RBCC Red Blood Cell Collection

IL2RG [Confidence: high (a blood group or CD marker)]
Cytokine receptor common subunit gamma (Interleukin-2 receptor subunit gamma; IL-2 receptor subunit gamma; IL-2R subunit gamma; IL-2RG; gammaC; p64; CD132; Flags: Precursor)

UniProt P31785
ID IL2RG_HUMAN Reviewed; 369 AA.
AC P31785; Q5FC12;
DT 01-JUL-1993, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-JUL-1993, sequence version 1.
DT 22-JAN-2014, entry version 166.
DE RecName: Full=Cytokine receptor common subunit gamma;
DE AltName: Full=Interleukin-2 receptor subunit gamma;
DE Short=IL-2 receptor subunit gamma;
DE Short=IL-2R subunit gamma;
DE Short=IL-2RG;
DE AltName: Full=gammaC;
DE AltName: Full=p64;
DE AltName: CD_antigen=CD132;
DE Flags: Precursor;
GN Name=IL2RG;
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] (ISOFORM 1), AND PARTIAL PROTEIN SEQUENCE.
RX PubMed=1631559; DOI=10.1126/science.1631559;
RA Takeshita T., Asao H., Ohtani K., Ishii N., Kumaki S., Tanaka N.,
RA Munakata H., Nakamura M., Sugamura K.;
RT "Cloning of the gamma chain of the human IL-2 receptor.";
RL Science 257:379-382(1992).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC TISSUE=Liver;
RX PubMed=8514792;
RA Noguchi M., Adelstein S., Cao X., Leonard W.J.;
RT "Characterization of the human interleukin-2 receptor gamma chain
RT gene.";
RL J. Biol. Chem. 268:13601-13608(1993).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS XSCID ASP-114 AND
RP ASN-153.
RX PubMed=8401490; DOI=10.1093/hmg/2.8.1099;
RA Puck J.M., Deschenes S.M., Porter J.C., Dutra A.S., Brown C.J.,
RA Willard H., Henthorn P.S.;
RT "The interleukin-2 receptor gamma chain maps to Xq13.1 and is mutated
RT in X-linked severe combined immunodeficiency, SCIDX1.";
RL Hum. Mol. Genet. 2:1099-1104(1993).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
RA Hayashi A., Sameshima E., Tabata Y., Iida K., Mitsuyama M., Kanai S.,
RA Furuya T., Saito T.;
RT "IL2RG mRNA, nirs splice variant 2.";
RL Submitted (FEB-2003) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT LYS-109.
RG SeattleSNPs variation discovery resource;
RL Submitted (JUL-2004) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15772651; DOI=10.1038/nature03440;
RA Ross M.T., Grafham D.V., Coffey A.J., Scherer S., McLay K., Muzny D.,
RA Platzer M., Howell G.R., Burrows C., Bird C.P., Frankish A.,
RA Lovell F.L., Howe K.L., Ashurst J.L., Fulton R.S., Sudbrak R., Wen G.,
RA Jones M.C., Hurles M.E., Andrews T.D., Scott C.E., Searle S.,
RA Ramser J., Whittaker A., Deadman R., Carter N.P., Hunt S.E., Chen R.,
RA Cree A., Gunaratne P., Havlak P., Hodgson A., Metzker M.L.,
RA Richards S., Scott G., Steffen D., Sodergren E., Wheeler D.A.,
RA Worley K.C., Ainscough R., Ambrose K.D., Ansari-Lari M.A., Aradhya S.,
RA Ashwell R.I., Babbage A.K., Bagguley C.L., Ballabio A., Banerjee R.,
RA Barker G.E., Barlow K.F., Barrett I.P., Bates K.N., Beare D.M.,
RA Beasley H., Beasley O., Beck A., Bethel G., Blechschmidt K., Brady N.,
RA Bray-Allen S., Bridgeman A.M., Brown A.J., Brown M.J., Bonnin D.,
RA Bruford E.A., Buhay C., Burch P., Burford D., Burgess J., Burrill W.,
RA Burton J., Bye J.M., Carder C., Carrel L., Chako J., Chapman J.C.,
RA Chavez D., Chen E., Chen G., Chen Y., Chen Z., Chinault C.,
RA Ciccodicola A., Clark S.Y., Clarke G., Clee C.M., Clegg S.,
RA Clerc-Blankenburg K., Clifford K., Cobley V., Cole C.G., Conquer J.S.,
RA Corby N., Connor R.E., David R., Davies J., Davis C., Davis J.,
RA Delgado O., Deshazo D., Dhami P., Ding Y., Dinh H., Dodsworth S.,
RA Draper H., Dugan-Rocha S., Dunham A., Dunn M., Durbin K.J., Dutta I.,
RA Eades T., Ellwood M., Emery-Cohen A., Errington H., Evans K.L.,
RA Faulkner L., Francis F., Frankland J., Fraser A.E., Galgoczy P.,
RA Gilbert J., Gill R., Gloeckner G., Gregory S.G., Gribble S.,
RA Griffiths C., Grocock R., Gu Y., Gwilliam R., Hamilton C., Hart E.A.,
RA Hawes A., Heath P.D., Heitmann K., Hennig S., Hernandez J.,
RA Hinzmann B., Ho S., Hoffs M., Howden P.J., Huckle E.J., Hume J.,
RA Hunt P.J., Hunt A.R., Isherwood J., Jacob L., Johnson D., Jones S.,
RA de Jong P.J., Joseph S.S., Keenan S., Kelly S., Kershaw J.K., Khan Z.,
RA Kioschis P., Klages S., Knights A.J., Kosiura A., Kovar-Smith C.,
RA Laird G.K., Langford C., Lawlor S., Leversha M., Lewis L., Liu W.,
RA Lloyd C., Lloyd D.M., Loulseged H., Loveland J.E., Lovell J.D.,
RA Lozado R., Lu J., Lyne R., Ma J., Maheshwari M., Matthews L.H.,
RA McDowall J., McLaren S., McMurray A., Meidl P., Meitinger T.,
RA Milne S., Miner G., Mistry S.L., Morgan M., Morris S., Mueller I.,
RA Mullikin J.C., Nguyen N., Nordsiek G., Nyakatura G., O'dell C.N.,
RA Okwuonu G., Palmer S., Pandian R., Parker D., Parrish J.,
RA Pasternak S., Patel D., Pearce A.V., Pearson D.M., Pelan S.E.,
RA Perez L., Porter K.M., Ramsey Y., Reichwald K., Rhodes S.,
RA Ridler K.A., Schlessinger D., Schueler M.G., Sehra H.K.,
RA Shaw-Smith C., Shen H., Sheridan E.M., Shownkeen R., Skuce C.D.,
RA Smith M.L., Sotheran E.C., Steingruber H.E., Steward C.A., Storey R.,
RA Swann R.M., Swarbreck D., Tabor P.E., Taudien S., Taylor T.,
RA Teague B., Thomas K., Thorpe A., Timms K., Tracey A., Trevanion S.,
RA Tromans A.C., d'Urso M., Verduzco D., Villasana D., Waldron L.,
RA Wall M., Wang Q., Warren J., Warry G.L., Wei X., West A.,
RA Whitehead S.L., Whiteley M.N., Wilkinson J.E., Willey D.L.,
RA Williams G., Williams L., Williamson A., Williamson H., Wilming L.,
RA Woodmansey R.L., Wray P.W., Yen J., Zhang J., Zhou J., Zoghbi H.,
RA Zorilla S., Buck D., Reinhardt R., Poustka A., Rosenthal A.,
RA Lehrach H., Meindl A., Minx P.J., Hillier L.W., Willard H.F.,
RA Wilson R.K., Waterston R.H., Rice C.M., Vaudin M., Coulson A.,
RA Nelson D.L., Weinstock G., Sulston J.E., Durbin R.M., Hubbard T.,
RA Gibbs R.A., Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence of the human X chromosome.";
RL Nature 434:325-337(2005).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=B-cell;
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 [8]
RP IDENTIFICATION AS A IL4R SUBUNIT.
RX PubMed=8266076; DOI=10.1126/science.8266076;
RA Kondo M., Takeshita T., Ishii N., Nakamura M., Watanabe S., Arai K.,
RA Sugamura K.;
RT "Sharing of the interleukin-2 (IL-2) receptor gamma chain between
RT receptors for IL-2 and IL-4.";
RL Science 262:1874-1877(1993).
RN [9]
RP IDENTIFICATION AS A IL4R SUBUNIT.
RX PubMed=8266078; DOI=10.1126/science.8266078;
RA Russell S.M., Kkegan A.D., Harada N., Nakamura Y., Noguchi M.,
RA Leland P., Friedmann M.C., Miyajima A., Puri R.K., Paul W.E.,
RA Leonard W.J.;
RT "Interleukin-2 receptor gamma chain: a functional component of the
RT interleukin-4 receptor.";
RL Science 262:1880-1883(1993).
RN [10]
RP IDENTIFICATION AS A IL7R SUBUNIT.
RX PubMed=8266077; DOI=10.1126/science.8266077;
RA Noguchi M., Nakamura Y., Russell S.M., Ziegler S.F., Tsang M., Cao X.,
RA Leonard W.J.;
RT "Interleukin-2 receptor gamma chain: a functional component of the
RT interleukin-7 receptor.";
RL Science 262:1877-1880(1993).
RN [11]
RP INTERACTION WITH HTLV-1 ACCESSORY PROTEIN P12I.
RX PubMed=8648694;
RA Mulloy J.C., Crownley R.W., Fullen J., Leonard W.J., Franchini G.;
RT "The human T-cell leukemia/lymphotropic virus type 1 p12I proteins
RT bind the interleukin-2 receptor beta and gammac chains and affects
RT their expression on the cell surface.";
RL J. Virol. 70:3599-3605(1996).
RN [12]
RP INTERACTION WITH SHB.
RX PubMed=12200137; DOI=10.1016/S0006-291X(02)02016-8;
RA Lindholm C.K.;
RT "IL-2 receptor signaling through the Shb adapter protein in T and NK
RT cells.";
RL Biochem. Biophys. Res. Commun. 296:929-936(2002).
RN [13]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-292, AND MASS
RP SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [14]
RP 3D-STRUCTURE MODELING OF 57-248.
RX PubMed=7529123; DOI=10.1016/S0969-2126(94)00085-9;
RA Bamborough P., Hedgecock C.J., Richards W.G.;
RT "The interleukin-2 and interleukin-4 receptors studied by molecular
RT modelling.";
RL Structure 2:839-851(1994).
RN [15]
RP X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 56-254 IN COMPLEX WITH IL2;
RP IL2RA AND IL2RB, DISULFIDE BONDS, AND GLYCOSYLATION AT ASN-71; ASN-84
RP AND ASN-159.
RX PubMed=16293754; DOI=10.1126/science.1117893;
RA Wang X., Rickert M., Garcia K.C.;
RT "Structure of the quaternary complex of interleukin-2 with its alpha,
RT beta, and gammac receptors.";
RL Science 310:1159-1163(2005).
RN [16]
RP X-RAY CRYSTALLOGRAPHY (3.0 ANGSTROMS) OF 23-255 IN COMPLEX WITH IL2;
RP IL2RA AND IL2RB, DISULFIDE BONDS, AND GLYCOSYLATION AT ASN-71; ASN-84
RP AND ASN-159.
RX PubMed=16477002; DOI=10.1073/pnas.0511161103;
RA Stauber D.J., Debler E.W., Horton P.A., Smith K.A., Wilson I.A.;
RT "Crystal structure of the IL-2 signaling complex: paradigm for a
RT heterotrimeric cytokine receptor.";
RL Proc. Natl. Acad. Sci. U.S.A. 103:2788-2793(2006).
RN [17]
RP VARIANTS XSCID PHE-115; CYS-240 AND ILE-241.
RX PubMed=8299698; DOI=10.1002/eji.1830240232;
RA Disanto J.P., Dautry-Varsat A., Certain S., Fischer A.,
RA de Saint Basile G.;
RT "Interleukin-2 (IL-2) receptor gamma chain mutations in X-linked
RT severe combined immunodeficiency disease result in the loss of high-
RT affinity IL-2 receptor binding.";
RL Eur. J. Immunol. 24:475-479(1994).
RN [18]
RP VARIANT XSCID LYS-68.
RX PubMed=8088810; DOI=10.1006/geno.1994.1265;
RA Markiewicz S., Subtil A., Dautry-Varsat A., Fischer A.,
RA de Saint Basile G.;
RT "Detection of three nonsense mutations and one missense mutation in
RT the interleukin-2 receptor gamma chain gene in SCIDX1 that differently
RT affect the mRNA processing.";
RL Genomics 21:291-293(1994).
RN [19]
RP VARIANT XSCID HIS-162.
RX PubMed=8027558;
RA Ishii N., Asao H., Kimura Y., Takeshita T., Nakamura M., Tsuchiya S.,
RA Konno T., Maeda M., Uchiyama T., Sugamura K.;
RT "Impairment of ligand binding and growth signaling of mutant IL-2
RT receptor gamma-chains in patients with X-linked severe combined
RT immunodeficiency.";
RL J. Immunol. 153:1310-1317(1994).
RN [20]
RP VARIANT XSCID ASN-39.
RX PubMed=7937790; DOI=10.1073/pnas.91.20.9466;
RA Disanto J.P., Rieux-Laucat F., Dautry-Varsat A., Fischer A.,
RA de Saint Basile G.;
RT "Defective human interleukin 2 receptor gamma chain in an atypical X
RT chromosome-linked severe combined immunodeficiency with peripheral T
RT cells.";
RL Proc. Natl. Acad. Sci. U.S.A. 91:9466-9470(1994).
RN [21]
RP VARIANTS XSCID CYS-226 AND HIS-226.
RX PubMed=7668284;
RA Pepper A.E., Buckley R.H., Small T.N., Puck J.M.;
RT "Two mutational hotspots in the interleukin-2 receptor gamma chain
RT gene causing human X-linked severe combined immunodeficiency.";
RL Am. J. Hum. Genet. 57:564-571(1995).
RN [22]
RP VARIANT XSCID SER-183.
RX PubMed=7557965; DOI=10.1007/BF00191801;
RA Clark P.A., Lester T., Genet S., Jones A.M., Hendriks R.,
RA Levinsky R.L., Kinnon C.;
RT "Screening for mutations causing X-linked severe combined
RT immunodeficiency in the IL-2R gamma chain gene by single-strand
RT conformation polymorphism analysis.";
RL Hum. Genet. 96:427-432(1995).
RN [23]
RP VARIANT XSCID GLN-HIS-TRP-237 INS.
RX PubMed=7860773; DOI=10.1172/JCI117740;
RA Puck J.M., Pepper A.E., Bedard P.-M., Laframboise R.;
RT "Female germ line mosaicism as the origin of a unique IL-2 receptor
RT gamma-chain mutation causing X-linked severe combined
RT immunodeficiency.";
RL J. Clin. Invest. 95:895-899(1995).
RN [24]
RP VARIANT XCID GLN-293.
RX PubMed=7883965; DOI=10.1172/JCI117765;
RA Schmalstieg F.C., Leonard W.J., Noguchi M., Berg M., Rudloff H.E.,
RA Denney R.M., Dave S.K., Brooks E.G., Goldman A.S.;
RT "Missense mutation in exon 7 of the common gamma chain gene causes a
RT moderate form of X-linked combined immunodeficiency.";
RL J. Clin. Invest. 95:1169-1173(1995).
RN [25]
RP VARIANT XSCID ARG-115.
RX PubMed=8900089; DOI=10.1056/NEJM199611213352104;
RA Stephan V., Wahn V., Le Deist F., Dirksen U., Broeker B.,
RA Mueller-Fleckenstein I., Horneff G., Schroten H., Fischer A.,
RA de Saint Basile G.;
RT "Atypical X-linked severe combined immunodeficiency due to possible
RT spontaneous reversion of the genetic defect in T cells.";
RL N. Engl. J. Med. 335:1563-1567(1996).
RN [26]
RP VARIANT XSCID GLN-285.
RX PubMed=9150740; DOI=10.1007/s004390050428;
RA Jones A.M., Clark P.A., Katz F., Genet S., McMahon C., Alterman L.,
RA Cant A., Kinnon C.;
RT "B-cell-negative severe combined immunodeficiency associated with a
RT common gamma chain mutation.";
RL Hum. Genet. 99:677-680(1997).
RN [27]
RP VARIANT XSCID TRP-224.
RX PubMed=9049783; DOI=10.1023/A:1027332327827;
RA O'Marcaigh A.S., Puck J.M., Pepper A.E., De Santes K., Cowan M.J.;
RT "Maternal mosaicism for a novel interleukin-2 receptor gamma-chain
RT mutation causing X-linked severe combined immunodeficiency in a Navajo
RT kindred.";
RL J. Clin. Immunol. 17:29-33(1997).
RN [28]
RP VARIANT XCID CYS-222.
RX PubMed=9399950; DOI=10.1172/JCI119858;
RA Sharfe N., Shahar M., Roifman C.M.;
RT "An interleukin-2 receptor gamma chain mutation with normal thymus
RT morphology.";
RL J. Clin. Invest. 100:3036-3043(1997).
CC -!- FUNCTION: Common subunit for the receptors for a variety of
CC interleukins.
CC -!- SUBUNIT: The gamma subunit is common to the IL2, IL4, IL7, IL15,
CC IL21 and probably also the IL13 receptors. Interacts with SHB upon
CC interleukin stimulation. Interacts with HTLV-1 accessory protein
CC p12I.
CC -!- INTERACTION:
CC P13232:IL7; NbExp=2; IntAct=EBI-80475, EBI-80516;
CC -!- SUBCELLULAR LOCATION: Membrane; Single-pass type I membrane
CC protein.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P31785-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P31785-2; Sequence=VSP_047581, VSP_047582;
CC -!- DOMAIN: The WSXWS motif appears to be necessary for proper protein
CC folding and thereby efficient intracellular transport and cell-
CC surface receptor binding.
CC -!- DOMAIN: The box 1 motif is required for JAK interaction and/or
CC activation.
CC -!- DISEASE: Severe combined immunodeficiency X-linked T-cell-
CC negative/B-cell-positive/NK-cell-negative (XSCID) [MIM:300400]: A
CC form of severe combined immunodeficiency (SCID), a genetically and
CC clinically heterogeneous group of rare congenital disorders
CC characterized by impairment of both humoral and cell-mediated
CC immunity, leukopenia, and low or absent antibody levels. Patients
CC present in infancy recurrent, persistent infections by
CC opportunistic organisms. The common characteristic of all types of
CC SCID is absence of T-cell-mediated cellular immunity due to a
CC defect in T-cell development. Note=The disease is caused by
CC mutations affecting the gene represented in this entry.
CC -!- DISEASE: X-linked combined immunodeficiency (XCID) [MIM:312863]:
CC Less severe form of X-linked immunodeficiency with a less severe
CC degree of deficiency in cellular and humoral immunity than that
CC seen in XSCID. Note=The disease is caused by mutations affecting
CC the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the type I cytokine receptor family. Type 5
CC subfamily.
CC -!- SIMILARITY: Contains 1 fibronectin type-III domain.
CC -!- WEB RESOURCE: Name=IL2RGbase; Note=X-linked SCID mutation
CC database;
CC URL="http://research.nhgri.nih.gov/scid/";
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/IL2RG";
CC -!- WEB RESOURCE: Name=SeattleSNPs;
CC URL="http://pga.gs.washington.edu/data/il2rg/";
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DR EMBL; D11086; BAA01857.1; -; mRNA.
DR EMBL; L12183; AAA59145.1; -; Genomic_DNA.
DR EMBL; L12178; AAA59145.1; JOINED; Genomic_DNA.
DR EMBL; L12176; AAA59145.1; JOINED; Genomic_DNA.
DR EMBL; L12177; AAA59145.1; JOINED; Genomic_DNA.
DR EMBL; L12179; AAA59145.1; JOINED; Genomic_DNA.
DR EMBL; L12180; AAA59145.1; JOINED; Genomic_DNA.
DR EMBL; L12181; AAA59145.1; JOINED; Genomic_DNA.
DR EMBL; L12182; AAA59145.1; JOINED; Genomic_DNA.
DR EMBL; L19546; AAC37524.1; -; Genomic_DNA.
DR EMBL; AB102794; BAD89385.1; -; mRNA.
DR EMBL; AY692262; AAT85803.1; -; Genomic_DNA.
DR EMBL; AL590764; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC014972; AAH14972.1; -; mRNA.
DR PIR; A42565; A42565.
DR RefSeq; NP_000197.1; NM_000206.2.
DR RefSeq; XP_005262319.1; XM_005262262.1.
DR UniGene; Hs.84; -.
DR PDB; 1ILL; Model; -; G=57-248.
DR PDB; 1ILM; Model; -; G=57-248.
DR PDB; 1ILN; Model; -; G=57-248.
DR PDB; 1ITE; Model; -; B=23-254.
DR PDB; 2B5I; X-ray; 2.30 A; C=56-254.
DR PDB; 2ERJ; X-ray; 3.00 A; C/G=23-255.
DR PDB; 3BPL; X-ray; 2.93 A; C=56-254.
DR PDB; 3QAZ; X-ray; 3.80 A; C/F/I/L/O/R/U/X/a/d/g/j=56-254.
DR PDB; 3QB7; X-ray; 3.24 A; C/D=55-254.
DR PDB; 4GS7; X-ray; 2.35 A; C=55-254.
DR PDBsum; 1ILL; -.
DR PDBsum; 1ILM; -.
DR PDBsum; 1ILN; -.
DR PDBsum; 1ITE; -.
DR PDBsum; 2B5I; -.
DR PDBsum; 2ERJ; -.
DR PDBsum; 3BPL; -.
DR PDBsum; 3QAZ; -.
DR PDBsum; 3QB7; -.
DR PDBsum; 4GS7; -.
DR ProteinModelPortal; P31785; -.
DR SMR; P31785; 56-249.
DR DIP; DIP-173N; -.
DR IntAct; P31785; 8.
DR MINT; MINT-1524852; -.
DR STRING; 9606.ENSP00000276110; -.
DR BindingDB; P31785; -.
DR ChEMBL; CHEMBL2364167; -.
DR DrugBank; DB00041; Aldesleukin.
DR DrugBank; DB00004; Denileukin diftitox.
DR PhosphoSite; P31785; -.
DR DMDM; 400048; -.
DR PaxDb; P31785; -.
DR PRIDE; P31785; -.
DR DNASU; 3561; -.
DR Ensembl; ENST00000374202; ENSP00000363318; ENSG00000147168.
DR Ensembl; ENST00000456850; ENSP00000388967; ENSG00000147168.
DR GeneID; 3561; -.
DR KEGG; hsa:3561; -.
DR UCSC; uc004dyw.2; human.
DR CTD; 3561; -.
DR GeneCards; GC0XM070327; -.
DR HGNC; HGNC:6010; IL2RG.
DR HPA; HPA046641; -.
DR MIM; 300400; phenotype.
DR MIM; 308380; gene.
DR MIM; 312863; phenotype.
DR neXtProt; NX_P31785; -.
DR Orphanet; 39041; Omenn syndrome.
DR Orphanet; 276; T-B+ severe combined immunodeficiency due to gamma chain deficiency.
DR PharmGKB; PA196; -.
DR eggNOG; NOG43995; -.
DR HOGENOM; HOG000276891; -.
DR HOVERGEN; HBG052111; -.
DR InParanoid; P31785; -.
DR KO; K05070; -.
DR OMA; DHSWTEQ; -.
DR OrthoDB; EOG7H4DV0; -.
DR PhylomeDB; P31785; -.
DR Reactome; REACT_6900; Immune System.
DR SignaLink; P31785; -.
DR ChiTaRS; IL2RG; human.
DR EvolutionaryTrace; P31785; -.
DR GeneWiki; Common_gamma_chain; -.
DR GenomeRNAi; 3561; -.
DR NextBio; 13908; -.
DR PMAP-CutDB; P31785; -.
DR PRO; PR:P31785; -.
DR ArrayExpress; P31785; -.
DR Bgee; P31785; -.
DR CleanEx; HS_IL2RG; -.
DR Genevestigator; P31785; -.
DR GO; GO:0009897; C:external side of plasma membrane; ISS:UniProtKB.
DR GO; GO:0005887; C:integral to plasma membrane; TAS:ProtInc.
DR GO; GO:0004896; F:cytokine receptor activity; IEA:InterPro.
DR GO; GO:0019976; F:interleukin-2 binding; ISS:UniProtKB.
DR GO; GO:0006955; P:immune response; TAS:ProtInc.
DR GO; GO:0038110; P:interleukin-2-mediated signaling pathway; TAS:GOC.
DR GO; GO:0035771; P:interleukin-4-mediated signaling pathway; TAS:GOC.
DR GO; GO:0038111; P:interleukin-7-mediated signaling pathway; TAS:GOC.
DR GO; GO:0019048; P:modulation by virus of host morphology or physiology; IEA:UniProtKB-KW.
DR Gene3D; 2.60.40.10; -; 2.
DR InterPro; IPR003961; Fibronectin_type3.
DR InterPro; IPR003531; Hempt_rcpt_S_F1_CS.
DR InterPro; IPR013783; Ig-like_fold.
DR InterPro; IPR015321; IL-6_rcpt_alpha-bd.
DR Pfam; PF00041; fn3; 1.
DR Pfam; PF09240; IL6Ra-bind; 1.
DR SMART; SM00060; FN3; 1.
DR SUPFAM; SSF49265; SSF49265; 2.
DR PROSITE; PS50853; FN3; 1.
DR PROSITE; PS01355; HEMATOPO_REC_S_F1; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Complete proteome;
KW Direct protein sequencing; Disease mutation; Disulfide bond;
KW Glycoprotein; Host-virus interaction; Membrane; Phosphoprotein;
KW Polymorphism; Receptor; Reference proteome; SCID; Signal;
KW Transmembrane; Transmembrane helix.
FT SIGNAL 1 22
FT CHAIN 23 369 Cytokine receptor common subunit gamma.
FT /FTId=PRO_0000010866.
FT TOPO_DOM 23 262 Extracellular (Potential).
FT TRANSMEM 263 283 Helical; (Potential).
FT TOPO_DOM 284 369 Cytoplasmic (Potential).
FT DOMAIN 156 253 Fibronectin type-III.
FT MOTIF 237 241 WSXWS motif.
FT MOTIF 286 294 Box 1 motif.
FT MOD_RES 292 292 Phosphothreonine.
FT CARBOHYD 24 24 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 71 71 N-linked (GlcNAc...).
FT CARBOHYD 75 75 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 84 84 N-linked (GlcNAc...).
FT CARBOHYD 159 159 N-linked (GlcNAc...).
FT CARBOHYD 249 249 N-linked (GlcNAc...) (Potential).
FT DISULFID 62 72
FT DISULFID 102 115
FT DISULFID 182 231
FT VAR_SEQ 1 8 MLKPSLPF -> MGMKTPQL (in isoform 2).
FT /FTId=VSP_047581.
FT VAR_SEQ 9 198 Missing (in isoform 2).
FT /FTId=VSP_047582.
FT VARIANT 39 39 D -> N (in XSCID).
FT /FTId=VAR_002668.
FT VARIANT 44 44 T -> S (in dbSNP:rs7885041).
FT /FTId=VAR_059301.
FT VARIANT 62 62 C -> G (in XSCID).
FT /FTId=VAR_002669.
FT VARIANT 68 68 E -> G (in XSCID).
FT /FTId=VAR_002670.
FT VARIANT 68 68 E -> K (in XSCID).
FT /FTId=VAR_002671.
FT VARIANT 84 84 N -> K (in XSCID).
FT /FTId=VAR_002672.
FT VARIANT 89 89 Y -> C (in XSCID).
FT /FTId=VAR_002673.
FT VARIANT 105 105 Y -> C (in XSCID).
FT /FTId=VAR_002674.
FT VARIANT 109 109 E -> K (in dbSNP:rs17875899).
FT /FTId=VAR_020611.
FT VARIANT 114 114 G -> D (in XSCID).
FT /FTId=VAR_002675.
FT VARIANT 115 115 C -> F (in XSCID).
FT /FTId=VAR_002676.
FT VARIANT 115 115 C -> R (in XSCID; atypical).
FT /FTId=VAR_002677.
FT VARIANT 123 123 H -> P (in XSCID).
FT /FTId=VAR_002678.
FT VARIANT 125 125 Y -> N (in XSCID).
FT /FTId=VAR_002679.
FT VARIANT 144 144 Q -> P (in XSCID).
FT /FTId=VAR_002680.
FT VARIANT 153 153 I -> N (in XSCID).
FT /FTId=VAR_002681.
FT VARIANT 156 156 A -> V (in XSCID).
FT /FTId=VAR_002682.
FT VARIANT 162 162 L -> H (in XSCID).
FT /FTId=VAR_002683.
FT VARIANT 172 172 L -> P (in XSCID).
FT /FTId=VAR_002684.
FT VARIANT 172 172 L -> Q (in XSCID).
FT /FTId=VAR_002685.
FT VARIANT 182 182 C -> R (in XSCID).
FT /FTId=VAR_002686.
FT VARIANT 183 183 L -> S (in XSCID).
FT /FTId=VAR_002687.
FT VARIANT 222 222 R -> C (in XCID).
FT /FTId=VAR_002688.
FT VARIANT 224 224 R -> W (in XSCID).
FT /FTId=VAR_002689.
FT VARIANT 226 226 R -> C (in XSCID).
FT /FTId=VAR_002690.
FT VARIANT 226 226 R -> H (in XSCID).
FT /FTId=VAR_002691.
FT VARIANT 227 227 F -> C (in XSCID).
FT /FTId=VAR_002692.
FT VARIANT 230 230 L -> P (in XSCID).
FT /FTId=VAR_002693.
FT VARIANT 231 231 C -> Y (in XSCID).
FT /FTId=VAR_002694.
FT VARIANT 232 232 G -> R (in XSCID).
FT /FTId=VAR_002695.
FT VARIANT 237 237 W -> WQHW (in XSCID).
FT /FTId=VAR_002696.
FT VARIANT 240 240 W -> C (in XSCID).
FT /FTId=VAR_002697.
FT VARIANT 241 241 S -> I (in XSCID).
FT /FTId=VAR_002698.
FT VARIANT 270 270 M -> R (in XSCID).
FT /FTId=VAR_002699.
FT VARIANT 285 285 R -> Q (in XSCID).
FT /FTId=VAR_002701.
FT VARIANT 293 293 L -> Q (in XCID).
FT /FTId=VAR_002702.
FT STRAND 61 65
FT TURN 66 68
FT STRAND 69 73
FT STRAND 78 81
FT STRAND 86 91
FT STRAND 94 96
FT STRAND 103 108
FT STRAND 111 118
FT HELIX 119 121
FT STRAND 124 126
FT STRAND 128 133
FT STRAND 135 137
FT STRAND 141 146
FT HELIX 148 150
FT STRAND 151 153
FT STRAND 158 166
FT STRAND 169 175
FT HELIX 180 182
FT STRAND 184 191
FT STRAND 198 202
FT STRAND 207 210
FT STRAND 215 217
FT STRAND 219 226
FT STRAND 229 231
FT STRAND 244 246
SQ SEQUENCE 369 AA; 42287 MW; 3B6215246D610215 CRC64;
MLKPSLPFTS LLFLQLPLLG VGLNTTILTP NGNEDTTADF FLTTMPTDSL SVSTLPLPEV
QCFVFNVEYM NCTWNSSSEP QPTNLTLHYW YKNSDNDKVQ KCSHYLFSEE ITSGCQLQKK
EIHLYQTFVV QLQDPREPRR QATQMLKLQN LVIPWAPENL TLHKLSESQL ELNWNNRFLN
HCLEHLVQYR TDWDHSWTEQ SVDYRHKFSL PSVDGQKRYT FRVRSRFNPL CGSAQHWSEW
SHPIHWGSNT SKENPFLFAL EAVVISVGSM GLIISLLCVY FWLERTMPRI PTLKNLEDLV
TEYHGNFSAW SGVSKGLAES LQPDYSERLC LVSEIPPKGG ALGEGPGASP CNQHSPYWAP
PCYTLKPET
//
read less

MIM 300400
*RECORD*
*FIELD* NO
300400
*FIELD* TI
#300400 SEVERE COMBINED IMMUNODEFICIENCY, X-LINKED; SCIDX1
;;SEVERE COMBINED IMMUNODEFICIENCY, X-LINKED, T CELL-NEGATIVE, B CELL-POSITIVE,
read moreNK CELL-NEGATIVE;;
SCIDX; XSCID;;
SCID, X-LINKED;;
IMMUNODEFICIENCY 4; IMD4
*FIELD* TX
A number sign (#) is used with this entry because T-, B+, NK- X-linked
severe combined immunodeficiency (SCID) is caused by mutation in the
gene encoding the gamma subunit of the interleukin-2 receptor (IL2RG;
308380). See also X-linked combined immunodeficiency (312863), a less
severe form of the disorder that is also caused by mutation in the IL2RG
gene.

An autosomal recessive form of T-, B+, NK- SCID (600802) is caused by
mutation in the JAK3 gene (600173) on chromosome 19p13. For a general
phenotypic description and a discussion of genetic heterogeneity of
autosomal recessive SCID, see 601457.

CLINICAL FEATURES

Severe combined immunodeficiency differs from the Bruton type (300755)
of agammaglobulinemia by the additional presence of lymphocytopenia
('alymphocytosis'), earlier age at death, vulnerability to viral and
fungal as well as bacterial infections, lack of delayed
hypersensitivity, atrophy of the thymus, and lack of benefit from gamma
globulin administration. Severe combined immunodeficiency, originally
termed 'Swiss type agammaglobulinemia' to distinguish it from Bruton
agammaglobulinemia, was first described in Switzerland by Hitzig and
Willi (1961). Those cases showed autosomal recessive inheritance (see
601457).

Rosen et al. (1966) reported 3 families with SCID inherited in an
X-linked recessive pattern: all patients were male, and 1 kindred had 9
affected males in 5 sibships spanning 3 generations connected through
females. Gitlin and Craig (1963) reported 15 boys with
hypogammaglobulinemia and noted that they could be divided into 2 groups
of almost equal size based on their clinical course. The first group had
onset of infections early in life, often before 3 months of age,
followed by lymphopenia and persistent pneumonitis, moniliasis, and
frequent rashes. This disorder was uniformly fatal in infancy even in
children treated with gammaglobulin. Autopsy showed an abnormally small
thymus with thymic alymphoplasia. The second group of patients had onset
of infections somewhat later, usually between 6 and 18 months of age.
Infection was intermittent rather than persistent, and gamma globulin
was clinically useful. These patients did not have lymphopenia, and in
those who died, the thymus was not found to be small, although lymph
nodes lacked germinal follicles and plasma cells. About half the
patients in each group had a family history of severe infections in male
relatives. The first group would be known now to have X-linked severe
combined immunodeficiency and the second group X-linked
agammaglobulinemia of Bruton.

Miller and Schieken (1967) suggested that one form of 'thymic dysplasia'
is X-linked. Thymic dysplasia is seen in SCID (Nezelof, 1992). An
impressive pedigree with 6 affected males in 3 generations was published
by Dooren et al. (1968), who, following the recommendations of a
workshop on immunologic deficiency diseases in man (Sanibel Island, Fort
Myers, Fla., Feb. 1-5, 1967), called the condition 'thymic epithelial
hypoplasia.' In the same workshop, Rosen et al. (1968) noted that
X-linked SCID had less profound lymphocytopenia than autosomal recessive
SCID.

Yount et al. (1978) studied a child with X-linked SCID. Adenosine
deaminase (ADA; 608958) and nucleoside phosphorylase (PNP; 164050)
levels were normal. The patient had virtual absence of lymphocytes
capable of rosetting with sheep red blood cells, absence of reactive
skin tests, and lack of in vitro responses to mitogens, antigens or
allogeneic cells. He had profound humoral immunodeficiency despite a
plethora of B lymphocytes. The authors suggested that B cells were
unable to undergo terminal differentiation into plasma cells capable of
synthesizing and secreting immunoglobulins. A brother of the patient
they studied died at age 10 months of Pneumocystis carinii pneumonia
complicated by disseminated influenza infection (Hong Kong strain).
Autopsy showed a hypoplastic thymus without epithelial corpuscles and
absence of germinal centers in lymph nodes and bowel lamina propria.

In 2 unrelated males with SCID and thymic alymphoplasia, Conley et al.
(1984) found that T cells demonstrated a typical XX female karyotype and
were probably of maternal origin, whereas the B cells had an XY male
karyotype. The authors suggested that there was maternal lymphoid
engraftment and that the SCID in these patients was the result of
graft-versus-host disease (GVHD; see 614395). Since this would
presumably affect only males, repetition in the family would simulate
X-linked recessive inheritance.

Kellermayer et al. (2006) reported an infant boy with X-linked SCID
confirmed by genetic analysis. Detailed cellular studies showed a subset
of 46,XX CD4+ T cells in the patient's peripheral blood, indicating a
chimeric lymphocyte population presumably derived from transplacental
maternal T lymphocytes. The patient exhibited a mild to moderate
recurrent eczematous rash consistent with spontaneous graft-versus-host
disease from recognition of these maternal cells, and was scheduled for
bone marrow transplant. Kellermayer et al. (2006) noted that although
transplacentally acquired maternal T lymphocytes are present in 40% of
SCID patients, untreated cases may still be fatal.

Speckmann et al. (2008) reported a boy with a relatively mild form of
X-linked SCID diagnosed by molecular analysis at age 5 years
(308380.0013). The main clinical symptom was recurrent bronchitis.
Immunologic investigations showed decreased circulating T and NK cells,
and normal numbers of B cells. Genetic analysis of peripheral blood
cells showed a dual signal, with the wildtype IL2RG gene in T cells and
a mutant IL2RG gene in B cells, NK cells, and granulocytes. His
unaffected mother was a carrier of the mutation. The findings were
consistent with reversion of the mutation within a common T-cell
precursor in the patient. In vitro functional analysis showed normal
T-cell function, despite low levels of T cells, and impaired B cell
antibody response. A similar patient with reversion of mutation in a
T-cell progenitor was reported by Stephan et al. (1996) (see
308380.0010). However, Speckmann et al. (2008) noted that the patient
reported by Stephan et al. (1996) ultimately showed a deteriorating
course and required bone marrow stem cell transplantation at almost 7
years of age. The findings indicated that close immunologic surveillance
is still needed in patients with mutation reversion.

OTHER FEATURES

- X Inactivation

By examining a differential pattern of methylation (Vogelstein et al.,
1987), Goodship et al. (1988) showed nonrandom X-chromosome inactivation
in T cells of 2 obligate XSCID carriers. The method was used to
distinguish autosomal recessive and X-linked forms of the disease and to
demonstrate carrier status in the mother of a sporadic case.

Conley et al. (1988) analyzed patterns of X-chromosome inactivation in B
cells from 9 obligate XSCID carriers. Using somatic cell hybrids to
distinguish between active and nonactive X chromosomes, the authors
found that all obligate carriers showed preferential use of the
nonmutant X chromosome in B cells. The small number of B-cell hybrids
that contained the mutant X were derived from an immature subset of B
cells. The results indicated that the XSCID gene product was required
for B-cell maturation.

Puck et al. (1986, 1987) showed that carriers for X-linked SCID could be
detected based on analysis of X-inactivation patterns. In a control
group of noncarrier women, Puck et al. (1992) found a wide range of
X-inactivation ratios; 20 to 86% of T cells had the paternal X
chromosome active, indicating random X-inactivation. Maximum likelihood
analysis suggested that mature human T cells were derived from a pool of
only about 10 randomly inactivated stem cells. X inactivation in XSCID
carriers was markedly skewed, favoring the nonmutant chromosome. The
authors developed a maximum-likelihood odds-ratio test which enabled
prediction of carrier status in XSCID pedigrees.

Conley et al. (1990) studied X-chromosome inactivation patterns in T
cells from 16 women who had sons with sporadic SCID. By analysis of
human/hamster hybrids that selectively retained the active human X
chromosome and use of an X-linked RFLP for which the woman in question
was heterozygous, they showed exclusive use of a single nonmutant X as
the active X in T-cell hybrids from 7 of the 16 women, identifying these
as carriers of the disorder. Studies on additional family members
confirmed the mutant nature of the inactive X and showed the source of
the new mutation in 3 of the families. The most consistent finding in 21
patients with X-linked SCID was an elevated proportion of B cells.

By the study of X-chromosome inactivation patterns, Goodship et al.
(1991) demonstrated that the mutation is expressed in B lymphocytes and
in granulocytes as well as in T lymphocytes. They concluded that this
disorder is not in a T-lymphocyte differentiation gene but rather in a
metabolic pathway as in ADA deficiency (102700) and PNP deficiency
(613179).

De Saint-Basile et al. (1992) reported 6 individuals in 2 sibships of a
French family with severe infections. The propositus, a 5-year-old boy,
had severe and progressive T- and B-cell functional immunodeficiency.
The mother and 1 sister showed nonrandom X chromosome inactivation of T
cells and, partially, of B cells but not of polymorphonuclear
leukocytes, a pattern similar to that observed in X-linked SCID
carriers. RFLP studies identified a haplotype segregating with the
abnormal locus that may be localized in the proximal part of the long
arm of the X chromosome. The authors suggested that the disorder may
represent either a new X-linked immunodeficiency or an 'attenuated
phenotype' of X-linked SCID.

Hendriks et al. (1992) raised the possibility of 2 distinct XSCID
defects. They determined the pattern of X-chromosome inactivation in 14
females, including 6 obligate carriers, from 3 unrelated pedigrees with
XSCID. All 6 obligate carriers showed nonrandom X-inactivation of the
mutant chromosome in T cells. Four obligate carriers had nonrandom
X-inactivation in B cells, and 4 did not, consistent with the
observation that B cells with the XSCID mutation exhibit a relative
maturation disadvantage rather than an absolute arrest in
differentiation. In carriers from 1 pedigree, granulocytes had complete
inactivation of the mutated X chromosome, whereas granulocytes from
carriers from the other 2 pedigrees showed a random X-chromosome
inactivation. The authors concluded that an XSCID phenotype with
involvement of granulocytes represented an XSCID variant.

Wengler et al. (1993) demonstrated that all 4 lymphoid cell populations
studied, NK cells, B cells, CD4+ T cells, and CD8+ T cells, from 3
heterozygous women exhibited exclusive use of a single X as the active
X, whereas both X chromosomes were used as the active X in neutrophils
and monocytes. The study was done by means of a PCR technique based on 2
observations: that active and inactive X chromosomes differ in
methylation and that throughout the genome there are highly polymorphic
sites consisting of sequences of 2-to-5 nucleotides that are repeated a
variable number of times.

CLINICAL MANAGEMENT

Shortly after the discovery of the HLA system (Amos and Bach, 1968),
Gatti et al. (1968) restored immune function in an infant with SCID by
transplantation of bone marrow from his HLA-identical sister. Over the
following decade, however, lethal GVHD was a major problem when bone
marrow from HLA-mismatched donors was transplanted. In the late 1970s,
studies in rats and mice demonstrated that allogeneic marrow or spleen
cells that were depleted of T cells rescued the recipient from lethal
irradiation without causing fatal GVHD, despite differences in MHC
antigens between the donor and the host. Techniques developed in the
early 1980s to deplete human marrow of T cells made it possible to
restore immune function by marrow transplantation in patients with any
form of SCID.

Borzy et al. (1984) reported a patient with SCID who had maternally
derived peripheral blood lymphocytes identified by chromosomal
heteromorphisms defined by the quinacrine banding technique. These
markers were also used to monitor the successful engraftment of
lymphocytes from a sister after bone marrow transplantation.

Flake et al. (1996) reported the successful treatment of a fetus with
X-linked SCID by the in utero transplantation of paternal bone marrow
that was enriched with hematopoietic cell progenitors. The mother had
lost a previous son at 7 months of age to this disease. Studies of that
child's DNA identified a splice site mutation in the IL2RG gene
(308380).

Buckley et al. (1999) reported on the outcome of hematopoietic stem cell
transplantation in 89 consecutive infants with SCID at Duke University
Medical Center over the previous 16.5 years and the extent of immune
reconstitution in the 72 surviving patients. Patients with X-linked SCID
represented the largest category with 43 patients, of whom 34 (79%)
survived. Other patients treated by Buckley et al. (1999) included 6
cases of JAK3 deficiency (600802), 2 cases of interleukin-7 receptor
alpha deficiency (IL7R; 608971), and 13 cases of adenosine deaminase
deficiency (102700). Twenty-one of the patients had autosomal recessive
SCID of unknown cause. At the time of latest evaluation, Buckley et al.
(1999) found that all but 4 of the 72 survivors had normal T-cell
function, and all the T cells in their blood were of donor origin;
however, B-cell function remained abnormal in many of the recipients of
haploidentical marrow. Forty-five of the 72 children were receiving
intravenous immune globulin. A striking finding of the study was that
all but 1 of the patients who were younger than 3.5 months of age when
they received a bone marrow graft had survived. The results emphasized
the necessity of early diagnosis of the disorder, which should be
considered a pediatric emergency. Whereas the absence of T cells
prevented GVHD, mild GVHD occurred most often in patients in whom
maternal T-cell engraftment, which occurred during pregnancy, was
detected. This finding strongly suggested that most of the transient
graft-versus-host reactions were actually graft-versus-graft reactions:
T cells in the graft vs maternal T cells.

Rosen (2002) reported that the infant boy with X-linked SCID who
received a successful bone marrow transplant from his HLA-identical
sister in 1968 (Gatti et al., 1968) was in robust health 34 years later.

Ting et al. (1999) showed that DNA from hair roots was particularly
useful for the diagnosis of X-linked SCID in children who had been
subjected to bone marrow transplantation where no pretransplant blood
had been stored. They performed mutation analysis in 13 unrelated boys
who had had bone marrow transplantation. Five boys had an affected male
relative. Mutations were found in 11 cases, 6 of which were sporadic,
and maternal mosaicism was found in 1 family. Three mothers of the 6
sporadic cases were identified as carriers.

- Gene Therapy

After preclinical studies, Cavazzano-Calvo et al. (2000) initiated gene
therapy trials for X-linked SCID based on the use of cDNA containing a
defective gamma-c Moloney retrovirus-derived vector and ex vivo
infection of CD34+ hematopoietic stem cells. After a 10-month follow-up,
gamma-c transgene (IL2RG)-expressing T and NK cells were detected in 2
patients. T, B, and NK cell counts and function, including
antigen-specific responses, were comparable to those of age-matched
controls. that

Cavazzano-Calvo (2002) noted that gene therapy for SCID is indicated
only for those patients for whom a satisfactory HLA match is not
available. Given an HLA match, bone marrow transplantation is the
treatment of choice. In the absence of T cells in an affected son, T
cells from the mother may persist in the affected son, resulting in
graph-versus-host manifestations such as dermatitis and enteritis. After
gene therapy with the patient's cells carrying a gamma-c transgene, the
maternal T cells (marked by the XX chromosomes) decline in a reciprocal
arrangement with the rise in T cells with the XY sex chromosome
constitution.

Hacein-Bey-Abina et al. (2002) reported successful treatment of 5 SCIDX
patients with autologous CD34+ bone marrow cells that had been
transduced in vivo with a defective retroviral vector carrying the IL2RG
gene (308380). Integration and expression of the transgene and
development of lymphocyte subgroups and their functions were
sequentially analyzed over a period of up to 2.5 years after gene
transfer. No adverse effects resulted from the procedure. Transduced T
cells and natural killer cells appeared in the blood of 4 of the 5
patients within 4 months. The numbers and phenotypes of T cells, the
repertoire of T-cell receptors, and the in vitro proliferative responses
of T cells to several antigens after immunization were nearly normal up
to 2 years after treatment. Thymopoiesis was documented by the presence
of naive T cells and T-cell antigen-receptor episomes and the
development of a normal-sized thymus gland. The frequency of transduced
B cells was low, but serum immunoglobulin levels and antibody production
after immunization were sufficient to avoid the need for intravenous
immunoglobulin. Correction of the immunodeficiency eradicated
established infections and allowed patients to have a normal life.

Hacein-Bey-Abina et al. (2003) stated the results of their earlier
studies (Hacein-Bey-Abina et al., 2002) had been confirmed in 4
additional patients with typical X-linked SCID who were treated by the
same ex vivo, retrovirally-mediated transfer of the IL2RG gene into
CD34+ cells. Of the first 4 successfully treated patients, 3 continued
to do well up to 3.6 years after gene therapy, whereas a serious adverse
event occurred in the fourth patient. At routine checkup 30 months after
gene therapy, the patient was found to have integration of the provirus
into 1 site on 11p within the LMO2 locus (180385), which had previously
been reported as the basis of acute lymphoblastic leukemia arising from
T cells with alpha/beta receptors, usually with the chromosomal
translocation t(11;14). Between 30 and 34 months after gene therapy, the
patient's lymphocyte count rose to 300,000 per cubic millimeter, and
hepatosplenomegaly developed. Response to chemotherapy regimen was
satisfactory at the time of report.

Marshall (2002, 2003) reported the development of leukemia in 2 children
who received gene therapy. Hacein-Bey-Abina et al. (2003) demonstrated
that in the 2 patients who developed T-cell leukemia after
retrovirus-mediated gene transfer into autologous CD34 cells, the
retrovirus vector integration was in proximity to the LMO2 protooncogene
promoter, leading to aberrant transcription and expression of LMO2.
Hacein-Bey-Abina et al. (2003) speculated that SCIDX1-related features
may have contributed to the unexpectedly high rate of leukemia-like
syndrome in their gene therapy-treated patients. They speculated that,
because of the differentiation block, there were more T-lymphocyte
precursors among CD34 cells in SCIDX1 marrow than in marrow of normal
controls, thus augmenting the number of cells at risk for vector
integration and further proliferation once the gamma-c transgene is
expressed.

By searching a database containing the sequences of more than 3,000
retroviral integration sites cloned from mouse retrovirally induced
hematopoietic tumors, Dave et al. (2004) identified 2 leukemias with
integrations at Lmo2 and 2 leukemias with integrations at Il2rg
(308380). One of these leukemias contained integrations at both sites.
These integrations were clonal, suggesting that they were acquired early
during the establishment of the leukemia. The authors noted that the
probability of finding a leukemia with clonal integrations at Lmo2 and
Il2rg by random chance was exceedingly small, providing genetic evidence
for cooperation between LMO2 and IL2RG. Leukemia 98-031 had a T-cell
phenotype and upregulated Lmo2 expression, a finding consistent with
that seen in SCIDX1 patient leukemias. Dave et al. (2004) suggested that
the results provided a genetic explanation for the high frequency of
leukemia in the gene therapy trials. In transplant patients, IL2RG is
expressed from the ubiquitous Moloney viral long terminal repeat.
Although this was expected to be safe, Dave et al. (2004) concluded that
retrovirally expressed IL2RG might be oncogenic due to some subtle
effect on growth or differentiation of infected cells. Dave et al.
(2004) further concluded that their results boded well for future gene
therapy trials, because in most trials the transplanted gene is unlikely
to be oncogenic and occurrences of insertional mutagenesis will be low.

Although gene therapy had been shown to be highly effective treatment
for infants with typical SCIDX1, the optimal treatment strategy in
patients with previous failed allogeneic transplantation and those with
attenuated disease who present late in life was unclear. Thrasher et al.
(2005) reported the failure of gene therapy in 2 such patients, despite
effective gene transfer to bone marrow CD34+ cells, suggesting that
there are intrinsic host-dependent restrictions to efficacy. The authors
considered it likely that initiation of normal thymopoiesis is time
dependent and suggested that gene therapy in such patients should be
considered as early as possible.

The low frequency of homologous recombination in human cells was an
impediment to permanent modification of the human genome. Urnov et al.
(2005) reported a general solution using 2 fundamental biologic
processes: DNA recognition by C2H2-zinc finger proteins and
homology-directed repair of DNA double-strand breaks. Zinc finger
proteins engineered to recognize a unique chromosomal site can be fused
to a nuclease domain, and a double-strand break induced by the resulting
zinc finger nuclease can create specific sequence alterations by
stimulating homologous recombination between the chromosome and an
extrachromosomal DNA donor. Urnov et al. (2005) showed that zinc finger
nucleases designed against an X-linked SCID mutation in the IL2RG gene
yielded more than 18% gene-modified human cells without selection.
Remarkably, about 7% of the cells acquired the desired genetic
modification on both X chromosomes, with cell genotype accurately
reflected at the mRNA and protein levels. Urnov et al. (2005) observed
comparably high frequencies in human T cells, raising the possibility of
strategies based on zinc finger nucleases for the treatment of disease.

Hacein-Bey-Abina et al. (2010) reported the results of a 9-year
follow-up of 9 SCID patients treated with retrovirus-mediated transfer
of the IL2RG gene to autologous CD34+ cells. Eight of 9 patients
initially had successful correction of the immune dysfunction, but 4
patients developed T-cell acute lymphoblastic leukemia, resulting in
death in 1. Transduced T cells were detected for up to 10.7 years after
gene therapy. Seven patients, including 3 with leukemia, had sustained
immune response; 3 required immunoglobulin replacement therapy.
Transduced B cells were not detected in long-term follow-up.

MAPPING

De Saint Basile et al. (1987) mapped the X-linked SCID locus to Xq11-q13
by linkage analysis with RFLPs. No recombination was observed with
marker DXS159. According to Mensink and Schuurman (1987), J. L. Mandel
found close linkage with the DXS159 marker at Xq12-q13 in 6 pedigrees.
They also suggested that there may be more than one X-linked SCID locus
because there was immunologic heterogeneity.

Puck et al. (1988) found linkage with loci in Xq12-q21.3, but concluded
that the exact localization remained uncertain and that heterogeneity
might exist. Puck et al. (1989) performed linkage analysis in 6 kindreds
using a random pattern of T-cell X-inactivation to rule out the carrier
state in at-risk women. Their findings, combined with analysis of Xq
interstitial deletions, allowed assignment of the locus to Xq13.1-q21.1
and defined flanking markers for prenatal diagnosis and carrier testing.
Smead et al. (1989) found no recombination among SCID, PGK1 (311800),
and DXS72. DXS72 is known to be distal to SCID because males with normal
immunity have been described with Xq21 interstitial deletions involving
DXS72. DXS159 and DXS3 appeared to be flanking markers for SCID.
Goodship et al. (1989) demonstrated no recombination between IMD4 and
DXS159, PGK1, or DXS72; the maximum lod score for linkage to PGK1 was
5.03.

MOLECULAR GENETICS

In 3 unrelated patients with X-linked SCID, Noguchi et al. (1993)
identified 3 different mutations in the IL2RG gene
(308380.0001-308380.0003).

POPULATION GENETICS

X-linked SCID is the most common form of SCID and has been estimated to
account for 46% (Buckley, 2004) to 70% of all SCID cases (Stephan et
al., 1993; Fischer et al., 1997).

In a study of 108 patients with SCID, Buckley et al. (1997) found that
IL2RG deficiency and JAK3 deficiency accounted for approximately 42% and
approximately 6% of cases, respectively.

NOMENCLATURE

X-linked SCID was earlier referred to as 'Swiss-type agammaglobulinemia'
or thymic epithelial hypoplasia (Nezelof, 1992).

Leonard (1993) suggested that the common gamma chain of IL2R be
designated gamma-c, and that X-linked SCID be termed gamma-c deficiency
XSCID. X-linked severe combined immunodeficiency has been known
colloquially as 'Bubble Boy disease' because it was the abnormality in a
patient who lived in an isolation unit in Houston for a prolonged
period.

See review by Leonard et al. (1994).

ANIMAL MODEL

By somatic cell hybrid analysis and methylation differences, Deschenes
et al. (1994) demonstrated that female dogs carrying X-linked SCID have
the same lymphocyte-limited skewed X-chromosome inactivation patterns as
human carriers. In canine XSCID, Henthorn et al. (1994) demonstrated a
4-bp deletion in the first exon of the IL2RG gene, resulting in a
nonfunctional protein.

In addition to XSCID caused by mutations in the common IL2RG gene, an
autosomal form of SCID (608971) with T-cell deficiency occurs in
patients with a mutation in the IL7R gene (146661). IL7 (146660) is
vital for B-cell development in mice, but not in humans. Ozaki et al.
(2002) developed a mouse model with a phenotype resembling human XSCID
by knocking out the genes for both Il4 (147780) and Il21r (605383). Mice
lacking only the Il21r gene had normal B- and T-cell phenotypes and
functions, with the exception of lower IgG1 and IgG2b and higher serum
IgE levels. After immunization with various antigens and with the
parasite Toxoplasma gondii, the normal increase in IgG1 antibodies, as
well as antigen-specific IgG2b and IgG3 antibodies, was significantly
lower than in wildtype mice, and there was an uncharacteristic marked
increase in antigen-specific IgE responses. In contrast, mice lacking
both Il4 and Il21r exhibited lower levels of IgG and IgA, but not IgM,
analogous to humans with XSCID. After immunization, these
double-knockout mice did not upregulate IgE, indicating that this
phenomenon is Il4-dependent, nor did they upregulate the IgG subclasses.
The double-knockout mice, but not mice lacking only Il4 or Il21r, had
disorganized germinal centers. Ozaki et al. (2002) proposed that
defective signaling by IL4 and IL21 (605384) might explain the B-cell
defect in XSCID.

To investigate the origin of T-cell lymphoma risk in XSCID patients
treated with IL2RG gene therapy, Woods et al. (2006) expressed IL2RG
inserted into a lentiviral vector in a murine model of XSCID, and
followed the fates of mice for up to 1.5 years posttransplantation.
Unexpectedly, 15 (33%) of these mice developed T-cell lymphomas that
were associated with a gross thymic mass. Lymphomic tissues shared a
common lymphomic stem cell, with similar vector-integration sites
evident in the DNA of the thymus, bone marrow, and spleen of individual
mice; however, no common integration targets were found between mice.
Woods et al. (2006) concluded that IL2RG itself may be oncogenic to
patients. They further cautioned that any preclinical experimental
treatments involving transgenes should include long-term follow-up
before they enter clinical trials.

*FIELD* SA
Rosen and Janeway (1966); Simar et al. (1972)
*FIELD* RF
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527-539, 1984.

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2004.

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L. W.; Harville, T. O.; Roberts, J. L.; Puck, J. M.: Human severe
combined immunodeficiency: genetic, phenotypic, and functional diversity
in one hundred eight infants. J. Pediat. 130: 378-387, 1997.

5. Buckley, R. H.; Schiff, S. E.; Schiff, R. I.; Markert, M. L.; Williams,
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7/25/2002.

7. Cavazzano-Calvo, M.; Hacein-Bey, S.; de Saint Basile, G.; Gross,
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severe combined immunodeficiency (SCID)-X1 disease. Science 288:
669-672, 2000.

8. Conley, M. E.; Buckley, R. H.; Hong, R.; Guerra-Hanson, C.; Roifman,
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combined immunodeficiency: diagnosis in males with sporadic severe
combined immunodeficiency and clarification of clinical findings. J.
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9. Conley, M. E.; Lavoie, A.; Briggs, C.; Brown, P.; Guerra, C.; Puck,
J. M.: Nonrandom X chromosome inactivation in B cells from carriers
of X chromosome-linked severe combined immunodeficiency. Proc. Nat.
Acad. Sci. 85: 3090-3094, 1988.

10. Conley, M. E.; Nowell, P. C.; Henle, G.; Douglas, S. D.: XX T
cells and XY B cells in two patients with severe combined immune deficiency. Clin.
Immun. Immunopath. 31: 87-95, 1984.

11. Dave, U. P.; Jenkins, N. A.; Copeland, N. G.: Gene therapy insertional
mutagenesis insights. Science 303: 333 only, 2004.

12. de Saint-Basile, G.; Le Deist, F.; Caniglia, M.; Lebranchu, Y.;
Griscelli, C.; Fischer, A.: Genetic study of a new X-linked recessive
immunodeficiency syndrome. J. Clin. Invest. 89: 861-866, 1992.

13. de Saint Basile, G.; Arveiler, B.; Oberle, I.; Malcolm, S.; Levinsky,
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14. Deschenes, S. M.; Puck, J. M.; Dutra, A. S.; Somberg, R. L.; Felsburg,
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15. Dooren, L. J.; de Vries, M. J.; van Bekkum, D. W.; Cleton, F.
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16. Fischer, A.; Cavazzana-Calvo, M.; de Saint Basile, G.; DeVillartay,
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: Naturally occurring primary deficiencies of the immune system. Annu.
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17. Flake, A. W.; Roncarolo, M.-G.; Puck, J. M.; Almeida-Porada, G.;
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1806-1810, 1996.

18. Gatti, R. A.; Meuwissen, J. J.; Allen, H. D.; Hong, R.; Good,
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20. Goodship, J.; Levinsky, R.; Malcolm, S.: Linkage of PGK1 to X-linked
severe combined immunodeficiency (IMD4) allows predictive testing
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21. Goodship, J.; Malcolm, S.; Lau, Y. L.; Pembrey, M. E.; Levinsky,
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22. Goodship, J.; Malcolm, S.; Levinsky, R. J.: Evidence that X-linked
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23. Hacein-Bey-Abina, S.; Hauer, J.; Lim, A.; Picard, C.; Wang, G.
P.; Berry, C. C.; Martinache, C.; Rieux-Laucat, F.; Latour, S.; Belohradsky,
B. H.; Leiva, L.; Sorensen, R.; Debre, M.; Casanova, J. L.; Blanche,
S.; Durandy, A.; Bushman, F. D.; Fischer, A.; Cavazzana-Calvo, M.
: Efficacy of gene therapy for X-linked severe combined immunodeficiency. New
Eng. J. Med. 363: 355-364, 2010.

24. Hacein-Bey-Abina, S.; Le Deist, F.; Carlier, F.; Bouneaud, C.;
Hue, C.; De Villartay, J.-P.; Thrasher, A. J.; Wulffraat, N.; Sorensen,
R.; Dupuis-Girod, S.; Fischer, A.; Cavazzana-Calvo, M.: Sustained
correction of X-linked severe combined immunodeficiency by ex vivo
gene therapy. New Eng. J. Med. 346: 1185-1193, 2002.

25. Hacein-Bey-Abina, S.; von Kalle, C.; Schmidt, M.; Le Deist, F.;
Wulffraat, N.; McIntyre, E.; Radford, I.; Villeval, J.-L.; Fraser,
C. C.; Cavazzana-Calvo, M.; Fischer, A.: A serious adverse event
after successful gene therapy for X-linked severe combined immunodeficiency.
(Letter) New Eng. J. Med. 348: 255-256, 2003.

26. Hacein-Bey-Abina, S.; Von Kalle, C.; Schmidt, M.; McCormack, M.
P.; Wulffraat, N.; Leboulch, P.; Lim, A.; Osborne, C. S.; Pawliuk,
R.; Morillon, E.; Sorensen, R.; Forster, A.; and 23 others: LMO2-associated
clonal T cell proliferation in two patients after gene therapy for
SCID-X1. Science 302: 415-419, 2003. Erratum: Science 302: 568 only,
2003.

27. Hendriks, R. W.; Kraakman, M. E. M.; Schuurman, R. K. B.: X chromosome
inactivation patterns in haematopoietic cells of female carriers of
X-linked severe combined immunodeficiency determined by methylation
analysis at the hypervariable DXS255 locus. Clin. Genet. 42: 114-121,
1992.

28. Henthorn, P. S.; Somberg, R. L.; Fimiani, V. M.; Puck, J. M.;
Patterson, D. F.; Felsburg, P. J.: IL-2R-gamma gene microdeletion
demonstrates that canine X-linked severe combined immunodeficiency
is a homologue of the human disease. Genomics 23: 69-74, 1994.

29. Hitzig, W. H.; Willi, H.: Hereditary lymphoplasmocytic dysgenesis
('alymphocytose mit agammaglobulinamia'). Schweiz. Med. Wschr. 91:
1625-1633, 1961.

30. Kellermayer, R.; Hsu, A. P.; Stankovics, J.; Balogh, P.; Hadzsiev,
K.; Vojcek, A.; Marodi, L.; Kajtar, P.; Kosztolanyi, G.; Puck, J.
M.: A novel IL2RG mutation associated with maternal T lymphocyte
engraftment in a patient with severe combined immunodeficiency. J.
Hum. Genet. 51: 495-497, 2006.

31. Leonard, W. J.: Personal Communication. Bethesda, Md. 11/26/1993.

32. Leonard, W. J.; Noguchi, M.; Russell, S. M.; McBride, O. W.:
The molecular basis of X-linked severe combined immunodeficiency:
the role of the interleukin-2 receptor gamma-chain as a common gamma-chain,
gamma-c. Immun. Rev. 138: 61-86, 1994.

33. Marshall, E.: Gene therapy a suspect in leukemia-like disease. Science 298:
34-35, 2002.

34. Marshall, E.: Second child in French trial is found to have leukemia. Science 299:
320 only, 2003.

35. Mensink, E. J. B. M.; Schuurman, R. K. B.: Immunodeficiency disease
genes on the X chromosome. Dis. Markers 5: 129-140, 1987.

36. Miller, M. E.; Schieken, R. M.: Thymic dysplasia: a separable
entity from 'Swiss agammaglobulinemia.'. Am. J. Med. Sci. 253: 741-750,
1967.

37. Nezelof, C.: Thymic pathology in primary and secondary immunodeficiencies. Histopathology 21:
499-511, 1992.

38. Noguchi, M.; Yi, H.; Rosenblatt, H. M.; Filipovich, A. H.; Adelstein,
S.; Modi, W. S.; McBride, O. W.; Leonard, W. J.: Interleukin-2 receptor
gamma chain mutation results in X-linked severe combined immunodeficiency
in humans. Cell 73: 147-157, 1993.

39. Ozaki, K.; Spolski, R.; Feng, C. G.; Qi, C.-F.; Cheng, J.; Sher,
A.; Morse, H. C., III; Liu, C.; Schwartzberg, P. L.; Leonard, W. J.
: A critical role for IL-21 in regulating immunoglobulin production. Science 298:
1630-1634, 2002.

40. Puck, J. M.; Nussbaum, R. L.; Briggs, C.; Brown, P.; Conley, M.
E.: Carrier detection in X-linked forms of agammaglobulinemia and
severe combined immunodeficiency. (Abstract) Am. J. Hum. Genet. 39:
A99 only, 1986.

41. Puck, J. M.; Nussbaum, R. L.; Conley, M. E.: Carrier detection
in X-linked severe combined immunodeficiency based on patterns of
X chromosome inactivation. J. Clin. Invest. 79: 1395-1400, 1987.

42. Puck, J. M.; Nussbaum, R. L.; Smead, D. L.; Conley, M. E.: X-linked
severe combined immunodeficiency: localization within the region Xq13.1-q21.1
by linkage and deletion analysis. Am. J. Hum. Genet. 44: 724-730,
1989.

43. Puck, J. M.; Nussbaum, R. L.; Smead, D. L.; Conley, M. E.: Regional
mapping of X-linked severe combined immunodeficiency to Xq13-21.3
using nonrandom X inactivation as a carrier test. (Abstract) Am.
J. Hum. Genet. 43: A156 only, 1988.

44. Puck, J. M.; Stewart, C. C.; Nussbaum, R. L.: Maximum-likelihood
analysis of human T-cell X chromosome inactivation patterns: normal
women versus carriers of X-linked severe combined immunodeficiency. Am.
J. Hum. Genet. 50: 742-748, 1992.

45. Rosen, F. S.: Successful gene therapy for severe combined immunodeficiency.
(Editorial) New Eng. J. Med. 346: 1241-1243, 2002.

46. Rosen, F. S.; Craig, J. M.; Vawter, G. F.; Janeway, C. A.: The
dysgammaglobulinemias and X-linked thymic hypoplasia.In: Bergsma,
D.; Good, R. A.: Immunologic Deficiency Diseases in Man. New York:
National Foundation (pub.) 1968. Pp. 67-70.

47. Rosen, F. S.; Gotoff, S. P.; Craig, J. M.; Ritchie, J.; Janeway,
C. A.: Further observations on the Swiss type of agammaglobulinemia
(alymphocytosis): the effect of syngeneic bone-marrow cells. New
Eng. J. Med. 274: 18-21, 1966.

48. Rosen, F. S.; Janeway, C. A.: The gamma globulins. III. The antibody
deficiency syndromes. New Eng. J. Med. 275: 709-715 and 769-775,
1966.

49. Simar, J.; Farriaux, J.-P.; Pauli, A.; Fournier, A.; Fontaine,
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889-896, 1972.

50. Smead, D. L.; Conley, M. E.; Puck, J. M.: Improved regional localization
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51. Speckmann, C.; Pannicke, U.; Wiech, E.; Schwarz, K.; Fisch, P.;
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: Clinical and immunological consequences of a somatic reversion in
a patient with X-linked severe combined immunodeficiency. Blood 112:
4090-4097, 2008.

52. Stephan, J. L.; Vlekova, V.; Le Deist, F.; Blanche, S.; Donadieu,
J.; de Saint-Basile, G.; Durandy, A.; Griscelli, C.; Fischer, A.:
Severe combined immunodeficiency: a retrospective single-center study
of clinical presentation and outcome in 117 patients. J. Pediat. 123:
564-572, 1993.

53. Stephan, V.; Wahn, V.; Le Deist, F.; Dirksen, U.; Broker, B.;
Muller-Fleckenstein, I.; Horneff, G.; Schroten, H.; Fischer, A.; de
Saint Basile, G.: Atypical X-linked severe combined immunodeficiency
due to possible spontaneous reversion of the genetic defect in T cells. New
Eng. J. Med. 335: 1563-1567, 1996.

54. Thrasher, A. J.; Hacein-Bey-Abina, S.; Gaspar, H. B.; Blanche,
S.; Davies, E. G.; Parsley, K.; Gilmour, K.; King, D.; Howe, S.; Sinclair,
J.; Hue, C.; Carlier, F.; von Kalle, C.; de Saint Basile, G.; Le Deist,
F.; Fischer, A.; Cavazzana-Calvo, M.: Failure of SCID-X1 gene therapy
in older patients. Blood 105: 4255-4257, 2005.

55. Ting, S. S.; Leigh, D.; Lindeman, R.; Ziegler, J. B.: Identification
of X-linked severe combined immunodeficiency by mutation analysis
of blood and hair roots. Brit. J. Haemat. 106: 190-194, 1999.

56. Urnov, F. D.; Miller, J. C.; Lee, Y.-L.; Beausejour, C. M.; Rock,
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57. Vogelstein, B.; Fearon, E. R.; Hamilton, S. R.; Preisinger, A.
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Clonal analysis using recombinant DNA probes from the X-chromosome. Cancer
Res. 47: 4806-4813, 1987.

58. Wengler, G. S.; Allen, R. C.; Parolini, O.; Smith, H.; Conley,
M. E.: Nonrandom X chromosome inactivation in natural killer cells
from obligate carriers of X-linked severe combined immunodeficiency. J.
Immun. 150: 700-704, 1993.

59. Woods, N.-B.; Bottero, V.; Schmidt, M.; von Kalle, C.; Verma,
I. M.: Therapeutic gene causing lymphoma. (Letter) Nature 440:
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*FIELD* CS
INHERITANCE:
X-linked recessive

GROWTH:
[Other];
Failure to thrive

HEAD AND NECK:
[Mouth];
Oral thrush;
[Pharynx];
Absent tonsils

RESPIRATORY:
[Lung];
Pneumonia

ABDOMEN:
[Liver];
Hepatomegaly;
[Gastrointestinal];
Chronic diarrhea

SKIN, NAILS, HAIR:
[Skin];
Candidal diaper rash;
Erythematous skin rashes

NEUROLOGIC:
[Central nervous system];
Recurrent bacterial meningitis

IMMUNOLOGY:
Frequent bacterial, fungal and viral infections;
Specific antibody production very poor;
Natural killer cells, reduced numbers and cytotoxicity;
Absent T lymphocytes;
Thymic hypoplasia;
Lymphoid depletion;
Lymph nodes are small and poorly developed

LABORATORY ABNORMALITIES:
Low absolute lymphocyte count;
Agammaglobulinemia

MISCELLANEOUS:
Death within first year of life

MOLECULAR BASIS:
Caused by mutation in the interleukin receptor gamma chain gene (IL2RG,
308380.0001)

*FIELD* CN
Ada Hamosh - reviewed: 4/19/2000
Assil Saleh - revised: 4/7/2000

*FIELD* CD
John F. Jackson: 6/15/1995

*FIELD* ED
joanna: 07/23/2013
joanna: 4/19/2000
kayiaros: 4/7/2000

*FIELD* CN
Cassandra L. Kniffin - updated: 7/29/2010
Cassandra L. Kniffin - updated: 7/6/2006
Ada Hamosh - updated: 5/15/2006
Victor A. McKusick - updated: 8/11/2005
Ada Hamosh - updated: 6/15/2005
Cassandra L. Kniffin - reorganized: 10/28/2004
Cassandra L. Kniffin - updated: 10/20/2004
Ada Hamosh - updated: 2/2/2004
Ada Hamosh - updated: 10/28/2003
Victor A. McKusick - updated: 6/27/2003
Victor A. McKusick - updated: 1/24/2003
Paul J. Converse - updated: 12/3/2002
Victor A. McKusick - updated: 9/9/2002
Victor A. McKusick - updated: 5/14/2002
Ada Hamosh - updated: 5/2/2000
Victor A. McKusick - updated: 9/29/1999
Victor A. McKusick - updated: 3/12/1999
Victor A. McKusick - updated: 11/10/1998

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

*FIELD* ED
mgross: 02/11/2014
mcolton: 1/23/2014
terry: 9/25/2012
carol: 3/26/2012
terry: 1/18/2012
mgross: 12/16/2011
terry: 9/9/2010
wwang: 8/6/2010
ckniffin: 7/29/2010
carol: 12/17/2009
wwang: 9/9/2009
terry: 3/27/2009
wwang: 3/18/2009
ckniffin: 3/9/2009
wwang: 7/13/2006
ckniffin: 7/6/2006
alopez: 5/23/2006
terry: 5/15/2006
wwang: 8/12/2005
terry: 8/11/2005
alopez: 6/15/2005
terry: 6/15/2005
carol: 10/28/2004
terry: 10/28/2004
ckniffin: 10/27/2004
ckniffin: 10/20/2004
alopez: 2/2/2004
tkritzer: 10/29/2003
terry: 10/28/2003
carol: 7/8/2003
terry: 6/27/2003
cwells: 2/3/2003
terry: 1/24/2003
mgross: 12/3/2002
alopez: 9/9/2002
terry: 5/14/2002
alopez: 5/2/2000
alopez: 2/29/2000
mgross: 10/13/1999
terry: 9/29/1999
carol: 3/15/1999
terry: 3/12/1999
carol: 11/17/1998
terry: 11/10/1998
dkim: 7/21/1998
mark: 6/10/1997
mark: 1/6/1997
terry: 1/3/1997
carol: 1/11/1995
jason: 6/28/1994
davew: 6/8/1994
mimadm: 3/29/1994
carol: 4/13/1993
carol: 10/27/1992

read less

MIM 308380
*RECORD*
*FIELD* NO
308380
*FIELD* TI
*308380 INTERLEUKIN 2 RECEPTOR, GAMMA; IL2RG
;;INTERLEUKIN RECEPTOR, COMMON GAMMA CHAIN;;
read moreINTERLEUKIN RECEPTOR, GAMMA-C;;
CD132 ANTIGEN; CD132
*FIELD* TX

DESCRIPTION

Cytokines are potent, soluble mediators that regulate homeostasis of the
immune system. IL2RG is known as the interleukin receptor common gamma
chain, or gamma-c, because it heterodimerizes with at least 6 unique
cytokine-specific interleukin receptor alpha chains, IL2RA (147730),
IL4RA (147781), IL7RA (146661), IL9RA (300007), IL15RA (601070), and
IL21RA (605383), to form distinct receptor complexes for the cytokines
IL2 (147680), IL4 (147780), IL7 (146660), IL9 (146931), IL15 (600554),
and IL21 (605384), respectively. The IL2 and IL21 receptor complexes are
heterotrimers that also include a shared beta chain, IL2RB/IL15RB
(146710) (Brandt et al., 2007).

CLONING

IL2 affects the growth and differentiation of T cells, B cells, natural
killer cells, glioma cells, and cells of the monocyte lineage after
specifically interacting with its receptors. The IL2 receptor (IL2R)
consists of 2 subunits, alpha (IL2RA) and beta (IL2RB). Takeshita et al.
(1992) identified a third IL2R subunit, the gamma chain, and isolated
the corresponding cDNA from a human T-cell line. The deduced 369-amino
acid protein has a molecular mass of 39.9 kD and shows sequence
similarity to members of the cytokine receptor family. Northern blot
analysis detected a dominant 1.8-kb mRNA transcript in human T and B
cells; a second 3.6-kb mRNA transcript was also detected. No IL2RG mRNA
transcripts were detected in human nonlymphoid cells, such as
promonocytes, epithelial cells, or hepatocytes.

Noguchi et al. (1993) found that the IL2RG protein, like the IL2RB
protein, contains 2 pairs of conserved cysteines typical of cytokine
receptor superfamily proteins.

GENE STRUCTURE

Noguchi et al. (1993) determined that the IL2RG gene contains 8 exons
and spans approximately 4.2 kb. Southern blot analysis suggested that
the gene is present in single copy.

Puck et al. (1993) sequenced the IL2RG gene and elucidated its genomic
organization.

MAPPING

By study of somatic cell hybrids, Noguchi et al. (1993) and Puck et al.
(1993) independently mapped the IL2RG gene to chromosome Xq13.
Relationships to markers in linkage studies suggested that IL2RG and
XSCID, the locus for X-linked severe combined immunodeficiency (300400),
had the same location. By fluorescence in situ hybridization and PCR
amplification of somatic cell hybrid DNAs, Puck et al. (1993) mapped
IL2RG to Xq13.1.

Cao et al. (1993) localized the murine Il2rg gene to the X chromosome
between Rsvp and Plp and demonstrated that a defect in the gene is not
responsible for the X-linked xid mutation, which maps to the same
region; see 300300.

GENE FUNCTION

Functional expression studies by Takeshita et al. (1992) showed that the
IL2 receptor gamma chain was necessary for formation of high- and
intermediate-affinity IL2 receptors, which consist of alpha-beta-gamma
heterotrimers and beta-gamma heterodimers, respectively. Takeshita et
al. (1992) concluded that the gamma chain is an indispensable component
of the functional IL2 receptor.

The gamma subunit of the IL2 receptor is a subunit also of the IL4
receptor and of the IL7 receptor, i.e., it is a shared or common
component of at least 3 cytokine receptors. The designation 'common
gamma chain' (gamma-c) was proposed (Kondo et al., 1993; Noguchi et al.,
1993; Russell et al., 1993).

Russell et al. (1993) suggested that the gamma-c subunit may be shared
with the interleukin-9 receptor. The sharing of the gamma subunit by
several receptors explained why humans and mice that lack IL2 entirely
show milder symptoms than those with IL2RG deficiency.

Sharfe et al. (1997) stated that the gamma-c chain is shared by 5
interleukin receptor complexes: IL2, IL4, IL7, IL9, and IL15.

Asao et al. (2001) showed that IL21 binds to IL21R in IL2RG-deficient
cell lines, but fails to transduce signals. In cell lines expressing
IL2RG, binding and activation of JAK1 (147795), JAK3 (600173), STAT1
(600555), and STAT3 (102582) occurs, indicating that IL2RG is an
indispensable subunit of the functional IL21R complex.

Lamaze et al. (2001) selectively blocked clathrin (see 118960)-dependent
endocytosis using dominant-negative mutants of EPS15 (600051) and showed
that clathrin-mediated endocytosis of transferrin (190000) was
inhibited, while endocytosis of the IL2Rs proceeded normally.
Ultrastructural and biochemical experiments showed that
clathrin-independent endocytosis of IL2Rs existed constitutively in
lymphocytes and was coupled to their association with
detergent-resistant membrane domains. Clathrin-independent endocytosis
required dynamin (see 602377) and was specifically regulated by Rho
family GTPases (see 604980). These results defined novel properties of
receptor-mediated endocytosis and established that IL2R is efficiently
internalized through this clathrin-independent pathway.

Using flow cytometry, Corrigall et al. (2001) detected expression of a
functional IL2R of intermediate affinity composed solely of IL2RB and
IL2RG on fibroblast-like synoviocytes (FLS) obtained from rheumatoid
arthritis and osteoarthritis patients. Addition of recombinant IL2, IL1B
(147720), or TNFA (191160) independently did not upregulate expression
of the receptors on FLS, but IL2 or IL1B significantly increased
expression of intracellular tyrosine-phosphorylated proteins and the
production of MCP1 (158105). Corrigall et al. (2001) proposed that MCP1
in the synovial membrane serves to recruit macrophages and perpetuate
inflammation in the joints of patients with rheumatoid arthritis.

BIOCHEMICAL FEATURES

- Crystal Structure

Wang et al. (2005) reported the crystal structure of the quaternary
complex of IL2 with IL2RA, IL2RB, and IL2RG at a resolution of 2.3
angstroms.

LaPorte et al. (2008) reported the crystal structures of the complete
set of IL4 and IL13 (147683) type I (IL4RA/IL2RG/IL4) and type II
(IL4RA/IL13RA1/IL4 and IL4RA/IL13RA1/IL13) ternary signaling complexes
at the 3.0-angstrom level. They noted that the type I receptor complex
is more active in regulating Th2 development, whereas the type II
receptor complex is not found on T cells and is more active in
regulating cells that mediate airway hypersensitivity and mucus
secretion. The type I complex revealed a structural basis for the
ability of IL2RG to recognize 6 different IL2RG cytokines.

MOLECULAR GENETICS

In 3 unrelated patients with X-linked severe combined immunodeficiency
(300400), Noguchi et al. (1993) identified 3 different mutations in the
IL2RG gene (308380.0001-308380.0003).

In 4 unrelated affected males with SCID Puck et al. (1993) identified
unique mutations in the IL2RG gene (308380.0004-308380.0007).

Pepper et al. (1995) found that of 40 IL2RG mutations found in unrelated
SCID males, 6 were point mutations at the CpG dinucleotide at cDNA
residues 690-691 encoding amino acid arg226. This residue lies in the
extracellular domain of the protein in a region not previously
recognized to be significantly conserved in the cytokine receptor gene
family, 11 amino acids upstream from the highly conserved WSXWS motif.
Three additional instances of mutation at another CpG dinucleotide at
cDNA residue 879 produced a premature termination signal in the
intracellular domain of IL2RG, resulting in loss of the SH2-homologous
intracellular domain known to be essential for signaling from the IL2
receptor complex. Pepper et al. (1995) stated that mutations at these 2
hotspots constituted more than 20% of all XSCID mutations.

Leonard (1996) provided a review of the molecular basis of X-linked SCID
with a listing of the mutations identified in the IL2RG gene. Fugmann et
al. (1998) studied the IL2RG gene in 31 patients with SCID. Among 11
patients with XSCID, 10 different mutations were identified in the IL2RG
gene, including 8 novel mutations.

In a patient with X-linked combined immunodeficiency (312863), Sharfe et
al. (1997) identified a mutation in the IL2RG gene (308380.0012), which
resulted in a protein that was sufficiently stable to be expressed at
the cell surface. Although clinically immunodeficient, the patient had
normal numbers of peripheral T and B cells, responded normally to
mitogenic stimuli, and had a normal thymus gland. While the T-cell
receptor repertoire appeared complete, suggesting normal T-cell
differentiation, the patient's T cells demonstrated a reduced ability to
bind IL2, resulting in immunodeficiency.

Cacalano and Johnston (1999) reviewed IL2 signaling in relation to
inherited immunodeficiency. Formal genetic proof that the IL2R
components are critical for T-cell development came with the
identification of patients lacking either IL2RG or JAK3 (600173). These
patients presented with phenotypically identical
T-negative/B-positive/NK-negative SCID, inherited as an X-linked
recessive or an autosomal recessive (600802) disorder, respectively.

Yu et al. (2014) performed deep sequencing on
complementarity-determining region-3 (CDR3) of T-cell receptor
(TCR)-beta (see 186930) in CD4 (186940)-positive and CD8 (see
186910)-positive T cells from 2 patients with RAG1 (179615) or IL2RG
mutations and autoimmunity and/or granulomatous disease, but not severe
immunodeficiency (see 233650 for information on the RAG1-associated
phenotype); 5 patients with Omenn syndrome (603554) caused by RAG1 or
RAG2 (179616) mutations; 2 patients with Omenn syndrome-like phenotypes
caused by a ZAP70 (176947) mutation (see 269840) or by atypical DiGeorge
syndrome (188400); and 4 healthy controls. They found that patients with
Omenn syndrome due to RAG1 or RAG2 mutations had poor TCR-beta diversity
compared with controls and patients with Omenn syndrome not due to RAG1
or RAG2 mutations. The 2 patients with RAG1 or IL2RG mutations
associated with autoimmunity and granulomatous disease did not have
diminished diversity, but instead had skewed V-J pairing and CDR3 amino
acid use. Yu et al. (2014) concluded that RAG enzymatic function may be
necessary for normal CDR3 junctional diversity and that aberrant TCR
generation, but not numeric diversity, may contribute to immune
dysregulation in patients with hypomorphic forms of SCID.

*FIELD* AV
.0001
SEVERE COMBINED IMMUNODEFICIENCY, X-LINKED
IL2RG, LYS97TER

In a patient with X-linked SCID (300400), Noguchi et al. (1993)
identified an A-to-T transversion in exon 3 of the IL2RG gene, resulting
in a lys97-to-ter (K97X) substitution and a truncation of the C-terminal
251 amino acids of the interleukin-2 receptor gamma chain.

.0002
SEVERE COMBINED IMMUNODEFICIENCY, X-LINKED
IL2RG, ARG267TER

In a patient with X-linked SCID (300400), Noguchi et al. (1993)
identified a C-to-T transition in exon 7 of the IL2RG gene, resulting in
an arg267-to-ter (R267X) substitution and truncation of 81 amino acids
of the protein.

.0003
SEVERE COMBINED IMMUNODEFICIENCY, X-LINKED
IL2RG, SER286TER

In a patient with X-linked SCID (300400), Noguchi et al. (1993)
identified a C-to-A transversion in exon 7 of the IL2RG gene, resulting
in a ser286-to-ter (S286X) substitution and the truncation of 62 amino
acids of the protein. This patient became known as Bubble Boy David
because he lived in an isolation bubble in Houston for a long time and
his disease became known as Bubble Boy disease. His early clinical
course and immune function were reported by South et al. (1977) and
Shearer et al. (1985). A male sib was also affected. His
immunodeficiency was characterized by panhypogammaglobulinemia,
lymphopenia with diminished T cells (varying from 10 to 40% over 12
years), elevated B cells, and essentially absent proliferation to
mitogens or antigens. Following T-depleted haploidentical bone marrow
transplantation from his sister, there was no improvement in immune
function. He died 124 days posttransplant from an EBV-associated
lymphoproliferative syndrome.

.0004
SEVERE COMBINED IMMUNODEFICIENCY, X-LINKED
IL2RG, CYS62TER

In a patient with X-linked SCID (300400), Puck et al. (1993) identified
a 200T-A transversion in exon 2 of the IL2RG gene, resulting in a
cys62-to-ter (C62X) substitution.

.0005
SEVERE COMBINED IMMUNODEFICIENCY, X-LINKED
IL2RG, GLY114ASP

In a patient with X-linked SCID (300400), Puck et al. (1993) identified
a 355G-A transition in exon 3 of the IL2RG gene, resulting in a
gly114-to-asp (G114D) substitution.

.0006
SEVERE COMBINED IMMUNODEFICIENCY, X-LINKED
IL2RG, IVS3DS, G-A, +1

In a boy with X-linked SCID (300400) and no detectable IL2RG mRNA, Puck
et al. (1993) identified a G-to-A transition in the first position of
the splice donor site of intron 3 of the IL2RG gene.

.0007
SEVERE COMBINED IMMUNODEFICIENCY, X-LINKED
IL2RG, ILE153ASN

In a boy with X-linked SCID (300400), Puck et al. (1993) identified a
472T-A transversion in exon 4 of the IL2RG gene, resulting in an
ile153-to-asn (I153N) substitution.

.0008
COMBINED IMMUNODEFICIENCY, X-LINKED
IL2RG, LEU271GLN

In 3 affected males with X-linked combined immunodeficiency (XCID;
312863), which is phenotypically milder than X-linked severe combined
immunodeficiency (300400), Schmalstieg et al. (1995) identified a
leu271-to-gln (L271Q) substitution in exon 7 of the IL2RG gene. A normal
brother did not have the mutation.

.0009
SEVERE COMBINED IMMUNODEFICIENCY, X-LINKED
IL2RG, 9-BP DUP, GLN-HIS-TRP INS

By genetic linkage studies in a large Canadian pedigree with XSCID
(300400), Puck et al. (1995) found the source of the mutation in the
proband's grandmother. Despite her having 1 affected son and 2 carrier
daughters with skewed X inactivation, her T cells did not show the
expected skewed inactivation. Single-strand conformation polymorphism
analysis of IL2RG in the affected proband demonstrated an abnormality in
exon 5; sequencing demonstrated a 9-nucleotide in-frame
duplication-insertion resulting in a duplication of 3 extracellular
amino acids (glutamine, histidine, and tryptophan) just adjacent to and
including the first tryptophan of the WSXWS motif found in all members
of the cytokine receptor gene superfamily. The 3 additional amino acids
were inserted just before residue 235. Mutation detection in the
pedigree confirmed that the founder grandmother's somatic cells had only
normal IL2RG, and that the SCID-associated X-chromosome haplotype was
inherited by 3 daughters, 1 with a wildtype IL2RG gene and 2 others with
the insertional mutation. The findings indicated that the grandmother
had germline mosaicism, an unusual finding in females. This X-linked
SCID family emphasized the limitations of genetic diagnosis by linkage
as compared with direct mutation analysis.

.0010
SEVERE COMBINED IMMUNODEFICIENCY, X-LINKED
IL2RG, CYS115ARG

In a male infant in whom XSCID (300400) was suspected at 1 year of age,
Stephan et al. (1996) identified a 343T-C transition in exon 3 of the
IL2RG gene, resulting in a cys115-to-arg (C115R) substitution. The
patient's mother was heterozygous for the mutation. A maternal uncle and
a maternal granduncle had died of pneumonia at ages 4 months and 6
months, respectively. The affected child had BCG vaccination at the age
of 2 weeks. At 6 months of age, he was hospitalized for severe
interstitial pneumonia. Physical examination at 1 year of age showed no
signs of graft-versus-host disease (GVHD; see 614395) and no
abnormalities except for a large abscess in the left lumbar region from
which acid-fast bacilli with genetic characteristics of the
Calmette-Guerin bacillus were identified. Immunologic investigations
showed a normal number of T cells, a high B-cell count, and
hypogammaglobulinemia with no detectable specific antibody responses.
The skin test for purified protein derivative was positive and there
were at least attenuated proliferative responses to antigens and
mitogens. These unusual findings led to genetic analysis which showed
that the gamma chain of IL2R was not expressed in the patient's B cells.
Because of the unexpected presence of circulating mature T cells,
Stephan et al. (1996) sorted and analyzed the patient's CD3+ T cells for
expression of the gamma-c chain. Surprisingly, expression of this chain
by T cells with either the CD4+ or CD8+ phenotype was normal, and
sequencing of the IL2RG gene revealed the wildtype sequence at position
343. In contrast, the sorted CD19+ B cells, the sorted CD14+ monocytes,
and the polymorphonuclear-cell population had no detectable expression
of the gamma-c chain on their surface and contained the C115R mutation.
The possibility that the patient's circulating T-cell population was
derived from the engraftment of T cells in the mother in utero was
excluded by T-cell karyotyping and HLA typing. In addition, the X
chromosome present in the patient's T-cell and B-cell populations was
assessed by study of 2 microsatellites flanking the IL2RG locus. These
cell populations had only 1 X chromosome derived from the mother with
the same X chromosome present in both T-cell and B-cell populations.
Stephan et al. (1996) suggested that a single reversion event had
occurred in a T-cell progenitor that gave rise to a number of
diversified T-cell clones.

.0011
SEVERE COMBINED IMMUNODEFICIENCY, X-LINKED
IL2RG, ARG285GLN

In a patient with T-, B+ X-linked SCID (300400), Clark et al. (1995)
identified a 2943G-A transition in the IL2RG gene, resulting in an
arg285-to-gln (R285Q) substitution.

Jones et al. (1997) noted that X-linked SCID is characterized by the
absence, or very low numbers, of T cells, with normal or even high
numbers of B cells. However, in a boy with SCID who had very low numbers
of both B cells and T cells, Jones et al. (1997) identified the R285Q
mutation. The patient's mother and a maternal aunt were both found to
have unilateral X inactivation in their T cells. Jones et al. (1997)
stated that in about one-third of the cases of typical SCIDX1, there is
no previous family history. In these families, the suspicion of SCIDX1
is raised by the phenotype and may be confirmed by X inactivation in T
cells and/or by mutation analysis. The authors cautioned that the
unexpected finding of low B cells may mistakenly suggest an autosomal
form of SCID.

.0012
COMBINED IMMUNODEFICIENCY, X-LINKED
IL2RG, ARG222CYS

In a 1-year-old Caucasian male with X-linked combined immunodeficiency
(312863), Sharfe et al. (1997) identified an arg222-to-cys (R222C)
mutation in the IL2RG gene. The mutation occurs in the extracellular
domain of the protein, which was predicted to affect ligand binding. The
authors noted that the mutation was distinctive in that the protein was
stable enough to be expressed at the cell surface.

.0013
SEVERE COMBINED IMMUNODEFICIENCY, X-LINKED
IL2RG, LEU151PRO

In a boy with a relatively mild form of X-linked SCID (300400),
Speckmann et al. (2008) identified a 466T-C transition in the IL2RG
gene, resulting in a leu151-to-pro (L151P) substitution. The mutation
was inherited from his unaffected mother. Genetic analysis of peripheral
blood cells in the patient showed a dual signal, with the wildtype IL2RG
gene in T cells and a mutant IL2RG gene in B cells, NK cells, and
granulocytes. The findings were consistent with reversion of the L151P
mutation within a common T-cell precursor in the patient. The patient
had normal T-cell function, despite low levels of T cells, and impaired
B cell antibody response. Functional analysis with mutant IL2RG showed a
poor response to IL2 in B cells. The absence of mutated T cells in the
patient suggested that mutant IL2RG did not allow proper T-cell
development. In addition, X-inactivation studies in the mother showed
that her T cells exclusively expressed the wildtype allele. A similar
patient with reversion of mutation in a T-cell progenitor was reported
by Stephan et al. (1996) (see 308380.0010). However, Speckmann et al.
(2008) noted that the patient reported by Stephan et al. (1996)
ultimately showed a deteriorating course and required bone marrow stem
cell transplantation at almost 7 years of age. The findings indicated
that close immunologic surveillance is still needed in patients with
mutation reversion.

*FIELD* SA
Cavazzano-Calvo et al. (2000); Dave et al. (2004); Hacein-Bey-Abina
et al. (2002)
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*FIELD* CN
Paul J. Converse - updated: 1/23/2014
Cassandra L. Kniffin - updated: 3/9/2009
Paul J. Converse - updated: 5/5/2008
Paul J. Converse - updated: 3/21/2008
Paul J. Converse - updated: 1/10/2006
Cassandra L. Kniffin - reorganized: 10/28/2004
Ada Hamosh - updated: 2/2/2004
Victor A. McKusick - updated: 5/14/2002
Jane Kelly - updated: 1/25/2002
Paul J. Converse - updated: 10/22/2001
Paul J. Converse - updated: 4/27/2001
Stylianos E. Antonarakis - updated: 4/17/2001
Ada Hamosh - updated: 5/4/2000
Victor A. McKusick - updated: 2/2/2000
Victor A. McKusick - updated: 1/21/1999
Victor A. McKusick - updated: 2/3/1998
Victor A. McKusick - updated: 5/16/1997

*FIELD* CD
Victor A. McKusick: 4/13/1993

*FIELD* ED
mgross: 02/11/2014
mcolton: 1/23/2014
mgross: 12/16/2011
wwang: 3/18/2009
ckniffin: 3/9/2009
mgross: 5/5/2008
mgross: 3/21/2008
mgross: 4/4/2006
terry: 3/16/2006
mgross: 1/10/2006
carol: 10/28/2004
terry: 10/28/2004
ckniffin: 10/27/2004
ckniffin: 10/20/2004
alopez: 2/2/2004
alopez: 11/10/2003
alopez: 6/10/2003
terry: 5/14/2002
carol: 2/15/2002
terry: 1/25/2002
mgross: 10/22/2001
mgross: 4/27/2001
mgross: 4/17/2001
alopez: 5/4/2000
mgross: 2/2/2000
terry: 1/21/1999
dkim: 7/2/1998
terry: 6/4/1998
alopez: 5/21/1998
psherman: 5/20/1998
mark: 2/5/1998
terry: 2/3/1998
carol: 6/23/1997
mark: 5/26/1997
terry: 5/16/1997
terry: 2/13/1997
jamie: 12/17/1996
jamie: 12/6/1996
terry: 11/26/1996
terry: 11/6/1996
mark: 1/31/1996
mark: 9/10/1995
carol: 5/16/1994
terry: 4/21/1994
warfield: 3/31/1994
mimadm: 2/27/1994
carol: 12/6/1993

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MIM 312863
*RECORD*
*FIELD* NO
312863
*FIELD* TI
#312863 COMBINED IMMUNODEFICIENCY, X-LINKED; CIDX
;;XCID;;
IMMUNODEFICIENCY 6; IMD6
read more*FIELD* TX
A number sign (#) is used with this entry because X-linked combined
immunodeficiency (CIDX) is caused by mutation in the gene encoding the
gamma subunit of the interleukin-2 receptor (IL2RG; 308380).

X-linked severe combined immunodeficiency (SCIDX1; 300400) is caused by
mutation in the same gene.

CLINICAL FEATURES

Brooks et al. (1990) described a family in which 5 living males had a
form of combined immunodeficiency inherited in an X-linked recessive
pattern. The disorder was different from the previously described forms
of X-linked immunodeficiency and specifically different from SCIDX1. The
age of the 5 affected males ranged from 2.5 to 34 years. The most
prominent clinical abnormalities were paucity of lymphoid tissue;
recurrent sinusitis, otitis media, bronchitis, and pneumonia; severe
varicella; and chronic papillomavirus infections. Immunologic analysis
showed normal concentrations of serum immunoglobulins, but restricted
formation of IgG antibodies to immunogens; normal numbers of B cells and
NK cells but decreased numbers of CD4+ and CD8+ T lymphocytes;
diminished proliferative responses of blood T cells to allogeneic cells,
mitogens, and antigens; and decreased production of interleukin-2 (IL2;
146680) by mitogen-stimulated blood lymphocytes. The pedigree showed
that 2 affected males, both deceased, had produced children; all 3 of
the children, 1 male and 2 females, were unaffected, but 1 female had an
affected son, thus proving herself to be a carrier.

Schmalstieg et al. (1995) showed that X-chromosome inactivation in
obligate carriers of CIDX is nonrandom in T and B lymphocytes, as in
SCIDX1. X-chromosome inactivation in polymorphic nuclear leukocytes was
variable.

Sharfe et al. (1997) reported a child who was normal until the age of 9
months when he developed progressive respiratory symptoms caused by
Pneumocystis carinii, which was treated successfully with
trimethoprim-sulfamethazole. Physical examination was normal, with
normal numbers of peripheral T and B cells, normal cervical lymph nodes,
and a normal thymus gland viewed by ultrasonography and biopsy. Although
immunoglobulin subtypes were normal, the patient had defective humoral
immunity. T cells showed an unusual lack of response to exogenous IL2
The patient received a matched unrelated bone marrow transplantation and
was doing well at the time of report. A maternal male cousin had
previously been diagnosed with an unusual combined immunodeficiency with
normal numbers of both B and T peripheral lymphocytes and normal levels
of immunoglobulins and specific antibodies. That patient died at the age
of 2 years after a mismatched bone marrow transplant following lectin
T-cell depletion.

MOLECULAR GENETICS

In 3 related males with CIDX, Schmalstieg et al. (1995) identified a
mutation in the IL2RG gene (308380.0008). A normal brother did not have
the mutation.

In a child with CIDX, Sharfe et al. (1997) identified a mutation in the
IL2RG gene (308380.0012). The authors noted that mutations in the IL2RG
gene can result in a spectrum of immunologic phenotypes.

*FIELD* RF
1. Brooks, E. G.; Schmalstieg, F. C.; Wirt, D. P.; Rosenblatt, H.
M.; Adkins, L. T.; Lookingbill, D. P.; Rudloff, H. E.; Rakusan, T.
A.; Goldman, A. S.: A novel X-linked combined immunodeficiency disease. J.
Clin. Invest. 86: 1623-1631, 1990.

2. Schmalstieg, F. C.; Leonard, W. J.; Noguchi, M.; Berg, M.; Rudloff,
H. E.; Denney, R. M.; Dave, S. K.; Brooks, E. G.; Goldman, A. S.:
Missense mutation in exon 7 of the common gamma chain gene causes
a moderate form of X-linked combined immunodeficiency. J. Clin. Invest. 95:
1169-1173, 1995.

3. Sharfe, N.; Shahar, M.; Roifman, C. M.: An interleukin-2 receptor
gamma chain mutation with normal thymus morphology. J. Clin. Invest. 100:
3036-3043, 1997.

*FIELD* CS
INHERITANCE:
X-linked recessive

HEAD AND NECK:
[Head];
Sinusitis;
[Ears];
Otitis media

RESPIRATORY:
[Airways];
Bronchitis;
[Lung];
Pneumonia

IMMUNOLOGY:
Paucity of lymphoid tissue;
Normal number of B cells;
Normal number of natural killer cells;
Decreased number of CD4+ T cells;
Decreased number of CD8+ T cells;
Diminished proliferative response of T cells to allogenic cells, mitogens,
and antigens;
Reduced production of interleukin 2 by mitogen stimulated blood lymphocytes

LABORATORY ABNORMALITIES:
Reduced IgG levels

MISCELLANEOUS:
Reduced life expectancy

MOLECULAR BASIS:
Caused by mutations in the interleukin-2 receptor, gamma chain, gene
(IL2RG, 308380.0008)

*FIELD* CN
Ada Hamosh - reviewed: 1/4/2001
Assil Saleh - revised: 8/25/2000

*FIELD* CD
John F. Jackson: 6/15/1995

*FIELD* ED
joanna: 01/05/2001
joanna: 1/4/2001
kayiaros: 8/25/2000

*FIELD* CN
Cassandra L. Kniffin - reorganized: 10/28/2004

*FIELD* CD
Victor A. McKusick: 11/16/1990

*FIELD* ED
carol: 10/28/2004
terry: 10/28/2004
ckniffin: 10/20/2004
carol: 2/17/2000
alopez: 12/2/1998
dkim: 7/21/1998
mark: 4/4/1995
mimadm: 2/28/1994
supermim: 3/17/1992
carol: 6/5/1991
carol: 11/30/1990
carol: 11/16/1990

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