.; Shankaran, V.; Dighe, A. S.; Stockert, E.; Aguet,
M.; Old, L. J.; Schreiber, R. D.: Demonstration of an interferon
gamma-dependent tumor surveillance system in immunocompetent mice. Proc.
Nat. Acad. Sci. 95: 7556-7561, 1998.

21. Kong, X.-F.; Vogt, G.; Chapgier, A.; Lamaze, C.; Bustamante, J.;
Prando, C.; Fortin, A.; Puel, A.; Feinberg, J.; Zhang, X.-X.; Gonnord,
P.; Pihkala-Saarinen, U. M.; Arola, M.; Moilanen, P.; Abel, L.; Korppi,
M.; Boisson-Dupuis, S.; Casanova, J.-L.: A novel form of cell type-specific
partial IFN-gamma-R1 deficiency caused by a germ line mutation of
the IFNGR1 initiation codon. Hum. Molec. Genet. 19: 434-444, 2010.

22. Le Coniat, M.; Alcaide-Loridan, C.; Fellous, M.; Berger, R.:
Human interferon gamma receptor 1 (IFNGR1) gene maps to chromosome
region 6q23-6q24. Hum. Genet. 84: 92-94, 1989.

23. Lekstrom-Himes, J. A.; Gallin, J. I.: Immunodeficiency diseases
caused by defects in phagocytes. New Eng. J. Med. 343: 1703-1714,
2000.

24. Levin, M.; Newport, M. J.; D'Souza, S.; Kalabalikis, P.; Brown,
I. N.; Lenicker, H. M.; Agius, P. V.; Davies, E. G.; Thrasher, A.;
Klein, N.; Blackwell, J. M.: Familial disseminated atypical mycobacterial
infection in childhood: a human mycobacterial susceptibility gene? Lancet 345:
79-83, 1995.

25. Maldonado, R. A.; Irvine, D. J.; Schreiber, R.; Glimcher, L. H.
: A role for the immunological synapse in lineage commitment of CD4
lymphocytes. Nature 431: 527-532, 2004.

26. Mariano, T. M.; Kozak, C. A.; Langer, J. A.; Pestka, S.: The
mouse immune interferon receptor gene is located on chromosome 10. J.
Biol. Chem. 262: 5812-5814, 1987.

27. Newport, M. J.; Huxley, C. M.; Huston, S.; Hawrylowicz, C. M.;
Oostra, B. A.; Williamson, R.; Levin, M.: A mutation in the interferon-gamma-receptor
gene and susceptibility to mycobacterial infection. New Eng. J. Med. 335:
1941-1949, 1996.

28. Novick, D.; Orchansky, P.; Revel, M.; Rubinstein, M.: The human
interferon-gamma receptor: purification, characterization, and preparation
of antibodies. J. Biol. Chem. 262: 8483-8487, 1987.

29. Orchansky, P.; Rubinstein, M.; Fischer, D. G.: The interferon-gamma
receptor in human monocytes is different from the one in nonhematopoietic
cells. J. Immun. 136: 169-173, 1986.

30. Papanicolaou, G. J.; Parsa, N. Z.; Meltzer, P. S.; Trent, J. M.
: Assignment of interferon gamma receptor (IFNGR1) to human chromosome
bands 6q24.1-q24.2 by in situ hybridization. Cytogenet. Cell Genet. 76:
181-182, 1997. Note: Erratum: Cytogenet. Cell Genet. 78: 132 only,
1997.

31. Pierre-Audigier, C.; Jouanguy, E.; Lamhamedi, S.; Altare, F.;
Rauzier, J.; Vincent, V.; Canioni, D.; Emile, J. F.; Fischer, A.;
Blanche, S.; Gaillard, J. L.; Casanova, J. L.: Fatal disseminated
Mycobacterium smegmatis infection in a child with inherited interferon
gamma receptor deficiency. Clin. Infect. Dis. 24: 982-984, 1997.

32. Rashidbaigi, A.; Langer, J. A.; Jung, V.; Jones, C.; Morse, H.
G.; Tischfield, J. A.; Trill, J. J.; Kung, H.-F.; Pestka, S.: The
gene for the human immune interferon receptor is located on chromosome
6. Proc. Nat. Acad. Sci. 83: 384-388, 1986.

33. Rettig, W. J.; Grzeschik, K.-H.; Yenamandra, A. K.; Garcia, E.;
Old, L. J.: Definition of selectable cell surface markers for human
chromosomes and chromosome segments in rodent-human hybrids. Somat.
Cell Molec. Genet. 14: 223-231, 1988.

34. Shankaran, V.; Ikeda, H.; Bruce, A. T.; White, J. M.; Swanson,
P. E.; Old, L. J.; Schreiber, R. D.: IFN-gamma and lymphocytes prevent
primary tumour development and shape tumour immunogenicity. Nature 410:
1107-1111, 2001.

35. Stein, C. M.; Zalwango, S.; Chiunda, A. B.; Millard, C.; Leontiev,
D. V.; Horvath, A. L.; Cartier, K. C.; Chervenak, K.; Boom, W. H.;
Elston, R. C.; Mugerwa, R. D.; Whalen, C. C.; Iyengar, S. K.: Linkage
and association analysis of candidate genes for TB and TNF-alpha cytokine
expression: evidence for association with IFNGR1, IL-10, and TNF receptor
1 genes. Hum. Genet. 121: 663-673, 2007.

36. Storgaard, M.; Varming, K.; Herlin, T.; Obel, N.: Novel mutation
in the interferon-gamma-receptor gene and susceptibility to myobacterial
(sic) infections. Scand. J. Immun. 64: 137-139, 2006.

37. Thye, T.; Burchard, G. D.; Nilius, M.; Muller-Myhsok, B.; Horstmann,
R. D.: Genomewide linkage analysis identifies polymorphism in the
human interferon-gamma receptor affecting Helicobacter pylori infection. Am.
J. Hum. Genet. 72: 448-453, 2003.

38. Zhou, J.; Chen, D.-Q.; Poon, V. K. M.; Zeng, Y.; Ng, F.; Lu, L.;
Huang, J.-D.; Yuen, K.-Y.; Zheng, B.-J.: A regulatory polymorphism
in interferon-gamma receptor 1 promoter is associated with the susceptibility
to chronic hepatitis B virus infection. Immunogenetics 61: 423-430,
2009.

*FIELD* CN
George E. Tiller - updated: 1/5/2011
Paul J. Converse - updated: 6/24/2010
Paul J. Converse - updated: 12/10/2009
Paul J. Converse - updated: 5/15/2009
Paul J. Converse - updated: 8/22/2007
Paul J. Converse - updated: 7/21/2006
Paul J. Converse - updated: 2/10/2005
Paul J. Converse - updated: 9/30/2004
Victor A. McKusick - updated: 2/27/2003
Victor A. McKusick - updated: 12/13/2002
Paul J. Converse - updated: 2/20/2002
Paul J. Converse - updated: 2/19/2002
Paul J. Converse - updated: 4/25/2001
Victor A. McKusick - updated: 1/4/2001
Victor A. McKusick - updated: 9/20/1999
Ada Hamosh - updated: 3/30/1999
Victor A. McKusick - updated: 5/8/1998
Victor A. McKusick - updated: 1/15/1998
Victor A. McKusick - updated: 7/14/1997

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mgross: 10/07/2013
mgross: 2/12/2013
wwang: 5/12/2011
wwang: 1/14/2011
terry: 1/5/2011
mgross: 6/25/2010
terry: 6/24/2010
mgross: 12/11/2009
terry: 12/10/2009
mgross: 5/18/2009
terry: 5/15/2009
mgross: 8/22/2007
mgross: 9/5/2006
terry: 7/21/2006
mgross: 12/19/2005
alopez: 6/14/2005
mgross: 5/3/2005
tkritzer: 4/14/2005
mgross: 2/10/2005
terry: 2/10/2005
alopez: 10/29/2004
mgross: 9/30/2004
tkritzer: 3/3/2003
terry: 2/27/2003
tkritzer: 12/18/2002
tkritzer: 12/16/2002
terry: 12/13/2002
mgross: 5/15/2002
mgross: 2/20/2002
mgross: 2/19/2002
alopez: 4/25/2001
alopez: 3/2/2001
cwells: 1/11/2001
cwells: 1/10/2001
terry: 1/4/2001
carol: 9/30/1999
jlewis: 9/29/1999
terry: 9/20/1999
psherman: 5/17/1999
terry: 4/30/1999
alopez: 3/30/1999
terry: 8/11/1998
terry: 7/9/1998
dholmes: 7/2/1998
carol: 6/30/1998
alopez: 6/19/1998
alopez: 6/18/1998
terry: 6/18/1998
alopez: 5/14/1998
terry: 5/8/1998
mark: 1/19/1998
terry: 1/15/1998
mark: 11/11/1997
terry: 7/14/1997
mark: 1/10/1997
jamie: 1/7/1997
terry: 1/6/1997
warfield: 4/7/1994
carol: 3/31/1992
supermim: 3/16/1992
carol: 11/8/1991
carol: 2/19/1991
supermim: 9/28/1990

MIM 209950
*RECORD*
*FIELD* NO
209950
*FIELD* TI
#209950 ATYPICAL MYCOBACTERIOSIS, FAMILIAL
;;ATYPICAL MYCOBACTERIAL INFECTION, DISSEMINATED;;
read moreATYPICAL MYCOBACTERIAL INFECTION, FAMILIAL DISSEMINATED;;
MYCOBACTERIAL DISEASE, MENDELIAN SUSCEPTIBILITY TO; MSMD
BCG INFECTION, GENERALIZED FAMILIAL, INCLUDED;;
BCG AND SALMONELLA INFECTION, DISSEMINATED, INCLUDED;;
BCG INFECTION, GENERALIZED FAMILIAL SEMIBENIGN, AUTOSOMAL DOMINANT,
INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
familial disseminated atypical mycobacterial infection and disseminated
BCG infection can be caused by defects in the genes encoding
interferon-gamma receptor-1 (IFNGR1; 107470) on chromosome 6q23-q24,
interferon-gamma receptor-2 (IFNGR2; 147569) on 21q22, the beta-1 chain
of the interleukin-12 receptor (IL12RB1; 601604) on 19p13, and signal
transducer and activator of transcription-1 (STAT1; 600555) on 2q32.
Disseminated infection with BCG and Salmonella enteritidis has been
associated with isolated deficiency of interleukin-12B (IL12B; 161561).
One form of X-linked susceptibility to mycobacterial disease (300636) is
caused by mutations in the IKBKG gene (300248). A second form of
X-linked susceptibility to mycobacterial disease (300645), in which
mutations in the IKBKG gene have been excluded, has also been reported.
Mutation in the TYK2 gene (176941) results in TYK2 deficiency (611521),
a disease entity that includes characteristic features of both autosomal
recessive hyper-IgE syndrome (243700) and mendelian susceptibility to
mycobacterial disease.

CLINICAL FEATURES

Families with multiple cases of disseminated atypical mycobacteriosis, a
rare disorder, were reported by Engbaek (1964) and Uchiyama et al.
(1981). Uchiyama et al. (1981) reported fatal disseminated atypical
mycobacteriosis in 2 young Mexican-American girls. The atypical
mycobacterium was of a different serotype in the 2 sisters. One of the
sisters died in 1964 and the other in 1977. Studies by the authors
suggested a congenital defect in monocyte microbicidal activity. Fischer
et al. (1980) observed defective monocyte function in a 12-month-old
child with fatal disseminated BCG infection.

Heyne (1976) described a brother and sister with generalized BCG
infection after inoculation in the newborn period. The boy later had
enteric salmonellosis, Salmonella osteomyelitis, and 'intestinal
pseudotuberculosis.' A defect of macrophages was postulated.

Levin et al. (1995) described 6 children with disseminated atypical
mycobacterial infection and no recognized form of immunodeficiency.
Four, including 2 brothers, came from a village in Malta, and 2 were
brothers of Greek Cypriot origin. They presented with fever, weight
loss, lymphadenopathy, and hepatosplenomegaly. They had anemia and an
acute phase response. A range of different mycobacteria (Mycobacterium
fortuitum, M. chelonei, and 4 strains of M. avium intracellulare) were
isolated. Treatment with multiple antibiotics failed to eradicate the
infection, although treatment with gamma-interferon was associated with
improvement. Three of the children had died and the 3 survivors had
chronic infection. TNF-alpha (191160) production in response to
endotoxin and gamma-interferon was found to be defective in the patients
and their parents. T-cell proliferative responses to mycobacterial and
recall antigens were reduced in parents of affected children, and
gamma-interferon production was diminished in the patients and their
parents. Levin et al. (1995) suggested that these patients are
phenotypically similar to Lsh/Ity/Bcg susceptible mice (see ANIMAL
MODEL).

Toyoda et al. (2004) examined the immunologic abnormality of a patient
with recurrent Mycobacterium avium infection. The patient had reduced
expression of IL12RB1 and IL12RB2 and a decreased ability to produce
IFNG (147570) and to proliferate in response to IL12. However, the
patient exhibited no deficiency in IL12-induced tyrosine and serine
phosphorylation of STAT4 (600558) in mitogen-activated T cells. EMSA,
confocal laser microscopy, and Western blot analysis demonstrated that
nuclear translocation of STAT4 in response to IL12 was reduced in the
patient compared with healthy control subjects. Pharmacologic treatment
indicated that the defect was not due to upregulated STAT4 export from
the nucleus. No mutations in IL12RB1, IL12RB2, STAT4, or the IFNG
STAT4-binding sequence were identified, and the exact mechanism for the
defect could not be determined.

DIAGNOSIS

Fieschi et al. (2001) found that children with complete IFNGR
deficiency, unlike patients with other genetic defects predisposing them
to mycobacterial diseases, have very high levels of IFNG in their
plasma. Fieschi et al. (2001) proposed this measurement as a simple,
inexpensive, and accurate diagnostic test for complete IFNGR. They noted
that early identification of such children, who do not respond to
exogenous IFNG or antibiotics, may improve management by leading to the
consideration of bone marrow transplantation.

MAPPING

Schurr et al. (1991) studied linkage of genetic markers on distal
chromosome 2q with susceptibility to tuberculosis and found a lod score
of 2.4. Shaw et al. (1993), however, could not confirm this finding.
They performed linkage analysis using a panel of markers from the
2q33-q37 region in 35 multicase families with infection by Mycobacterium
leprae, M. tuberculosis, and Leishmania sp. Data from all 3 types of
families were pooled to produce a detailed RFLP map of the region. The
order of genes in the human was consistent with that determined for the
same loci in the mouse. Nonetheless, Shaw et al. (1993) could not
demonstrate linkage of infection susceptibility to this region.

Newport et al. (1995) excluded NRAMP (600266) as the site of the
mutation causing this disorder, which they referred to as familial
disseminated atypical mycobacterial infection, in a Maltese kindred.
They typed 8 markers in the region of 2q34-q37 where NRAMP maps.

MOLECULAR GENETICS

- IFNGR1 Deficiency

Newport et al. (1996) and Jouanguy et al. (1996) demonstrated that
mutations in the interferon-gamma-receptor-1 gene (107470) conferred
susceptibility to mycobacterium infection.

Heyne (2002) noted that the family reported by Heyne (1976), later
reported as family C by Jouanguy et al. (1999), had an autosomal
dominant form of partial interferon gamma receptor-1 deficiency and
deletion of 4 nucleotides in the IFNGR1 gene (107470.0006).

- IFNGR2 Deficiency

Vogt et al. (2005) studied 4 children with severe mycobacterial disease
from 3 unrelated families, all consanguineous. One was from an Austrian
family, 1 from an Iranian family, and 2 were from a Saudi Arabian
family. The severity of the clinical phenotype and the absence of
detectable mutations in IFNGR1 led to a study of IFNGR2 (147569). The
Iranian patient and the 2 Saudi Arabian patients were homozygous with
respect to a missense mutation in the IFNGR2 gene (147569.0002). The
Austrian patient was homozygous for an in-frame 27-bp microdeletion of
nucleotides 663-689 (147569.0003). The parents of the 4 children were
healthy and were heterozygous with respect to the corresponding
mutations. All 4 children with the disorder referred to by Vogt et al.
(2005) as mendelian susceptibility to mycobacterial disease had complete
IFN-gamma-R2 deficiency.

Vogt et al. (2008) reported a child of consanguineous parents with M.
avium disease who was homozygous for an in-frame 6-bp duplication in
IFNGR2, resulting in duplication thr128 and met129 (147569.0004). 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. Vogt et al. (2008) found that the mutant IFNGR2
protein was predominantly retained intracellularly, and that the
fraction expressed on the surface had a high molecular mass, was
abnormally folded, was N-glycosylated, was resistant to endoglycosidase
H, and did not respond to IFNG. 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.

- IL12RB1 Deficiency

Altare et al. (1998) and de Jong et al. (1998) found that severe
atypical mycobacterial infections, as well as Salmonella infections,
occurred in patients with mutations in the gene for the beta-1 chain of
the interleukin-12 receptor (601604.0001-601604.0004).

By SSCP and sequence analysis of the IL12RB1 gene in 120 unrelated
probands, including 100 with atypical mycobacteriosis, Fieschi et al.
(2003) identified 41 patients in 29 kindreds from 17 countries in
Africa, America, Europe, and Asia with complete IL12RB1 surface
expression deficiency. The patients were homozygous or compound
heterozygous for 4 nonsense mutations, 4 splice site mutations, 6
missense mutations, 1 small insertion, 2 large deletions, and 4
deletion/insertions, for a total of 21 mutant alleles. None of the
mutations were found in 50 unrelated healthy individuals from
corresponding ethnic groups. Opportunistic childhood infections with
weakly virulent Salmonella and Mycobacteria were observed in 34
patients, but 3 patients had clinical tuberculosis, including 1 with
salmonellosis. Salmonellosis, but not the mycobacterial infections, was
recurrent. BCG vaccination and disease protected against environmental
mycobacteriosis but not against salmonellosis. BCG disease occurred in
only 9 of 27 inoculated children. Fatality before age 8 occurred in 5
patients, 3 due to M. avium in non-BCG-vaccinated children and 2 due to
disseminated BCG; the remaining patients were alive and well. Fieschi et
al. (2003) proposed that IL12RB1 deficiency should be considered in
children with opportunistic mycobacteriosis or salmonellosis and that
the diagnosis should be pursued in healthy sibs of probands and in
selected cases of tuberculosis. They concluded that the overall
prognosis is good due to broad resistance to infection, low clinical
penetrance, and the favorable outcome of the infections. Fieschi et al.
(2003) noted the unexpected finding that IL12 is redundant in protective
immunity against most microorganisms other than Mycobacteria and
Salmonella, possibly reflecting the difference in the natural course of
infection in humans as opposed to the courses of experimental infections
in animal models.

Ozbek et al. (2005) reported an 11-year-old Turkish girl with severe
abdominal tuberculosis. She was the fourth child of healthy,
consanguineous parents. Like her parents and sibs, she had had no
adverse effect from BCG vaccination, and there was no family history of
mycobacterial disease or other intracellular infectious diseases. The
patient did not show augmented production of IFNG in response to antigen
plus IL12. Ozbek et al. (2005) identified a homozygous splice site
mutation in the IL12RB1 gene that led to skipping of exon 9
(601604.0006). They concluded that a diagnosis of IL12RB1 deficiency
should be considered for children with unusually severe tuberculosis,
even if they have no personal or family history of infection with weakly
virulent Mycobacterium or Salmonella species.

- STAT1 Deficiency

In cells from a French patient with a history of disseminated BCG
infection with no mutations in the IL12, IL12RB, or IFNGR genes, Dupuis
et al. (2001) observed severely impaired nuclear protein binding to IFNG
(147570)-activating sequences when the cells were stimulated with IFNG
or IFNA (147660). Sequence analysis identified a mutation in the STAT1
gene (600555.0001). The patient's daughter, who was not vaccinated with
BCG, had a similar cellular phenotype in vitro and carried the same
mutation. An unrelated American patient with a history of M. avium
infection was heterozygous for the same mutation. The mutation was not
detected in healthy cohorts or in patients with mycobacterial disease.

ANIMAL MODEL

There is a mouse gene, variously symbolized Lsh, Ity, and Bcg, on murine
chromosome 1 which encodes resistance to bacterial and parasitic
infections and affects the function of macrophages (Skamene et al.,
1982; Brown et al., 1982; Goto et al., 1984; Plant et al., 1982; Swanson
and O'Brien, 1983; Nickol and Bonventre, 1985). Bcg is expressed in 2
allelic forms, the dominant resistance allele and the recessive
susceptibility allele. The Bcg region on proximal mouse chromosome 1
shows homology of synteny with the telomeric portion of human 2q; a
35-cM fragment around the murine Bcg locus (from Col3a1 (120180) to
Col6a3 (120250)), has been conserved between the 2 species, the human
region being 2q32-q37.

*FIELD* RF
1. Altare, F.; Durandy, A.; Lammas, D.; Emile, J.-F.; Lamhamedi, S.;
Le Deist, F.; Drysdale, P.; Jouanguy, E.; Doffinger, R.; Bernaudin,
F.; Jeppsson, O.; Gollob, J. A.; Meinl, E.; Segal, A. W.; Fischer,
A; Kumararatne, D.; Casanova, J.-L.: Impairment of mycobacterial
immunity in human interleukin-12 receptor deficiency. Science 280:
1432-1435, 1998.

2. Brown, I. N.; Glynn, A. A.; Plant, J.: Inbred mouse strain resistance
to Mycobacterium lepraemurium follows the Ity/Lsh pattern. Immunology 47:
149-156, 1982.

3. de Jong, R.; Altare, F.; Haagen, I.-A.; Elferink, D. G.; de Boer,
T.; van Breda Vriesman, P. J. C.; Kabel, P. J.; Draaisma, J. M. T.;
van Dissel, J. T.; Kroon, F. P.; Casanova, J.-L.; Ottenhoff, T. H.
M.: Severe mycobacterial and Salmonella infections in interleukin-12
receptor-deficient patients. Science 280: 1435-1438, 1998.

4. Dupuis, S.; Dargemont, C.; Fieschi, C.; Thomassin, N.; Rosenzweig,
S.; Harris, J.; Holland, S. M.; Schreiber, R. D.; Casanova, J.-L.
: Impairment of mycobacterial but not viral immunity by a germline
human STAT1 mutation. Science 293: 300-303, 2001.

5. Engbaek, H. C.: Three cases in the same family of fatal infection
M. avium. Acta Tuberc. Scand. 45: 105-117, 1964.

6. Fieschi, C.; Dupuis, S.; Catherinot, E.; Feinberg, J.; Bustamante,
J.; Breiman, A.; Altare, F.; Baretto, R.; Le Deist, F.; Kayal, S.;
Koch, H.; Richter, D.; and 33 others: Low penetrance, broad resistance,
and favorable outcome of interleukin 12 receptor beta-1 deficiency:
medical and immunological implications. J. Exp. Med. 197: 527-535,
2003.

7. Fieschi, C.; Dupuis, S.; Picard, C.; Smith, C. I. E.; Holland,
S. M.; Casanova, J.-L.: High levels of interferon gamma in the plasma
of children with complete interferon gamma receptor deficiency. Pediatrics 107:
E48, 2001. Note: Electronic Article.

8. Fischer, A.; Virelizier, J. L.; Griscelli, C.; Durandy, A.; Nezelof,
C.; Trong, P. H.: Defective monocyte functions in a child with fatal
disseminated BCG infection. Clin. Immun. Immunopath. 17: 296-306,
1980.

9. Goto, Y.; Nakamura, R. M.; Takahashi, H.; Tokunaga, T.: Genetic
control of resistance to Mycobacterium intracellulare infection in
mice. Infect. Immun. 46: 135-140, 1984.

10. Heyne, K.: Personal Communication. Kiel, Germany 8/9/2002.

11. Heyne, K.: Generalisatio BCG familiaris semibenigna, Osteomyelitis
salmonellosa und Pseudotuberculosis intestinalis--folgen eines familiaeren
Makrophagendefektes? Europ. J. Pediat. 121: 179-189, 1976.

12. Jouanguy, E.; Altare, F.; Lamhamedi, S.; Revy, P.; Emile, J.-F.;
Newport, M.; Levin, M.; Blanche, S.; Seboun, E.; Fischer, A.; Casanova,
J.-L.: Interferon-gamma-receptor deficiency in an infant with fatal
bacille Calmette-Guerin infection. New Eng. J. Med. 335: 1956-1961,
1996.

13. Jouanguy, E.; Lamhamedi-Cherradi, S.; Lammas, D.; Dorman, S. E.;
Fondaneche, M.-C.; Dupuis, S.; Doffinger, R.; Altare, F.; Girdlestone,
J.; Emile, J.-F.; Ducoulombier, H.; Edgar, D.; and 10 others: A
human IFNGR1 small deletion hotspot associated with dominant susceptibility
to mycobacterial infection. Nature Genet. 21: 370-378, 1999.

14. Levin, M.; Newport, M. J.; D'Souza, S.; Kalabalikis, P.; Brown,
I. N.; Lenicker, H. M.; Agius, P. V.; Davies, E. G.; Thrasher, A.;
Klein, N.; Blackwell, J. M.: Familial disseminated atypical mycobacterial
infection in childhood: a human mycobacterial susceptibility gene? Lancet 345:
79-83, 1995.

15. Newport, M.; Levin, M.; Blackwell, J.; Shaw, M.-A.; Williamson,
R.; Huxley, C.: Evidence for exclusion of a mutation in NRAMP as
the cause of familial disseminated atypical mycobacterial infection
in a Maltese kindred. J. Med. Genet. 32: 904-906, 1995.

16. Newport, M. J.; Huxley, C. M.; Huston, S.; Hawrylowicz, C. M.;
Oostra, B. A.; Williamson, R.; Levin, M.: A mutation in the interferon-gamma-receptor
gene and susceptibility to mycobacterial infection. New Eng. J. Med. 335:
1941-1949, 1996.

17. Nickol, A. D.; Bonventre, P. F.: Visceral leishmaniasis in congenic
mice of susceptible and resistant phenotypes: immunosuppression by
adherent spleen cells. Infect. Immun. 50: 160-168, 1985.

18. Ozbek, N.; Fieschi, C.; Yilmaz, B. T.; de Beaucoudrey, L.; Demirhan,
B.; Feinberg, J.; Bikmaz, Y. E.; Casanova, J.-L.: Interleukin-12
receptor beta-1 chain deficiency in a child with disseminated tuberculosis. Clin.
Infect. Dis. 40: e55-e58, 2005.

19. Plant, J. E.; Blackwell, J. M.; O'Brien, A. D.; Bradley, D. J.;
Glynn, A. A.: Are the Lsh and Ity disease resistance genes at one
locus on mouse chromosome 1? Nature 297: 510-511, 1982.

20. Schurr, E.; Radzioch, D.; Malo, D.; Ros, P.; Skamene, E.: Molecular
genetics of inherited susceptibility to intracellular parasites. Behring
Inst. Mitt. 88: 1-12, 1991.

21. Shaw, M. A.; Atkinson, S.; Dockrell, H.; Hussain, R.; Lins-Lainson,
Z.; Shaw, J.; Ramos, F.; Silveira, F.; Mehdi, S. Q.; Kaukab, F.; Khaliq,
S.; Chiang, T.; Blackwell, J.: An RFLP map for 2q33-q37 from multicase
mycobacterial and leishmanial disease families: no evidence for an
Lsh/Ity/Bcg gene homologue influencing susceptibility to leprosy. Ann.
Hum. Genet. 57: 251-271, 1993.

22. Skamene, E.; Gros, P.; Forget, A.; Kongshavn, P. A. L.; St. Charles,
C.; Taylor, B. A.: Genetic regulation of resistance to intracellular
pathogens. Nature 297: 506-509, 1982.

23. Swanson, R. N.; O'Brien, A. D.: Genetic control of the innate
resistance of mice to Salmonella typhimurium: Ity gene is expressed
in vivo by 24 hours after infection. J. Immun. 131: 3014-3020, 1983.

24. Toyoda, H.; Ido, M.; Hayashi, T.; Gabazza, E. C.; Suzuki, K.;
Bu, J.; Tanaka, S.; Nakano, T.; Kamiya, H.; Chipeta, J.; Kisenge,
R. R.; Kang, J.; Hori, H.; Komada, Y.: Impairment of IL-12-dependent
STAT4 nuclear translocation in a patient with recurrent Mycobacterium
avium infection. J. Immun. 172: 3905-3912, 2004.

25. Uchiyama, N.; Greene, G. R.; Warren, B. J.; Morozume, P. A.; Spear,
G. S.; Galant, S. P.: Possible monocyte killing defect in familial
atypical mycobacteriosis. J. Pediat. 98: 785-788, 1981.

26. 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.

27. 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.

*FIELD* CS
Misc:
Generalized BCG infection after newborn inoculation

Heme:
Macrophage defect

GI:
Enteric salmonellosis;
'Intestinal pseudotuberculosis'

Skeletal:
Salmonella osteomyelitis

Inheritance:
Autosomal recessive

*FIELD* ED
joanna: 01/09/1997

*FIELD* CN
Paul J. Converse - updated: 10/2/2012
Paul J. Converse - updated: 2/27/2006
Paul J. Converse - updated: 11/8/2005
Natalie E. Krasikov - updated: 2/9/2004
Paul J. Converse - updated: 12/18/2003
Victor A. McKusick - updated: 12/13/2002
Paul J. Converse - updated: 8/8/2001
Victor A. McKusick - updated: 12/30/1998
Victor A. McKusick - updated: 5/26/1998

*FIELD* CD
Victor A. McKusick: 6/3/1986

*FIELD* ED
mgross: 10/08/2012
terry: 10/2/2012
alopez: 3/13/2009
mgross: 3/19/2008
mgross: 3/22/2007
mgross: 2/5/2007
mgross: 6/22/2006
terry: 2/27/2006
joanna: 12/20/2005
mgross: 11/8/2005
alopez: 7/5/2005
alopez: 6/15/2005
terry: 6/3/2005
ckniffin: 5/4/2005
carol: 2/9/2004
mgross: 12/18/2003
tkritzer: 12/18/2002
tkritzer: 12/16/2002
terry: 12/13/2002
mgross: 2/20/2002
mgross: 8/8/2001
terry: 6/11/1999
carol: 1/13/1999
terry: 12/30/1998
carol: 6/30/1998
alopez: 5/28/1998
terry: 5/26/1998
joanna: 8/12/1997
joanna: 1/9/1997
jamie: 1/7/1997
terry: 1/6/1997
jamie: 12/6/1996
terry: 12/3/1996
mark: 1/30/1996
terry: 1/24/1996
mark: 7/18/1995
carol: 2/27/1995
jason: 7/1/1994
pfoster: 4/1/1994
warfield: 3/31/1994
mimadm: 2/19/1994

MIM 600263
*RECORD*
*FIELD* NO
600263
*FIELD* TI
#600263 HELICOBACTER PYLORI INFECTION, SUSCEPTIBILITY TO
*FIELD* TX
A number sign (#) is used with this entry because a polymorphism in the
read moreinterferon-gamma receptor-1 gene (IFNGR1; 107470) is associated with
Helicobacter pylori infection. In addition, variation in the Lewis(b)
blood group antigen (111100), an epithelial receptor for H. pylori, may
be related to variation in susceptibility to H. pylori infection.

DESCRIPTION

Helicobacter pylori is a microaerophilic, gram-negative bacterium that
colonizes the gastric mucosa of approximately 50% of the world's
population, and is a primary pathogenic factor in benign and malignant
gastroduodenal disease (Warren and Marshall, 1983; Blaser and Parsonnet,
1994). Tomb et al. (1997) reported the complete sequence of the circular
genome of H. pylori. The 1,667,867-bp genome contains 1,590 predicted
coding sequences (genes). Sequence analysis of these genes indicated
that the organism has systems for motility, for scavenging iron, and for
DNA restriction and modification. Its survival in acid conditions
depends, in part, on its ability to establish a positive inside-membrane
potential in low pH.

CLINICAL FEATURES

Malaty et al. (1994) determined the H. pylori status in monozygotic and
dizygotic twins from the Swedish Twin Registry: 36 MZ twin pairs reared
apart, 64 MZ twin pairs reared together, 88 DZ twin pairs reared apart,
and 81 DZ twin pairs reared together. The H. pylori status was
determined by testing for anti-H. pylori IgG. The concordance rate for
infection was higher in monozygotic twin pairs (81%) than in dizygotic
twin pairs (63%). For 124 pairs of twins reared apart, the concordance
rates were 82% and 66% for MZ and DZ twins, respectively. The
correlation coefficient was 0.66 for monozygotic twins reared apart.
Malaty et al. (1994) concluded that genetic effects influence the
acquisition of H. pylori infection but that sharing the same rearing
environment also contributes to the familial tendency.

Mendall and Northfield (1995) stated that most studies of H. pylori
transmission have shown an increased rate of infection in the families
of seropositive children, but there have been no controlled studies for
variation in socioeconomic circumstances of the families. Hence, the
findings may merely represent greater environmental exposure of the
index positive children. In a large study involving 277 couples in a
fertility clinic, Perez-Perez et al. (1991) found no increased rate of
infection among the spouses of seropositive index cases. Mendall and
Northfield (1995) noted that the study by Perez-Perez et al. (1991) was
the only such study with sufficient power to detect modest effects and
the only one to control for socioeconomic circumstances. Mendall and
Northfield (1995) stated that it is unlikely that H. pylori could
multiply in the environment, suggesting that humans were probably the
only source of H. pylori infection.

Because H. pylori is rarely found in deeper portions of the gastric
mucosa, where O-glycans are expressed that have terminal
alpha-1,4-linked N-acetylglucosamine, Kawakubo et al. (2004) tested
whether these O-glycans might affect H. pylori growth. Kawakubo et al.
(2004) reported that these O-glycans have antimicrobial activity against
H. pylori, inhibiting its biosynthesis of
cholesteryl-alpha-D-glucopyranoside, a major cell wall component. Thus,
the unique O-glycans in gastric mucin appeared to function as a natural
antibiotic, protecting the host from H. pylori infection.

OTHER FEATURES

Peek and Blaser (2002) reviewed the relationship between H. pylori and
gastrointestinal tract adenocarcinomas. Although gastric adenocarcinoma
is associated with the presence of H. pylori in the stomach, only a
small fraction of colonized individuals develop this common malignancy.
The authors suggested that H. pylori strain and host genotypes probably
influence the risk of carcinogenesis by differentially affecting host
inflammatory responses and epithelial cell physiology.

PATHOGENESIS

Kwok et al. (2007) found that the H. pylori adhesin protein CagL was
targeted to the bacterial type IV secretion pilus surface, where it
bound and activated the ITGA5 (135620)/ITGB1 (135630) receptor on
gastric epithelial cells through its arg-gly-asp motif. CagL interaction
with the integrin receptor triggered delivery of the H. pylori
oncoprotein CagA into target cells and activation of FAK (PTK2; 600758)
and SRC (190090) tyrosine kinases. Kwok et al. (2007) suggested that
CagL may be used as a molecular tool to better understand integrin
signaling and the mechanism by which H. pylori causes gastric ulcer and
cancer.

MOLECULAR GENETICS

Thye et al. (2003) performed a genomewide linkage analysis among
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 observations of high prevalences and relatively low pathogenicity of
H. pylori in Africa.

Peek (2003) considered it possible that genetic variation in the
protein-tyrosine phosphatase receptor type-zeta gene (PTPRZ; 176891) may
account for some of the heterogeneity in disease presentation among H.
pylori-colonized patients. Peek (2003) noted that such is the case with
other immune response genes, such as interleukin 1-beta (IL1B; 147720),
in which high-expression alleles increase the risk of distal gastric
cancer, but only among persons infected with H. pylori.

The Lewis(b) antigen, Le(b) (111100), is an epithelial receptor for H.
pylori (Boren et al., 1993). The H. pylori adhesin that binds Lewis(b)
is BabA, which is encoded by babA2, a strain-specific gene (Peek, 2003).
H. pylori strains that are isolated from patients with gastric cancer
more commonly possess this gene than do strains isolated from patients
with gastritis alone.

The Lewis(b) antigen is encoded by the FUT3 gene, which has
polymorphisms affecting both the transmembrane and catalytic domains,
some of which affect the activity of the Lewis enzyme. Serpa et al.
(2003) studied FUT3 gene polymorphisms in a Caucasian Portuguese
population with a high rate of H. pylori infection and evaluated the
implications of mutant enzymes in Le(b) expression in the gastric
mucosa. No relationship was observed between the FUT3 polymorphisms and
the presence of H. pylori infections, although such had been suggested
by the study of Ikehara et al. (2001). The results suggested that, at
least in a population with a high rate of H. pylori infection, the FUT3
polymorphisms do not affect the presence or absence of infection.

- Associations Pending Confirmation

Tanikawa et al. (2012) performed a genomewide association analysis in a
total of 7,035 individuals with duodenal ulcer and 25,323 controls from
Japan, and identified 2 susceptibility loci, one at the PSCA gene
(602470) at 8q24 and another at the ABO blood group locus (110300) at
9q34. The C allele of dbSNP rs2294008 at PSCA was associated with an
increased risk of duodenal ulcer (odds ratio = 1.84; p = 3.92 x 10(-33))
in a recessive model but was associated with decreased risk of gastric
cancer (odds ratio = 0.79; p = 6.79 x 10(-12)), as reported by Sakamoto
et al. (2008). The T allele of dbSNP rs2294008 encodes a translation
initiation codon upstream of the reported site and changes protein
localization from the cytoplasm to the cell surface. Tanikawa et al.
(2012) noted that their data indicated that these SNPs are likely to be
associated with duodenal ulcer development after H. pylori infection and
not with susceptibility to persistent H. pylori infection per se.

POPULATION GENETICS

Wirth et al. (2004) showed that DNA sequences from H. pylori can
distinguish between closely related human populations and are superior
in this respect to classic human genetic markers. H. pylori from
Buddhists and Muslims, the 2 major ethnic communities in the Ladakh
region of India, differed in their population-genetic structure.
Moreover, the prokaryotic diversity was found to be consistent with the
Buddhists having arisen from an introgression of Tibetan speakers into
an ancient Ladakhi population. H. pylori from Muslims contained a much
stronger ancestral Ladakhi component, except for several isolates with
an Indo-European signature, probably reflecting genetic flux from the
Near East. These signatures in H. pylori sequences were congruent with
the recent history of population movements in Ladakh, whereas similar
signatures in human microsatellites or mtDNA were only marginally
significant.

ANIMAL MODEL

The vacuolating cytotoxin VacA produced by H. pylori causes massive
cellular vacuolation in vitro (Cover and Blaser, 1992) and gastric
damage in vivo, leading to gastric ulcers, when administered
intragastrically (Telford et al., 1994). Fujikawa et al. (2003) found
that mice deficient in Ptprz do not show mucosal damage by VacA,
although VacA is incorporated into the gastric epithelial cells to the
same extent as in wildtype mice. Primary cultures of gastric epithelial
cells from Ptprz +/+ and Ptprz -/- mice also showed similar
incorporation of VacA, cellular vacuolation, and reduction in cellular
proliferation, but only Ptprz +/+ cells showed marked detachment from a
reconstituted basement membrane 24 hours after treatment with VacA. VacA
bound to PTPRZ, and the levels of tyrosine phosphorylation of the G
protein-coupled receptor kinase-interactor-1 (GIT1; 608434), a PTPRZ
substrate, were higher after treatment with VacA, indicating that VacA
behaves as a ligand for PTPRZ. Furthermore, pleiotrophin (PTN; 162095),
an endogenous ligand of PTPRZ, also induced gastritis specifically in
Ptprz +/+ mice when administered orally. Taken together, these data
indicated that erroneous PTPRZ signaling induces gastric ulcers.

Falk et al. (1995) created transgenic mice with the human Le gene and
showed that H. pylori attached to gastric epithelial cells in the
transgenic mice but not in their normal littermates. This implies that
Le/Le individuals may have an advantage in avoiding H. pylori infection.

In a study of Helicobacter infection and the immune response regulation
of acid secretion, Zavros et al. (2003) demonstrated that treatment with
the Th1 cytokine Ifng (147570) induced gastritis, increased gastrin
(137250), and decreased somatostatin (183450) in mice, recapitulating
changes seen with Helicobacter infection. In contrast, the Th2 cytokine
Il4 (147780) increased somatostatin levels and suppressed gastrin
expression and secretion. Il4 pretreatment prevented gastritis in
infected wildtype but not in somatostatin-null mice; treatment of mice
chronically infected with H. felis with a somatostatin analog resolved
the inflammation. Zavros et al. (2003) concluded that IL4 resolves
inflammation in the stomach by stimulating the release of somatostatin
from gastric D cells.

By microarray and immunohistochemical analyses, Mueller et al. (2003)
found strikingly different transcriptional profiles in stomachs of mice
immunized with H. felis in conjunction with cholera toxin compared with
nonprotected or control mice. Among the genes upregulated in protected
mice were adipocyte-specific factors, such as adipsin (134350), resistin
(RETN; 605565), and adiponectin (605441), as well as the adipocyte
surface marker CD36 (173510). Potentially protective T and B lymphocytes
could be found within adipose tissue surrounding protected stomachs, but
never in control or unprotected stomachs, and adipsin-specific
immunohistochemical staining revealed molecular cross-talk between
adjacent lymphoid and adipose cell populations.

*FIELD* RF
1. Blaser, M. J.; Parsonnet, J.: Parasitism by the 'slow' bacterium
Helicobacter pylori leads to altered gastric homeostasis and neoplasia. J.
Clin. Invest. 94: 4-8, 1994.

2. Boren, T.; Falk, P.; Roth, K. A.; Larson, G.; Normark, S.: Attachment
of Helicobacter pylori to human gastric epithelium mediated by blood
group antigens. Science 262: 1892-1895, 1993.

3. Cover, T. L.; Blaser, M. J.: Purification and characterization
of the vacuolating toxin from Helicobacter pylori. J. Biol. Chem. 267:
10570-10575, 1992.

4. Falk, P. G.; Bry, L.; Holgersson, J.; Gordon, J. I.: Expression
of a human alpha-1,3/4-fucosyltransferase in the pit cell lineage
of FVB/N mouse stomach results in production of Leb-containing glycoconjugates:
a potential transgenic mouse model for studying helicobacter pylori
infection. Proc. Nat. Acad. Sci. 92: 1515-1519, 1995.

5. Fujikawa, A.; Shirasaka, D.; Yamamoto, S.; Ota, H.; Yahiro, K.;
Fukada, M.; Shintani, T.; Wada, A.; Aoyama, N.; Hirayama, T.; Fukamachi,
H.; Noda, M.: Mice deficient in protein tyrosine phosphatase receptor
type Z are resistant to gastric ulcer induction by VacA of Helicobacter
pylori. Nature Genet. 33: 375-381, 2003. Note: Erratum: Nature Genet.
33: 533 only, 2003.

6. Ikehara, Y.; Nishihara, S.; Yasutomi, H.; Kitamura, T.; Matsuo,
K.; Shimizu, N.; Inada, K.; Kodera, Y.; Yamamura, Y.; Narimatsu, H.;
Hamajima, N.; Tatematsu, M.: Polymorphisms of two fucosyltransferase
genes (Lewis and secretor genes) involving type I Lewis antigens are
associated with the presence of anti-Helicobacter pylori IgG antibody. Cancer
Epidem. Biomarkers Prev. 10: 971-977, 2001.

7. Kawakubo, M.; Ito, Y.; Okimura, Y.; Kobayashi, M.; Sakura, K.;
Kasama, S.; Fukuda, M. N.; Fukuda, M.; Katsuyama, T.; Nakayama, J.
: Natural antibiotic function of a human gastric mucin against Helicobacter
pylori infection. Science 305: 1003-1006, 2004.

8. Kwok, T.; Zabler, D.; Urman, S.; Rohde, M.; Hartig, R.; Wessler,
S.; Misselwitz, R.; Berger, J.; Sewald, N.; Konig, W.; Backert, S.
: Helicobacter exploits integrin for type IV secretion and kinase
activation. Nature 449: 862-866, 2007.

9. Malaty, H. M.; Engstrand, L.; Pedersen, N. L.; Graham, D. Y.:
Helicobacter pylori infection: genetic and environmental influences--a
study of twins. Ann. Intern. Med. 120: 982-986, 1994.

10. Mendall, M. A.; Northfield, T. C.: Transmission of Helicobacter
pylori infection. Gut 37: 1-3, 1995.

11. Mueller, A.; O'Rourke, J.; Chu, P.; Kim, C. C.; Sutton, P.; Lee,
A.; Falkow, S.: Protective immunity against Helicobacter is characterized
by a unique transcriptional signature. Proc. Nat. Acad. Sci. 100:
12289-12294, 2003.

12. Peek, R. M., Jr.: Personal Communication. Nashville, Tenn.
2/27/2003.

13. Peek, R. M., Jr.; Blaser, M. J.: Helicobacter pylori and gastrointestinal
tract adenocarcinomas. Nature Rev. Cancer 2: 28-37, 2002.

14. Perez-Perez, G. I.; Witkin, S. S.; Decker, M. D.; Blaser, M. J.
: Seroprevalence of Helicobacter pylori infection in couples. J.
Clin. Microbiol. 29: 642-644, 1991.

15. Sakamoto, H.; Yoshimura, K.; Saeki, N.; Katai, H.; Shimoda, T.;
Matsuno, Y.; Saito, D.; Sugimura, H.; Tanioka, F.; Kato, S.; Matsukura,
N.; Matsuda, N.; and 31 others: Genetic variation in PSCA is associated
with susceptibility to diffuse-type gastric cancer. Nature Genet. 40:
730-740, 2008.

16. Serpa, J.; Almeida, R.; Oliveira, C.; Silva, F. S.; Silva, E.;
Reis, C.; Le Pendu, J.; Oliveira, G.; Ribeiro, L. M. C.; David, L.
: Lewis enzyme (alpha-1-3/4 fucosyltransferase) polymorphisms do not
explain the Lewis phenotype in the gastric mucosa of a Portuguese
population. J. Hum. Genet. 48: 183-189, 2003.

17. Tanikawa, C.; Urabe, Y.; Matsuo, K.; Kubo, M.; Takahashi, A.;
Ito, H.; Tajima, K.; Kamatani, N.; Nakamura, Y.; Matsuda, K.: A genome-wide
association study identifies two susceptibility loci for duodenal
ulcer in the Japanese population. Nature Genet. 44: 430-434, 2012.

18. Telford, J. L.; Ghiara, P.; Dell'Orco, M.; Comanducci, M.; Burroni,
D.; Bugnoli, M.; Tecce, M. F.; Censini, S.; Covacci, A.; Xiang, Z.
: Gene structure of the Helicobacter pylori cytotoxin and evidence
of its key role in gastric disease. J. Exp. Med. 179: 1653-1658,
1994.

19. Thye, T.; Burchard, G. D.; Nilius, M.; Muller-Myhsok, B.; Horstmann,
R. D.: Genomewide linkage analysis identifies polymorphism in the
human interferon-gamma receptor affecting Helicobacter pylori infection. Am.
J. Hum. Genet. 72: 448-453, 2003.

20. Tomb, J.-F.; White, O.; Kerlavage, A. R.; Clayton, R. A.; Sutton,
G. G.; Fleischmann, R. D.; Ketchum, K. A.; Klenk, H. P.; Gill, S.;
Dougherty, B. A.; Nelson, K.; Quackenbush, J.; and 30 others: The
complete genome sequence of the gastric pathogen Helicobacter pylori. Nature 388:
539-547, 1997. Note: Erratum: Nature 389: 412 only, 1997.

21. Warren, J. R.; Marshall, B.: Unidentified curved bacilli on gastric
epithelium in active chronic gastritis. (Letter) Lancet 321: 1273-1275,
1983. Note: Originally Volume I.

22. Wirth, T.; Wang, X.; Linz, B.; Novick, R. P.; Lum, J. K.; Blaser,
M.; Morelli, G.; Falush, D.; Achtman, M.: Distinguishing human ethnic
groups by means of sequences from Helicobacter pylori: lessons from
Ladakh. Proc. Nat. Acad. Sci. 101: 4746-4751, 2004.

23. Zavros, Y.; Rathinavelu, S.; Kao, J. Y.; Todisco, A.; Del Valle,
J.; Weinstock, J. V.; Low, M. J.; Merchant, J. L.: Treatment of Helicobacter
gastritis with IL-4 requires somatostatin. Proc. Nat. Acad. Sci. 100:
12944-12949, 2003.

*FIELD* CS

GI:
Helicobacter pylori infection susceptibility

Inheritance:
Not determined

*FIELD* CN
Ada Hamosh - updated: 08/01/2012
Paul J. Converse - updated: 12/20/2007
Paul J. Converse - updated: 2/10/2006
Marla J. F. O'Neill - updated: 2/2/2006
Ada Hamosh - updated: 11/30/2004
Victor A. McKusick - updated: 5/10/2004
Victor A. McKusick - updated: 11/4/2003
Victor A. McKusick - updated: 8/22/2003
Victor A. McKusick - updated: 5/14/2003
Victor A. McKusick - updated: 3/26/2003
Victor A. McKusick - updated: 2/27/2003
Victor A. McKusick - updated: 2/25/2003
Victor A. McKusick - updated: 8/13/1997

*FIELD* CD
Victor A. McKusick: 12/22/1994

*FIELD* ED
alopez: 08/01/2012
terry: 7/27/2012
carol: 6/3/2009
terry: 4/3/2009
mgross: 12/20/2007
mgross: 2/10/2006
wwang: 2/3/2006
terry: 2/2/2006
terry: 11/10/2005
ckniffin: 5/3/2005
terry: 11/30/2004
carol: 10/13/2004
tkritzer: 5/25/2004
terry: 5/10/2004
mgross: 1/29/2004
tkritzer: 11/6/2003
terry: 11/4/2003
carol: 8/22/2003
terry: 8/22/2003
terry: 6/9/2003
tkritzer: 5/16/2003
terry: 5/14/2003
tkritzer: 4/3/2003
tkritzer: 3/28/2003
terry: 3/26/2003
tkritzer: 3/3/2003
terry: 2/27/2003
alopez: 2/25/2003
terry: 2/25/2003
mark: 8/18/1997
terry: 8/13/1997
jamie: 1/17/1997
jamie: 1/15/1997
terry: 1/10/1997
mark: 10/2/1995
mimadm: 9/23/1995
carol: 12/22/1994

RBCC Red Blood Cell Collection

Full text data of IFNGR1