RBCC

Full text data of IL7R

IL7R [Confidence: high (a blood group or CD marker)]
Interleukin-7 receptor subunit alpha; IL-7 receptor subunit alpha; IL-7R subunit alpha; IL-7R-alpha; IL-7RA (CDw127; CD127; Flags: Precursor)

UniProt P16871
ID IL7RA_HUMAN Reviewed; 459 AA.
AC P16871; B2RCS6; B4DVT1; Q05CU8; Q6NSP4; Q6NWM0; Q6NWM1; Q6NWM2;
read moreAC Q6NWM3; Q6SV45; Q9UPC1;
DT 01-AUG-1990, integrated into UniProtKB/Swiss-Prot.
DT 25-NOV-2008, sequence version 2.
DT 22-JAN-2014, entry version 148.
DE RecName: Full=Interleukin-7 receptor subunit alpha;
DE Short=IL-7 receptor subunit alpha;
DE Short=IL-7R subunit alpha;
DE Short=IL-7R-alpha;
DE Short=IL-7RA;
DE AltName: Full=CDw127;
DE AltName: CD_antigen=CD127;
DE Flags: Precursor;
GN Name=IL7R;
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), ALTERNATIVE SPLICING, AND
RP VARIANT VAL-356.
RC TISSUE=B-cell;
RX PubMed=2317865; DOI=10.1016/0092-8674(90)90342-C;
RA Goodwin R.G., Friend D., Ziegler S.F., Jerzy R., Falk B.A., Gimpel S.,
RA Cosman D., Dower S.K., March C.J., Namen A.E., Park L.S.;
RT "Cloning of the human and murine interleukin-7 receptors:
RT demonstration of a soluble form and homology to a new receptor
RT superfamily.";
RL Cell 60:941-951(1990).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), AND VARIANT VAL-356.
RX PubMed=2038316;
RA Pleiman C.M., Gimpel S.D., Park L.S., Harada H., Taniguchi T.,
RA Ziegler S.F.;
RT "Organization of the murine and human interleukin-7 receptor genes:
RT two mRNAs generated by differential splicing and presence of a type I-
RT interferon-inducible promoter.";
RL Mol. Cell. Biol. 11:3052-3059(1991).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM 1), VARIANTS
RP T(-)/B(+)/NK(+) SCID ILE-66 AND VAL-138, AND VARIANT ILE-244.
RX PubMed=9843216; DOI=10.1038/3877;
RA Puel A., Ziegler S.F., Buckley R.H., Leonard W.J.;
RT "Defective IL7R expression in T(-)B(+)NK(+) severe combined
RT immunodeficiency.";
RL Nat. Genet. 20:394-397(1998).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 4), AND VARIANT
RP VAL-356.
RC TISSUE=Spleen;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM 1), VARIANTS
RP T(-)/B(+)/NK(+) SCID ILE-66 AND VAL-138, AND VARIANTS ASP-113 AND
RP ILE-244.
RG SeattleSNPs variation discovery resource;
RL Submitted (OCT-2003) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], AND VARIANTS
RP T(-)/B(+)/NK(+) SCID ILE-66 AND VAL-138.
RX PubMed=15372022; DOI=10.1038/nature02919;
RA Schmutz J., Martin J., Terry A., Couronne O., Grimwood J., Lowry S.,
RA Gordon L.A., Scott D., Xie G., Huang W., Hellsten U., Tran-Gyamfi M.,
RA She X., Prabhakar S., Aerts A., Altherr M., Bajorek E., Black S.,
RA Branscomb E., Caoile C., Challacombe J.F., Chan Y.M., Denys M.,
RA Detter J.C., Escobar J., Flowers D., Fotopulos D., Glavina T.,
RA Gomez M., Gonzales E., Goodstein D., Grigoriev I., Groza M.,
RA Hammon N., Hawkins T., Haydu L., Israni S., Jett J., Kadner K.,
RA Kimball H., Kobayashi A., Lopez F., Lou Y., Martinez D., Medina C.,
RA Morgan J., Nandkeshwar R., Noonan J.P., Pitluck S., Pollard M.,
RA Predki P., Priest J., Ramirez L., Retterer J., Rodriguez A.,
RA Rogers S., Salamov A., Salazar A., Thayer N., Tice H., Tsai M.,
RA Ustaszewska A., Vo N., Wheeler J., Wu K., Yang J., Dickson M.,
RA Cheng J.-F., Eichler E.E., Olsen A., Pennacchio L.A., Rokhsar D.S.,
RA Richardson P., Lucas S.M., Myers R.M., Rubin E.M.;
RT "The DNA sequence and comparative analysis of human chromosome 5.";
RL Nature 431:268-274(2004).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), VARIANTS
RP T(-)/B(+)/NK(+) SCID ILE-66 AND VAL-138, AND VARIANT VAL-356.
RC TISSUE=Testis;
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 X-RAY CRYSTALLOGRAPHY (2.7 ANGSTROMS) OF 21-239 IN COMPLEX WITH IL7,
RP SUBUNIT, GLYCOSYLATION AT ASN-49; ASN-65 AND ASN-151, AND DISULFIDE
RP BONDS.
RX PubMed=19141282; DOI=10.1016/j.str.2008.10.019;
RA McElroy C.A., Dohm J.A., Walsh S.T.;
RT "Structural and biophysical studies of the human IL-7/IL-7Ralpha
RT complex.";
RL Structure 17:54-65(2009).
RN [9]
RP VARIANT T(-)/B(+)/NK(+) SCID SER-132.
RX PubMed=11023514;
RA Roifman C.M., Zhang J., Chitayat D., Sharfe N.;
RT "A partial deficiency of interleukin-7R alpha is sufficient to
RT abrogate T-cell development and cause severe combined
RT immunodeficiency.";
RL Blood 96:2803-2807(2000).
RN [10]
RP VARIANT ILE-244, AND ASSOCIATION WITH MS3.
RX PubMed=17660817; DOI=10.1038/ng2103;
RA Gregory S.G., Schmidt S., Seth P., Oksenberg J.R., Hart J., Prokop A.,
RA Caillier S.J., Ban M., Goris A., Barcellos L.F., Lincoln R.,
RA McCauley J.L., Sawcer S.J., Compston D.A., Dubois B., Hauser S.L.,
RA Garcia-Blanco M.A., Pericak-Vance M.A., Haines J.L.;
RT "Interleukin 7 receptor alpha chain (IL7R) shows allelic and
RT functional association with multiple sclerosis.";
RL Nat. Genet. 39:1083-1091(2007).
CC -!- FUNCTION: Receptor for interleukin-7. Also acts as a receptor for
CC thymic stromal lymphopoietin (TSLP).
CC -!- SUBUNIT: The IL7 receptor is a heterodimer of IL7R and IL2RG. The
CC TSLP receptor is a heterodimer of CRLF2 and IL7R.
CC -!- INTERACTION:
CC P13232:IL7; NbExp=3; IntAct=EBI-80490, EBI-80516;
CC -!- SUBCELLULAR LOCATION: Isoform 1: Cell membrane; Single-pass type I
CC membrane protein.
CC -!- SUBCELLULAR LOCATION: Isoform 3: Cell membrane; Single-pass type I
CC membrane protein.
CC -!- SUBCELLULAR LOCATION: Isoform 4: Secreted.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=4;
CC Name=1; Synonyms=H20;
CC IsoId=P16871-1; Sequence=Displayed;
CC Name=3; Synonyms=H1;
CC IsoId=P16871-2; Sequence=VSP_001714;
CC Name=4; Synonyms=H6, Secreted;
CC IsoId=P16871-3; Sequence=VSP_001713;
CC Name=2; Synonyms=Secreted;
CC IsoId=P16871-4; Sequence=VSP_012618, VSP_012619;
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 -!- PTM: N-glycosylated IL-7Ralpha binds IL7 300-fold more tightly
CC than the unglycosylated form.
CC -!- DISEASE: Severe combined immunodeficiency autosomal recessive T-
CC cell-negative/B-cell-positive/NK-cell-positive (T(-)B(+)NK(+)
CC SCID) [MIM:608971]: A form of severe combined immunodeficiency
CC (SCID), a genetically and clinically heterogeneous group of rare
CC congenital disorders characterized by impairment of both humoral
CC and cell-mediated immunity, leukopenia, and low or absent antibody
CC levels. Patients present in infancy recurrent, persistent
CC infections by opportunistic organisms. The common characteristic
CC of all types of SCID is absence of T-cell-mediated cellular
CC immunity due to a defect in T-cell development. Note=The disease
CC is caused by mutations affecting the gene represented in this
CC entry.
CC -!- DISEASE: Multiple sclerosis 3 (MS3) [MIM:612595]: A
CC multifactorial, inflammatory, demyelinating disease of the central
CC nervous system. Sclerotic lesions are characterized by
CC perivascular infiltration of monocytes and lymphocytes and appear
CC as indurated areas in pathologic specimens (sclerosis in plaques).
CC The pathological mechanism is regarded as an autoimmune attack of
CC the myelin sheath, mediated by both cellular and humoral immunity.
CC Clinical manifestations include visual loss, extra-ocular movement
CC disorders, paresthesias, loss of sensation, weakness, dysarthria,
CC spasticity, ataxia and bladder dysfunction. Genetic and
CC environmental factors influence susceptibility to the disease.
CC Note=Disease susceptibility is associated with variations
CC affecting the gene represented in this entry. A polymorphism at
CC position 244 strongly influences susceptibility to multiple
CC sclerosis. Overtransmission of the major 'C' allele coding for
CC Thr-244 is detected in offspring affected with multiple sclerosis.
CC In vitro analysis of transcripts from minigenes containing either
CC 'C' allele (Thr-244) or 'T' allele (Ile-244) shows that the 'C'
CC allele results in an approximately two-fold increase in the
CC skipping of exon 6, leading to increased production of a soluble
CC form of IL7R. Thus, the multiple sclerosis associated 'C' risk
CC allele of IL7R would probably decrease membrane-bound expression
CC of IL7R. As this risk allele is common in the general population,
CC some additional triggers are probably required for the development
CC and progression of MS.
CC -!- SIMILARITY: Belongs to the type I cytokine receptor family. Type 4
CC subfamily.
CC -!- SIMILARITY: Contains 1 fibronectin type-III domain.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAH20717.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Potential poly-A sequence;
CC -!- WEB RESOURCE: Name=IL7Rbase; Note=IL7R mutation db;
CC URL="http://bioinf.uta.fi/IL7Rbase/";
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/IL7R";
CC -!- WEB RESOURCE: Name=SeattleSNPs;
CC URL="http://pga.gs.washington.edu/data/il7r/";
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DR EMBL; M29696; AAA59157.1; -; mRNA.
DR EMBL; AF043129; AAC83204.1; -; Genomic_DNA.
DR EMBL; AF043123; AAC83204.1; JOINED; Genomic_DNA.
DR EMBL; AF043124; AAC83204.1; JOINED; Genomic_DNA.
DR EMBL; AF043125; AAC83204.1; JOINED; Genomic_DNA.
DR EMBL; AF043126; AAC83204.1; JOINED; Genomic_DNA.
DR EMBL; AF043127; AAC83204.1; JOINED; Genomic_DNA.
DR EMBL; AF043128; AAC83204.1; JOINED; Genomic_DNA.
DR EMBL; AK301220; BAG62793.1; -; mRNA.
DR EMBL; AK315251; BAG37673.1; -; mRNA.
DR EMBL; AY449709; AAR08908.1; -; Genomic_DNA.
DR EMBL; BC020717; AAH20717.1; ALT_SEQ; mRNA.
DR EMBL; BC067537; AAH67537.1; -; mRNA.
DR EMBL; BC067538; AAH67538.1; -; mRNA.
DR EMBL; BC067539; AAH67539.1; -; mRNA.
DR EMBL; BC067540; AAH67540.1; -; mRNA.
DR EMBL; BC069999; AAH69999.1; -; mRNA.
DR PIR; A34791; A34791.
DR PIR; B34791; B34791.
DR PIR; C34791; C34791.
DR RefSeq; NP_002176.2; NM_002185.3.
DR UniGene; Hs.591742; -.
DR PDB; 3DI2; X-ray; 2.70 A; B/D=21-239.
DR PDB; 3DI3; X-ray; 2.90 A; B=21-239.
DR PDB; 3UP1; X-ray; 2.15 A; A/B=21-239.
DR PDBsum; 3DI2; -.
DR PDBsum; 3DI3; -.
DR PDBsum; 3UP1; -.
DR ProteinModelPortal; P16871; -.
DR SMR; P16871; 32-232.
DR DIP; DIP-3045N; -.
DR IntAct; P16871; 2.
DR PhosphoSite; P16871; -.
DR DMDM; 215274000; -.
DR PaxDb; P16871; -.
DR PRIDE; P16871; -.
DR DNASU; 3575; -.
DR Ensembl; ENST00000303115; ENSP00000306157; ENSG00000168685.
DR GeneID; 3575; -.
DR KEGG; hsa:3575; -.
DR UCSC; uc003jjs.4; human.
DR CTD; 3575; -.
DR GeneCards; GC05P035892; -.
DR H-InvDB; HIX0024815; -.
DR HGNC; HGNC:6024; IL7R.
DR HPA; CAB010215; -.
DR MIM; 146661; gene.
DR MIM; 608971; phenotype.
DR MIM; 612595; phenotype.
DR neXtProt; NX_P16871; -.
DR Orphanet; 39041; Omenn syndrome.
DR Orphanet; 169154; T-B+ severe combined immunodeficiency due to IL-7Ralpha deficiency.
DR PharmGKB; PA29840; -.
DR eggNOG; NOG39823; -.
DR HOVERGEN; HBG055773; -.
DR InParanoid; P16871; -.
DR KO; K05072; -.
DR Reactome; REACT_6900; Immune System.
DR SignaLink; P16871; -.
DR EvolutionaryTrace; P16871; -.
DR GeneWiki; Interleukin-7_receptor-%CE%B1; -.
DR GenomeRNAi; 3575; -.
DR NextBio; 13972; -.
DR PRO; PR:P16871; -.
DR ArrayExpress; P16871; -.
DR Bgee; P16871; -.
DR CleanEx; HS_IL7R; -.
DR Genevestigator; P16871; -.
DR GO; GO:0009897; C:external side of plasma membrane; IEA:Ensembl.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR GO; GO:0016021; C:integral to membrane; IEA:UniProtKB-KW.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0003823; F:antigen binding; TAS:ProtInc.
DR GO; GO:0004917; F:interleukin-7 receptor activity; TAS:ProtInc.
DR GO; GO:0042100; P:B cell proliferation; IEA:Ensembl.
DR GO; GO:0016049; P:cell growth; IEA:Ensembl.
DR GO; GO:0000902; P:cell morphogenesis; IEA:Ensembl.
DR GO; GO:0048872; P:homeostasis of number of cells; IEA:Ensembl.
DR GO; GO:0006955; P:immune response; TAS:ProtInc.
DR GO; GO:0002377; P:immunoglobulin production; IEA:Ensembl.
DR GO; GO:0048535; P:lymph node development; IEA:Ensembl.
DR GO; GO:0001915; P:negative regulation of T cell mediated cytotoxicity; IEA:Ensembl.
DR GO; GO:0010628; P:positive regulation of gene expression; IEA:Ensembl.
DR GO; GO:0033089; P:positive regulation of T cell differentiation in thymus; IEA:Ensembl.
DR GO; GO:0008361; P:regulation of cell size; IEA:Ensembl.
DR GO; GO:0000018; P:regulation of DNA recombination; TAS:ProtInc.
DR GO; GO:0030217; P:T cell differentiation; IEA:Ensembl.
DR Gene3D; 2.60.40.10; -; 1.
DR InterPro; IPR003961; Fibronectin_type3.
DR InterPro; IPR003531; Hempt_rcpt_S_F1_CS.
DR InterPro; IPR013783; Ig-like_fold.
DR Pfam; PF00041; fn3; 1.
DR SUPFAM; SSF49265; SSF49265; 1.
DR PROSITE; PS50853; FN3; 1.
DR PROSITE; PS01355; HEMATOPO_REC_S_F1; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Cell membrane; Complete proteome;
KW Disease mutation; Disulfide bond; Glycoprotein; Membrane;
KW Phosphoprotein; Polymorphism; Receptor; Reference proteome; SCID;
KW Secreted; Signal; Transmembrane; Transmembrane helix.
FT SIGNAL 1 20
FT CHAIN 21 459 Interleukin-7 receptor subunit alpha.
FT /FTId=PRO_0000010909.
FT TOPO_DOM 21 239 Extracellular (Potential).
FT TRANSMEM 240 264 Helical; (Potential).
FT TOPO_DOM 265 459 Cytoplasmic (Potential).
FT DOMAIN 131 231 Fibronectin type-III.
FT MOTIF 217 221 WSXWS motif.
FT MOTIF 272 280 Box 1 motif.
FT COMPBIAS 184 189 Ser/Thr-rich.
FT MOD_RES 282 282 Phosphothreonine; by PKC (Potential).
FT CARBOHYD 49 49 N-linked (GlcNAc...).
FT CARBOHYD 65 65 N-linked (GlcNAc...).
FT CARBOHYD 151 151 N-linked (GlcNAc...).
FT CARBOHYD 182 182 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 232 232 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 233 233 N-linked (GlcNAc...) (Potential).
FT DISULFID 42 57
FT DISULFID 74 82
FT DISULFID 108 118
FT VAR_SEQ 237 459 EMDPILLTISILSFFSVALLVILACVLWKKRIKPIVWPSLP
FT DHKKTLEHLCKKPRKNLNVSFNPESFLDCQIHRVDDIQARD
FT EVEGFLQDTFPQQLEESEKQRLGGDVQSPNCPSEDVVITPE
FT SFGRDSSLTCLAGNVSACDAPILSSSRSLDCRESGKNGPHV
FT YQDLLLSLGTTNSTLPPPFSLQSGILTLNPVAQGQPILTSL
FT GSNQEEAYVTMSSFYQNQ -> LSLSYGPVSPIIRRLWNIF
FT VRNQEK (in isoform 4).
FT /FTId=VSP_001713.
FT VAR_SEQ 237 252 EMDPILLTISILSFFS -> LSLSYGPVSPIIRQEL (in
FT isoform 2).
FT /FTId=VSP_012618.
FT VAR_SEQ 253 459 Missing (in isoform 2).
FT /FTId=VSP_012619.
FT VAR_SEQ 293 459 NLNVSFNPESFLDCQIHRVDDIQARDEVEGFLQDTFPQQLE
FT ESEKQRLGGDVQSPNCPSEDVVITPESFGRDSSLTCLAGNV
FT SACDAPILSSSRSLDCRESGKNGPHVYQDLLLSLGTTNSTL
FT PPPFSLQSGILTLNPVAQGQPILTSLGSNQEEAYVTMSSFY
FT QNQ -> VSVFGA (in isoform 3).
FT /FTId=VSP_001714.
FT VARIANT 66 66 T -> I (in T(-)/B(+)/NK(+) SCID;
FT dbSNP:rs1494558).
FT /FTId=VAR_021286.
FT VARIANT 113 113 E -> D (in dbSNP:rs11567735).
FT /FTId=VAR_021287.
FT VARIANT 132 132 P -> S (in T(-)/B(+)/NK(+) SCID).
FT /FTId=VAR_034870.
FT VARIANT 138 138 I -> V (in T(-)/B(+)/NK(+) SCID;
FT dbSNP:rs1494555).
FT /FTId=VAR_021288.
FT VARIANT 244 244 T -> I (in dbSNP:rs6897932).
FT /FTId=VAR_021289.
FT VARIANT 356 356 I -> V (in dbSNP:rs3194051).
FT /FTId=VAR_021290.
FT VARIANT 414 414 T -> M (in dbSNP:rs2229232).
FT /FTId=VAR_047742.
FT CONFLICT 39 39 S -> T (in Ref. 7; AAH67539).
FT CONFLICT 52 52 Q -> R (in Ref. 7; AAH67538).
FT CONFLICT 384 384 S -> P (in Ref. 7; AAH67537).
FT CONFLICT 386 386 R -> G (in Ref. 7; AAH67539).
FT HELIX 35 38
FT STRAND 40 49
FT STRAND 52 61
FT STRAND 69 79
FT STRAND 81 84
FT STRAND 86 88
FT STRAND 91 97
FT STRAND 102 111
FT STRAND 114 122
FT HELIX 123 125
FT STRAND 133 140
FT TURN 141 144
FT STRAND 145 151
FT HELIX 153 156
FT STRAND 158 160
FT STRAND 163 173
FT STRAND 179 191
FT HELIX 192 194
FT STRAND 200 209
FT STRAND 211 213
FT STRAND 224 227
SQ SEQUENCE 459 AA; 51581 MW; EE556426C22A182B CRC64;
MTILGTTFGM VFSLLQVVSG ESGYAQNGDL EDAELDDYSF SCYSQLEVNG SQHSLTCAFE
DPDVNTTNLE FEICGALVEV KCLNFRKLQE IYFIETKKFL LIGKSNICVK VGEKSLTCKK
IDLTTIVKPE APFDLSVIYR EGANDFVVTF NTSHLQKKYV KVLMHDVAYR QEKDENKWTH
VNLSSTKLTL LQRKLQPAAM YEIKVRSIPD HYFKGFWSEW SPSYYFRTPE INNSSGEMDP
ILLTISILSF FSVALLVILA CVLWKKRIKP IVWPSLPDHK KTLEHLCKKP RKNLNVSFNP
ESFLDCQIHR VDDIQARDEV EGFLQDTFPQ QLEESEKQRL GGDVQSPNCP SEDVVITPES
FGRDSSLTCL AGNVSACDAP ILSSSRSLDC RESGKNGPHV YQDLLLSLGT TNSTLPPPFS
LQSGILTLNP VAQGQPILTS LGSNQEEAYV TMSSFYQNQ
//

MIM 146661
*RECORD*
*FIELD* NO
146661
*FIELD* TI
*146661 INTERLEUKIN 7 RECEPTOR; IL7R
;;INTERLEUKIN 7 RECEPTOR-ALPHA;;
IL7R-ALPHA; IL7RA;;
read moreCD127
*FIELD* TX

DESCRIPTION

The IL7R gene encodes a receptor for interleukin-7 (IL7; 146660), a
25-kD glycoprotein involved in the regulation of lymphopoiesis. This
ligand-receptor complex is essential for the normal development of T
cells (summary by Goodwin et al., 1990 and Zenatti et al., 2011).

CLONING

Goodwin et al. (1990) isolated cDNA clones encoding the human and murine
interleukin-7 receptor and expressed them in COS-7 cells. In addition,
several cDNA clones were isolated that encoded a secreted form of the
receptor capable of binding IL7 in solution. Another member of the same
family, the receptor for IL4 (147781) also exists in both membrane-bound
and soluble forms.

MAPPING

Lynch et al. (1992) mapped the IL7R gene to chromosome 5p13 by a
combination of in situ hybridization and Southern blot analysis of
rodent/human hybrid cell lines.

GENE FUNCTION

Noguchi et al. (1993) and Kondo et al. (1994) demonstrated that the
interleukin-2 receptor gamma chain (IL2RG; 308380) is a necessary
component of functional interleukin-7 receptor. They pointed out that
the participation of the gamma subunit in more than 1 receptor helped
explain the mechanism of X-linked severe combined immunodeficiency
(300400).

Pursuing the possibility that a common gamma chain is critically
important to IL7 function, Lai et al. (1997) performed
structure/function analyses of the IL7R complex using a chimeric
receptor system and demonstrated that the gamma chain is indeed
critical. Nonetheless, only a limited portion of the cytoplasmic domain
of the gamma chain is necessary for IL7R signal transduction.
Furthermore, replacement of the gamma chain cytoplasmic domain by a
severely truncated erythropoietin receptor (133171) does not affect
measured IL7R signaling events. These findings supported a model in
which the gamma(c) chain serves primarily to activate signal
transduction by the IL7R complex, while the alpha chain of IL7R
determines specific signaling events through its association with
cytoplasmic signaling molecules. Finally, these studies were consistent
with the hypothesis that the molecular pathogenesis of X-linked SCID is
due primarily to gamma(c)-mediated defects in the IL7/IL7R system.

Reche et al. (2001) showed that expression of thymic stromal
lymphopoietin receptor (TSLPR, or CRLF2; 300357) and IL7R, together but
not alone, induced a proliferative response to TSLP (607003), but not to
IL7, indicating that the functional TSLP receptor consists of these 2
subunits. PCR analysis of cDNA libraries suggested that DCs and
monocytes coexpress IL7R and TSLPR. Incubation of DCs or monocytes with
TSLP enhanced the expression of CCL17 (601520), CCL18 (603757), CCL22
(602957), and CCL19 (602227). IL7, on the other hand, induced expression
of CCL17, CCL22, and CCL19, but also CXCL8 (146930), CXCL7 (121010),
CXCL5 (600324), CXCL1 (155730), CXCL2 (139110), and CXCL3 (139111).
Functional analysis indicated that TSLP enhances the DC maturation
process, as evidenced by upregulation of DC markers and costimulatory
molecules and stronger T-cell proliferation.

Kaech et al. (2003) showed that about 5 to 15% of murine effector cells
at the peak of the CD8 T-cell response had high expression of Il7ra.
Using adoptive transfer analysis, they showed that, in the presence of
Il7, this subset of cells survived and became memory cells with
protective recall responses. Flow cytometric analysis demonstrated that
CD8 cells expressing high levels of Il7r also expressed slightly higher
levels of the antiapoptotic markers Bcl2 (151430) and Bclxl (600039),
whereas nearly all cells expressing the cleaved form of the
apoptosis-related cysteine protease Casp3 (600636) had low levels of
Il7r. Kaech et al. (2003) proposed that the IL7R marker would be useful
in predicting the number of memory T cells generated by infection or
immunization and in facilitating the discovery of signals and mechanisms
that regulate memory cell formation.

Using RT-PCR, Western blot, ELISA, and mass spectrometric analyses, Rose
et al. (2009) showed that soluble forms of both components of IL7R,
gamma-c and IL7R-alpha, were present in plasma of healthy individuals.
These 2 components formed heterocomplexes and bound IL7 with similar
affinity to that of membrane-bound IL7R. Chronically HIV-1-infected
individuals showed no significant variation in plasma gamma-c levels,
but plasma IL7R-alpha levels were significantly decreased compared with
healthy individuals.

SNPs in the IL7R gene are associated with susceptibility to multiple
sclerosis (MS; see MOLECULAR GENETICS and 612595). Liu et al. (2010)
showed that Il7 directly expanded pathogenic Th17 (see IL17; 603149)
cells in experimental autoimmune encephalomyelitis (EAE), a mouse model
of MS, but was not required for Th17 differentiation. IL7 also directly
expanded human Th17 cells from patients with MS. Antagonism of Il7r
rendered differentiated Th17 cells, but not Th1 or regulatory T (Treg)
cells, susceptible to apoptosis through inhibition of the Jak (see
147795)-Stat5 (601511) pathway and altered expression of Bcl2 and Bax
(600040), leading to decreased EAE severity. The selectivity for Th17
cells was attributable to low expression of Il7r in Treg cells and
correlated with high Socs (603597) expression in Th1 cells. Liu et al.
(2010) concluded that IL7R antagonism is efficacious in treatment of EAE
through its effects on Th17 cells and is a potential treatment for MS.

MOLECULAR GENETICS

- T-, B+, NK+ Severe Combined Immunodeficiency

In 2 patients with T-, B+, NK+ SCID (608971), Puel et al. (1998)
identified mutations in the IL7R gene (146661.0001-146661.0004). Since
defective IL7R expression caused T-, B+, NK+ SCID, the authors concluded
that the T-cell, but not the NK-cell, defect in X-linked T-, B+, NK-
SCID (300400), caused by mutation in the common interleukin receptor
gamma (308380), results from inactivation of IL7R signaling.

In 3 patients with SCID from a consanguineous Sicilian family, Roifman
et al. (2000) identified a homozygous mutation (146661.0005) in the IL7R
gene.

- Susceptibility to Multiple Sclerosis

For discussion of an association between variation in the IL7R gene and
multiple sclerosis, see MS3 (612595).

- Somatic Mutations in Childhood Acute Lymphoblastic Leukemias

By screening 133 bone marrow samples from patients with B-cell precursor
acute lymphoblastic leukemia (BCP-ALL) with or without Down syndrome
(190685) and with aberrant or no expression of CRLF2 (300357), Shochat
et al. (2011) identified 9 leukemias with heterozygous somatic mutations
in the IL7R gene. Eight of the mutations were in patients with aberrant
CRLF2. Four patients had a ser185-to-cys (S185C) substitution, while the
remainder had in-frame insertions and deletions that resulted in the
addition of 3 to 7 amino acids in the transmembrane domain. Although the
inserted amino acids varied among patients, cysteine was always
included. The mutant IL7R proteins in the BCP-ALL patients formed
functional receptors with CRLF2 for TSLP (607003). Biochemical and
functional analyses revealed that the IL7R mutations were activating
mutations that conferred cytokine-independent growth of progenitor
lymphoid cells. Screening 295 bone marrow samples from patients with
childhood T-ALL revealed 30 somatic mutations in the IL7R gene. All of
these mutations were at the transmembrane domain encoded by exon 6, and
all but 1 were in-frame insertions and deletions. Of the 30 mutations in
T-ALL, 27 involved insertion of a cysteine. Shochat et al. (2011)
concluded that addition of cysteine to the juxtamembranous domains is a
general mechanism for mutational activation of type I cytokine receptors
in leukemia.

Zenatti et al. (2011) identified heterozygous somatic mutations in the
IL7R gene on chromosome 5p13 in 17 (9%) of 201 T-cell acute
lymphoblastic leukemia samples from 3 independent cohorts. All mutations
affected exon 6, in the juxtamembrane-transmembrane domain at the
interface with the extracellular region, and were shown in several cell
lines to result in ligand-independent constitutive activation of
IL7R-mediated downstream signaling pathways, most prominently PI3K-Akt
(see 164730), JAK1 (147795), and STAT5 (601511). JAK3 (600173) signaling
was not involved. Most IL7R mutations (14/17; 82%) created an unpaired
cysteine residue in the interface, leading to homotypic dimerization
and/or oligomerization and thus bypassing the requirement for
ligand-dependent activation. These mutations were enriched in the T-ALL
subgroup comprising TLX3 (604640)-rearranged and HOXA
(614060)-deregulated cases. In vitro and in vivo mouse studies
demonstrated the oncogenic potential of the IL7R mutants. T-ALL cells
carrying the IL7R mutations were sensitive to inhibition of the JAK-STAT
pathway, suggesting therapeutic implications.

ANIMAL MODEL

Peschon et al. (1994) found an approximately 10-fold reduction in
precursor B cells with complete IgH rearrangements and in surface IgM+ B
lymphocytes in IL7R-alpha -/- mice when compared to age-matched
heterozygous controls. In such mice, Corcoran et al. (1998) showed that
D(H)-J(H) recombination proceeded normally but that V(H)-D(H)-J(H)
joining was decreased; this decrease was greater with increasing
distance of the V(H) segment from D(H)/J(H). Germline transcripts from
distal, unrearranged V segments, a marker of chromatin changes that
precede recombination, were specifically silenced. Thus, ligands of the
IL7 receptor deliver an extrinsic signal that targets V segment
recombination in the heavy chain locus by altering the accessibility of
DNA substrates to the recombinase.

Maki et al. (1996) cited reports showing that gene inactivation of IL7,
IL7R, and IL2RG (308380) (which encodes the common gamma chain) in mice
resulted in severe impairment of B and T lymphopoiesis. In addition,
IL2R-gamma-deficient mice lacked gamma/delta T cells in the skin and had
impaired development of natural killer (NK) cells and intraepithelial
lymphocytes. To explore the role of the IL7/IL7R system in gamma/delta
T- and NK-cell development, Maki et al. (1996) generated and analyzed
IL7R-deficient mice. Gamma/delta T cells were absent from skin, gut,
liver, and spleen in the deficient mice. In contrast, alpha/beta T and B
cells were detected in reduced numbers and NK cells developed normally.
The gamma/delta T-cell development in fetal and adult thymus was also
completely blocked. The investigators stated that their results clearly
demonstrate the signal from IL7R is indispensable for gamma/delta T-cell
development in both thymic and extrathymic pathways. On the contrary,
NK-cell development appears to require cytokine(s) other than IL7.

Since IL7 is required for normal T-cell development, Khaled et al.
(2002) evaluated the role of BAX (600040) in vivo by generating mice
deficient in both Bax and Il7r. Bax deficiency protected cells from
death due to the absence of Il7 signaling up to 4 weeks of age. By 12
weeks of age, Bax- and Il7r-deficient mice exhibited a loss of thymic
cellularity comparable to that observed in mice deficient in Il7r alone.
Khaled et al. (2002) determined that Bad (603167) and Bim (BCL2L11;
603827) were also part of the death pathway repressed by Il7. Khaled et
al. (2002) concluded that, in young mice, Bax is an essential protein in
the death pathway induced by Il7 deficiency.

Pellegrini et al. (2004) generated mice deficient in both Il7r and Bim.
Loss of Bim significantly increased thymocyte numbers, restored near
normal numbers of mature T lymphocytes in blood and spleen, and enhanced
cytotoxic function against virus infection compared with mice deficient
in Il7r only. Pellegrini et al. (2004) concluded that BIM cooperates
with other proapoptotic proteins in the death of IL7-deprived progenitor
T cells and is the major inducer of the apoptotic pathway in mature T
cells. They proposed that pharmacologic inhibition of BIM might be
useful in boosting immune responses in immunodeficient patients.

Using mice deficient in Il7r and/or the common cytokine receptor gamma
chain, Il2rg, Vobhenrich et al. (2003) determined the cytokines
responsible for fetal and perinatal lymphopoiesis in the absence of Il7.
Fetal and perinatal B-cell lymphopoiesis occurred in the bone marrow of
Il2rg -/- mice until 12 weeks of age, but it was absent in Il7r -/- mice
by 4 weeks of age. Lymphopoiesis in Il7r -/- mice was restricted to
fetal liver and was dependent on the presence of Tslp. The residual
lymphopoiesis that occurred in Il7r -/- mice was dependent on Flk2
(136351). Vobhenrich et al. (2003) concluded that TSLP is the main
factor driving IL7-independent fetal and perinatal lymphopoiesis,
although FLK2 is involved.

*FIELD* AV
.0001
SEVERE COMBINED IMMUNODEFICIENCY, AUTOSOMAL RECESSIVE, T CELL-NEGATIVE,
B CELL-POSITIVE, NK CELL-POSITIVE
IL7R, THR66ILE

In a patient with T-, B+, NK+ SCID (608971), Puel et al. (1998)
identified 2 homozygous mutations in the IL7R gene: a C-to-T
(thr66-to-ile) transition in exon 2 resulting in a thr66-to-ile (T66I)
substitution, and an A-to-G transition in exon 4 resulting in an
ile138-to-val (I138V; 146661.0002) substitution. The patient was
homozygous and both parents were heterozygous for both mutations. Each
parent expressed mRNA only from the wildtype allele.

.0002
SEVERE COMBINED IMMUNODEFICIENCY, AUTOSOMAL RECESSIVE, T CELL-NEGATIVE,
B CELL-POSITIVE, NK CELL-POSITIVE
IL7R, ILE138VAL

See 146661.0001 and Puel et al. (1998).

.0003
SEVERE COMBINED IMMUNODEFICIENCY, AUTOSOMAL RECESSIVE, T CELL-NEGATIVE,
B CELL-POSITIVE, NK CELL-POSITIVE
IL7R, IVS4, G-A, -1

In a patient with T-, B+, NK+ SCID (608971), Puel et al. (1998)
identified compound heterozygosity for an AG-to-AA splice junction
acceptor mutation in intron 4 of the IL7R gene, and a G-to-A transition,
resulting in a trp-to-ter mutation (W217X; 176661.0004). The splice site
mutation was maternal, but neither parent was found to carry the
nonsense mutation. Paternity was confirmed by HLA typing.

.0004
SEVERE COMBINED IMMUNODEFICIENCY, AUTOSOMAL RECESSIVE, T CELL-NEGATIVE,
B CELL-POSITIVE, NK CELL-POSITIVE
IL7R, TRP217TER

See 146661.0003 and Puel et al. (1998).

.0005
SEVERE COMBINED IMMUNODEFICIENCY, AUTOSOMAL RECESSIVE, T CELL-NEGATIVE,
B CELL-POSITIVE, NK CELL-POSITIVE
IL7R, PRO132SER

In 3 patients with T-, B+, NK+ SCID (608971) from a consanguineous
Sicilian family, Roifman et al. (2000) identified a homozygous 394C-T
transition in exon 4 of the IL7R gene, resulting in a pro132-to-ser
(P132S) substitution in the extracellular domain. Heterozygous relatives
had no clinical or immunologic aberrations. The mutation did not affect
mRNA or protein expression, but severely compromised affinity to IL7 and
signal transduction. Stimulation with IL7 resulted in markedly reduced
JAK3 (600173) phosphorylation in patient cells and in cells transfected
with the mutant IL7R.

*FIELD* RF
1. Corcoran, A. E.; Riddell, A.; Krooshoop, D.; Venkitaraman, A. R.
: Impaired immunoglobulin gene rearrangement in mice lacking the IL-7
receptor. Nature 391: 904-907, 1998.

2. Goodwin, R. G.; Friend, D.; Ziegler, S. F.; Jerzy, R.; Falk, B.
A.; Gimpel, S.; Cosman, D.; Dower, S. K.; March, C. J.; Namen, A.
E.; Park, L. S.: Cloning of the human and murine interleukin-7 receptors:
demonstration of a soluble form and homology to a new receptor superfamily. Cell 60:
941-951, 1990.

3. Kaech, S. M.; Tan, J. T.; Wherry, E. J.; Konieczny, B. T.; Surh,
C. D.; Ahmed, R.: Selective expression of the interleukin 7 receptor
identifies effector CD8 T cells that give rise to long-lived memory
cells. Nature Immun. 4: 1191-1198, 2003.

4. Khaled, A. R.; Li, W. Q.; Huang, J.; Fry, T. J.; Khaled, A. S.;
Mackall, C. L.; Muegge, K.; Young, H. A.; Durum, S. K.: Bax deficiency
partially corrects interleukin-7 receptor-alpha deficiency. Immunity 17:
561-573, 2002.

5. Kondo, M.; Takeshita, T.; Higuchi, M.; Nakamura, M.; Sudo, T.;
Nishikawa, S.-I.; Sugamura, K.: Functional participation of the IL-2
receptor gamma chain in IL-7 receptor complexes. Science 263: 1453-1454,
1994.

6. Lai, S. Y.; Molden, J.; Goldsmith, M. A.: Shared gamma(c) subunit
within the human interleukin-7 receptor complex: a molecular basis
for the pathogenesis of X-linked severe combined immunodeficiency. J.
Clin. Invest. 99: 169-177, 1997.

7. Liu, X.; Leung, S.; Wang, C.; Tan, Z.; Wang, J.; Guo, T. B.; Fang,
L.; Zhao, Y.; Wan, B.; Qin, X.; Lu, L.; Li, R.; Pan, H.; Song, M.;
Liu, A.; Hong, J.; Lu, H.; Zhang, J. Z.: Crucial role of interleukin-7
in T helper type 17 survival and expansion in autoimmune disease. Nature
Med. 16: 191-197, 2010.

8. Lynch, M.; Baker, E.; Park, L. S.; Sutherland, G. R.; Goodwin,
R. G.: The interleukin-7 receptor gene is at 5p13. Hum. Genet. 89:
566-568, 1992.

9. Maki, K.; Sunaga, S.; Komagata, Y.; Kodaira, Y.; Mabuchi, A.; Karasuyama,
H.; Yokomuro, K.; Miyazaki, J.; Ikuta, K.: Interleukin 7 receptor-deficient
mice lack gamma/delta T cells. Proc. Nat. Acad. Sci. 93: 7172-7177,
1996.

10. Noguchi, M.; Nakamura, Y.; Russell, S. M.; Ziegler, S. F.; Tsang,
M.; Cao, X.; Leonard, W. J.: Interleukin-2 receptor gamma chain:
a functional component of the interleukin-7 receptor. Science 262:
1877-1880, 1993.

11. Pellegrini, M.; Bouillet, P.; Robati, M.; Belz, G. T.; Davey,
G. M.; Strasser, A.: Loss of Bim increases T cell production and
function in interleukin 7 receptor-deficient mice. J. Exp. Med. 200:
1189-1195, 2004.

12. Peschon, J. J.; Morrissey, P. J.; Grabstein, K. H. et al.: Early
lymphocyte expansion is severely impaired in interleukin 7 receptor-deficient
mice. J. Exp. Med. 180: 1955-1960, 1994.

13. Puel, A.; Ziegler, S. F.; Buckley, R. H.; Leonard, W. J.: Defective
IL7R expression in T-B+NK+ severe combined immunodeficiency. Nature
Genet. 20: 394-397, 1998.

14. Reche, P. A.; Soumelis, V.; Gorman, D. M.; Clifford, T.; Liu,
M.; Travis, M.; Zurawski, S. M.; Johnston, J.; Liu, Y.-J.; Spits,
H.; de Waal Malefyt, R.; Kastelein, R. A.; Bazan, J. F.: Human thymic
stromal lymphopoietin preferentially stimulates myeloid cells. J.
Immun. 167: 336-343, 2001.

15. Roifman, C. M.; Zhang, J.; Chitayat, D.; Sharfe, N.: A partial
deficiency of interleukin-7R-alpha is sufficient to abrogate T-cell
development and cause severe combined immunodeficiency. Blood 96:
2803-2807, 2000.

16. Rose, T.; Lambotte, O.; Pallier, C.; Delfraissy, J.-F.; Colle,
J.-H.: Identification and biochemical characterization of human plasma
soluble IL-7R: lower concentrations in HIV-1-infected patients. J.
Immun. 182: 7389-7397, 2009.

17. Shochat, C.; Tal, N.; Bandapalli, O. R.; Palmi, C.; Ganmore, I.;
Kronnie, G.; Cario, G.; Cazzaniga, G.; Kulozik, A. E.; Stanulla, M.;
Schrappe, M.; Biondi, A.; Basso, G.; Bercovich, D.; Muckenthaler,
M. U.; Izraeli, S.: Gain-of-function mutations in interleukin-7 receptor-alpha
(IL7R) in childhood acute lymphoblastic leukemias. J. Exp. Med. 208:
901-908, 2011. Note: Erratum: J. Exp. Med. 208: preceding 901, 2011;
Erratum: J. Exp. Med. 208: 1333 only, 2011.

18. Vobhenrich, C. A. J.; Cumano, A.; Muller, W.; Di Santo, J. P.;
Vieira, P.: Thymic stromal-derived lymphopoietin distinguishes fetal
from adult B cell development. Nature Immun. 4: 773-779, 2003.

19. Zenatti, P. P.; Ribeiro, D.; Li, W.; Zuurbier, L.; Silva, M. C.;
Paganin, M.; Tritapoe, J.; Hixon, J. A.; Silveira, A. B.; Cardoso,
B. A.; Sarmento, L. M.; Correia, N.; and 10 others: Oncogenic IL7R
gain-of-function mutations in childhood T-cell acute lymphoblastic
leukemia. Nature Genet. 43: 932-939, 2011.

*FIELD* CN
Cassandra L. Kniffin - updated: 11/7/2011
Paul J. Converse - updated: 10/6/2011
Paul J. Converse - updated: 10/26/2010
Paul J. Converse - updated: 3/10/2010
Marla J. F. O'Neill - updated: 12/10/2008
Victor A. McKusick - updated: 3/19/2008
Cassandra L. Kniffin - updated: 9/13/2007
Paul J. Converse - updated: 4/6/2006
Paul J. Converse - updated: 1/12/2006
Cassandra L. Kniffin - updated: 10/28/2004
Paul J. Converse - updated: 5/13/2004
Paul J. Converse - updated: 9/10/2003
Paul J. Converse - updated: 5/31/2002
Paul J. Converse - updated: 12/11/2000
Wilson H. Y. Lo - updated: 7/23/1999
Victor A. McKusick - updated: 11/24/1998
Victor A. McKusick - updated: 8/26/1998
Victor A. McKusick - updated: 2/20/1997

*FIELD* CD
Victor A. McKusick: 6/25/1991

*FIELD* ED
carol: 01/09/2013
carol: 11/7/2011
ckniffin: 11/7/2011
mgross: 10/10/2011
terry: 10/6/2011
wwang: 5/19/2011
mgross: 1/26/2011
terry: 12/20/2010
mgross: 10/27/2010
terry: 10/26/2010
mgross: 3/10/2010
terry: 3/10/2010
wwang: 2/13/2009
ckniffin: 2/9/2009
carol: 12/10/2008
alopez: 3/25/2008
terry: 3/19/2008
alopez: 9/24/2007
ckniffin: 9/13/2007
mgross: 4/6/2006
mgross: 4/4/2006
terry: 3/16/2006
mgross: 1/12/2006
carol: 10/28/2004
ckniffin: 10/20/2004
mgross: 5/13/2004
mgross: 9/10/2003
alopez: 6/10/2003
mgross: 5/31/2002
mgross: 12/12/2000
terry: 12/11/2000
carol: 7/23/1999
alopez: 12/4/1998
alopez: 12/3/1998
alopez: 12/2/1998
alopez: 12/1/1998
terry: 11/24/1998
carol: 8/26/1998
terry: 8/26/1998
dkim: 7/2/1998
mark: 2/20/1997
terry: 2/13/1997
terry: 11/12/1996
terry: 11/4/1996
carol: 12/30/1994
carol: 9/18/1992
supermim: 3/16/1992
carol: 6/25/1991

MIM 608971
*RECORD*
*FIELD* NO
608971
*FIELD* TI
#608971 SEVERE COMBINED IMMUNODEFICIENCY, AUTOSOMAL RECESSIVE, T CELL-NEGATIVE,
B CELL-POSITIVE, NK CELL-POSITIVE
read more;;SCID, AUTOSOMAL RECESSIVE, T CELL-NEGATIVE, B CELL-POSITIVE, NK CELL-POSITIVE
*FIELD* TX
A number sign (#) is used with this entry because of evidence that T
cell-negative (T-), B cell-positive (B+), natural killer cell-positive
(NK+) severe combined immunodeficiency (SCID) can be caused by
homozygous or compound heterozygous mutation in the interleukin-7
receptor gene (IL7R; 146661) on chromosome 5p13 or the CD45 gene
(151460) on chromosome 1q31. CD45-deficient T-, B+, NK+ SCID can also be
caused by uniparental disomy (see 151460.0004).

For a general phenotypic description and a discussion of genetic
heterogeneity of autosomal recessive SCID, see 601457.

CLINICAL FEATURES

Cale et al. (1997) reported a child, born of consanguineous Turkish
parents, who presented at age 2 months with a fever, rash,
hepatosplenomegaly, lymphadenopathy, pneumonitis, and pancytopenia.
Cytomegalovirus was detected in buffy coats, a liver biopsy,
nasopharyngeal aspirates, and urine. Laboratory investigation showed low
T-cell numbers and decreased immunoglobulins with normal B-cell numbers.
All nucleated hematopoietic cells had abnormal expression of CD45.

Puel et al. (1998) reported a patient who presented at age 2 months with
gastroesophageal reflux. Despite a Nissen fundoplication and pylorotomy,
he continued to cough and had poor weight gain. He also had recurrent
otitis, thrush, and a monilial diaper dermatitis. Immunologic evaluation
showed elevated IgG and IgA, both of which contained paraproteins. A
second unrelated patient presented at age 1 month with recurrent otitis
media resistant to treatment, persistent oral moniliasis, diarrhea,
fevers, and poor growth. At the age of 13 months, he developed
parainfluenza type 3. Both patients had normal or elevated numbers of
CD20+ B cells, greatly diminished CD3+ T cells, and normal or elevated
CD16+ NK cells. Proliferation to mitogen and allogeneic cells was
defective, but NK-cell killing of K562 target cells was normal. The
second patient received a haploidentical bone marrow transplant, with
which full immunologic reconstitution was achieved, and was clinically
well more than 4 years posttransplantation.

Roifman et al. (2000) reported 3 patients from a consanguineous Sicilian
family with markedly reduced circulating T cells, an absence of serum Ig
in spite of normal B-cell numbers, and preserved NK cell numbers and
function. Although the Ig levels and NK phenotype were distinct from
X-linked SCID (300400), the patients were indistinguishable clinically,
with severe and persistent viral and protozoal infections.

MOLECULAR GENETICS

- IL7R Gene

In 2 unrelated patients with T-, B+, NK+ SCID, Puel et al. (1998)
identified mutations in the IL7R gene (146661.0001-146661.0004).

In 3 affected patients from a consanguineous Sicilian family with T-,
B+, NK+ SCID, Roifman et al. (2000) identified a homozygous mutation in
the IL7R gene (146661.0005).

- CD45 Gene

In a patient with T-, B+, NK+ SCID previously reported by Cale et al.
(1997), Tchilian et al. (2001) identified a homozygous deletion in the
CD45 gene (151460.0003).

Roberts et al. (2012) identified a boy with CD45-deficient T-, B+, NK-
SCID who was born to nonconsanguineous parents. The patient was
successfully treated by maternal bone marrow transplantation at age 10
months and appeared to be phenotypically normal at age 5 years. The
patient's mother was heterozygous for a lys540-to-ter (K540X;
151460.0004) mutation in the CD45 gene, but the paternal alleles
exhibited no detectable mutation. The patient had no change in copy
number, but loss of heterozygosity, for the entire length of chromosome
1, indicating that SCID was caused by uniparental disomy (UPD) with
isodisomy of the entire maternal chromosome 1 bearing the mutant allele.
Nonlymphoid cells retained UPD of the entire maternal chromosome 1. The
faulty chromosome also carried mutations in 7 other genes predicted to
have deleterious effects on protein function. Roberts et al. (2012)
proposed that UPD should be considered in SCID and other recessive
disorders, particularly when only 1 patient appears to be homozygous for
an abnormal gene found in only 1 parent.

*FIELD* RF
1. Cale, C. M.; Klein, N. J.; Novelli, V.; Veys, P.; Jones, A. M.;
Morgan, G.: Severe combined immunodeficiency with abnormalities in
expression of the common leucocyte antigen, CD45. Arch. Dis. Child. 76:
163-164, 1997.

2. Puel, A.; Ziegler, S. F.; Buckley, R. H.; Leonard, W. J.: Defective
IL7R expression in T-B+NK+ severe combined immunodeficiency. Nature
Genet. 20: 394-397, 1998.

3. Roberts, J. L.; Buckley, R. H.; Luo, B.; Pei, J.; Lapidus, A.;
Peri, S.; Wei, Q.; Shin, J.; Parrott, R. E.; Dunbrack, R. L., Jr.;
Testa, J. R.; Zhong, X.-P.; Wiest, D. L.: CD45-deficient severe combined
immunodeficiency caused by uniparental disomy. Proc. Nat. Acad. Sci. 109:
10456-10461, 2012.

4. Roifman, C. M.; Zhang, J.; Chitayat, D.; Sharfe, N.: A partial
deficiency of interleukin-7R-alpha is sufficient to abrogate T-cell
development and cause severe combined immunodeficiency. Blood 96:
2803-2807, 2000.

5. Tchilian, E. Z.; Wallace, D. L.; Wells, R. S.; Flower, D. R.; Morgan,
G.; Beverley, P. C. L.: A deletion in the gene encoding the CD45
antigen in a patient with SCID. J. Immun. 166: 1308-1313, 2001.

*FIELD* CS
INHERITANCE:
Autosomal recessive

GROWTH:
[Other];
Failure to thrive secondary to recurrent infections

HEAD AND NECK:
[Ears];
Otitis media;
[Mouth];
Candida albicans infection;
Thrush

RESPIRATORY:
[Lung];
Recurrent acute pneumonia

ABDOMEN:
[Liver];
Hepatomegaly;
[Spleen];
Splenomegaly;
[Gastrointestinal];
Diarrhea

SKIN, NAILS, HAIR:
[Skin];
Dermatitis

IMMUNOLOGY:
Frequent opportunistic infections;
Lymphadenopathy;
Normal or elevated numbers of functional natural killer cells (NK);
Normal or elevated number of peripheral blood B cells;
Absent peripheral blood T cells;
Serum immunoglobulins may be absent, normal, or increased

MISCELLANEOUS:
Presents at 2 to 3 months of age;
Death within several months if untreated

MOLECULAR BASIS:
Caused by mutation in the interleukin 7 receptor gene (IL7R, 146661.0001);
Caused by mutation in the protein tyrosine phosphatase, receptor type,
c polypeptide gene (PTPRC, 151460.0002);
Caused by mutation in the CD3 antigen, delta subunit gene (CD3D,
186790.0001);
Caused by mutation in the CD3 antigen, epsilon subunit gene (CD3E,
186830.0003)

*FIELD* CD
Cassandra L. Kniffin: 10/20/2004

*FIELD* ED
joanna: 10/08/2010
ckniffin: 10/20/2004

*FIELD* CN
Paul J. Converse - updated: 8/20/2013
Marla J. F. O'Neill - updated: 1/19/2005

*FIELD* CD
Cassandra L. Kniffin: 10/15/2004

*FIELD* ED
ckniffin: 01/29/2014
mgross: 8/20/2013
terry: 3/15/2013
carol: 4/30/2012
terry: 3/21/2012
carol: 2/1/2005
terry: 1/19/2005
carol: 10/28/2004
ckniffin: 10/20/2004

MIM 612595
*RECORD*
*FIELD* NO
612595
*FIELD* TI
%612595 MULTIPLE SCLEROSIS, SUSCEPTIBILITY TO, 3; MS3
*FIELD* TX
For a discussion of genetic heterogeneity of multiple sclerosis (MS),
read moresee MS1 (126200).

MAPPING

- Association with the IL7R Gene

Gregory et al. (2007) found a significant association between a T-to-C
SNP (dbSNP rs6897932; thr244 to ile) in the transmembrane domain of the
IL7R gene (146661) on chromosome 5p13 and susceptibility to multiple
sclerosis. The findings were observed in 1,055 individuals with MS (P =
0.0006 for the C allele) and replicated in 3 independent European
populations or populations of European descent comprising 438, 1,338,
and 1,077 patients, respectively. A combined analysis of all the
family-based and case-control data sets resulted in a p value of 2.9 x
10(-7). Functional expression studies showed that the C allele of dbSNP
rs6897932 affects alternative splicing of exon 6, leading to increased
skipping of the exon and increased production of soluble IL7R in
individuals carrying the risk allele. This results in decreased
expression of membrane-bound IL7R, thus causing decreased IL7
(146660)/IL7R signaling.

Among 1,210 patients with MS from Nordic countries, Lundmark et al.
(2007) found an association between disease development and several SNPs
in the IL7R gene (dbSNP rs6897932, dbSNP rs6871748, and dbSNP
rs2303137). All were significant after Bonferroni correction. Further
analyses, including estimation of haplotype frequencies, indicated that
dbSNP rs6897932 was most strongly associated with risk of MS. Lundmark
et al. (2007) also found increased expression of IL7R mRNA in
cerebrospinal fluid of MS individuals compared to controls.

In a multistage genomewide association study involving a total of 1,540
MS family trios, 2,322 case subjects, and 5,418 control subjects, the
International Multiple Sclerosis Genetics Consortium (2007) confirmed
significant association of dbSNP rs6897932 with MS.

O'Doherty et al. (2008) studied 2 independent case-control collections
from Olmsted County, Minnesota, and Belfast, Northern Ireland, involving
208 MS patients and 413 controls, and 463 MS patients and 532 controls,
respectively. Association of the dbSNP rs6897932 C allele with MS was
confirmed in the Olmsted County group but not in the Belfast group.

D'Netto et al. (2009) found an association between MS and dbSNP
rs6897932 in a case-control study of 211 MS patients and 182 unrelated
controls (OR, 1.54; p = 0.013). However, there was no significant
association between the SNP and MS in the 211 patients and 521
unaffected relatives from 43 multiplex MS families.

Fang et al. (2011) found a significant association between the C allele
of dbSNP rs6897932 and the CC genotype among 107 Japanese patients with
conventional MS compared to 158 controls. The frequency of the C allele
was 90.65% in patients with conventional MS and 79.75% in controls (OR
of 2.46, corrected p value of 0.0020). The frequency of the CC genotype
was 81.31% in patients with conventional MS and 63.29% in controls (OR
of 2.52, corrected p value of 0.0048). Similar results were obtained
when the patients were categorized as non-NMO (neuromyelitis optica) MS.
No association was observed between this SNP and patients with
opticospinal MS or NMO. Fang et al. (2011) concluded that this SNP is a
strong risk factor for non-NMO MS and conventional MS in the Asian
population.

- Association with the C7 Gene

In Southern Ostrobothnia, Finland, the prevalence and familial
occurrence of multiple sclerosis are exceptionally high. Kallio et al.
(2009) screened haplotypes at chromosome 5p15-q11 risk region in 72
Finnish MS cases, the majority of which share distant genealogic
relatedness due to origin from Southern Ostrobothnia. Haplotype analysis
over the 45-Mb risk region in Finnish MS families revealed only modest
association for the IL7R gene (p = 0.04), whereas most significant
association was found with an 8-SNP haplotype covering the C7 gene
(217070) and the HEATR7B2 gene (p = 0.0001), located 5.1-Mb centromeric
of the IL7R gene. An independent sample of Finnish isolate MS patients
showed significant association (p = 4.0 x 10(-4)) with a 24-SNP
haplotype, and the combined data set showed significant linkage to the
C7-HEATR7B2 region (p = 3.2 x 10(-6), corrected p = 0.012, OR = 2.73).
In serum and plasma from 20 Finnish MS patients and 32 unaffected
controls, terminal complement complex, which includes C7, showed
increased activity in individuals with the identified risk haplotype.
The authors reported that the C7-HEATR7B2 and IL7R loci were not in
linkage disequilibrium. Kallio et al. (2009) noted that studies with
more heterogeneous populations from Finland, Norway, Sweden, and the
U.S. showed suggestive association with other C7-HEATR7B2 risk
haplotypes.

*FIELD* RF
1. D'Netto, M. J.; Ward, H.; Morrison, K. M.; Ramagopalan, S. V.;
Dyment, D. A.; DeLuca, G. C.; Handunnetthi, L.; Sadovnick, A. D.;
Ebers, G. C.: Risk alleles for multiple sclerosis in multiplex families. Neurology 72:
1984-1988, 2009.

2. Fang, L.; Isobe, N.; Yoshimura, S.; Yonekawa, T.; Matsushita, T.;
Masaki, K.; Doi, H.; Ochi, K.; Miyamoto, K.; Kawano, Y.; Kira, J.
: Interleukin-7 receptor alpha gene polymorphism influences multiple
sclerosis risk in Asians. Neurology 76: 2125-2127, 2011.

3. Gregory, S. G.; Schmidt, S.; Seth, P.; Oksenberg, J. R.; Hart,
J.; Prokop, A.; Caillier, S. J.; Ban. M.; Goris, A.; Barcellos, L.
F.; Lincoln, R.; McCauley, J. L.; Sawcer, S. J.; Compston, D. A. S.;
Dubois, B.; Hauser, S. L.; Garcia-Blanco, M. A.; Pericak-Vance, M.
A.; Haines, J. L.; Multiple Sclerosis Genetics Group: Interleukin
7 receptor alpha chain (IL7R) shows allelic and functional association
with multiple sclerosis. Nature Genet. 39: 1083-1091, 2007.

4. International Multiple Sclerosis Genetics Consortium: Risk alleles
for multiple sclerosis identified by a genomewide study. New Eng.
J. Med. 357: 851-862, 2007.

5. Kallio, S. P.; Jakkula, E.; Purcell, S.; Suvela, M.; Koivisto,
K.; Tienari, P. J.; Elovaara, I.; Pirttila, T.; Reunanen, M.; Bronnikov,
D.; Viander, M.; Meri, S.; and 10 others: Use of a genetic isolate
to identify rare disease variants: C7 on 5p associated with MS. Hum.
Molec. Genet. 18: 1670-1683, 2009.

6. Lundmark, F.; Duvefelt, K.; Iacobaeus, E.; Kockum, I.; Wallstrom,
E.; Khademi, M.; Oturai, A.; Ryder, L. P.; Saarela, J.; Harbo, H.
F.; Celius, E. G.; Salter, H.; Olsson, T.; Hillert, J.: Variation
in interleukin 7 receptor alpha chain (IL7R) influences risk of multiple
sclerosis. Nature Genet. 39: 1108-1113, 2007.

7. O'Doherty, C.; Kantarci, O.; Vandenbroeck, K.: IL7RA polymorphisms
and susceptibility to multiple sclerosis. (Letter) New Eng. J. Med. 358:
753-754, 2008.

*FIELD* CN
Cassandra L. Kniffin - updated: 12/8/2011
Cassandra L. Kniffin - updated: 12/29/2009
George E. Tiller - updated: 10/15/2009

*FIELD* CD
Cassandra L. Kniffin: 2/9/2009

*FIELD* ED
carol: 12/20/2011
ckniffin: 12/20/2011
ckniffin: 12/8/2011
wwang: 1/13/2010
ckniffin: 12/29/2009
wwang: 10/16/2009
terry: 10/15/2009
wwang: 2/13/2009
ckniffin: 2/9/2009

RBCC Red Blood Cell Collection

Full text data of IL7R