RBCC Red Blood Cell Collection

TNFRSF1B (TNFBR, TNFR2) [Confidence: high (a blood group or CD marker)]
Tumor necrosis factor receptor superfamily member 1B (Tumor necrosis factor receptor 2; TNF-R2; Tumor necrosis factor receptor type II; TNF-RII; TNFR-II; p75; p80 TNF-alpha receptor; CD120b; Etanercept; Tumor necrosis factor receptor superfamily member 1b, membrane form; Tumor necrosis factor-binding protein 2; TBP-2; TBPII; Flags: Precursor)

UniProt P20333
ID TNR1B_HUMAN Reviewed; 461 AA.
AC P20333; B1AJZ3; Q16042; Q6YI29; Q9UIH1;
DT 01-FEB-1991, integrated into UniProtKB/Swiss-Prot.
read moreDT 27-MAY-2002, sequence version 3.
DT 22-JAN-2014, entry version 163.
DE RecName: Full=Tumor necrosis factor receptor superfamily member 1B;
DE AltName: Full=Tumor necrosis factor receptor 2;
DE Short=TNF-R2;
DE AltName: Full=Tumor necrosis factor receptor type II;
DE Short=TNF-RII;
DE Short=TNFR-II;
DE AltName: Full=p75;
DE AltName: Full=p80 TNF-alpha receptor;
DE AltName: CD_antigen=CD120b;
DE AltName: INN=Etanercept;
DE Contains:
DE RecName: Full=Tumor necrosis factor receptor superfamily member 1b, membrane form;
DE Contains:
DE RecName: Full=Tumor necrosis factor-binding protein 2;
DE AltName: Full=TBP-2;
DE AltName: Full=TBPII;
DE Flags: Precursor;
GN Name=TNFRSF1B; Synonyms=TNFBR, TNFR2;
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 VARIANT ARG-196.
RX PubMed=2172983; DOI=10.1073/pnas.87.21.8331;
RA Kohno T., Brewer M.T., Baker S.L., Schwartz P.E., King M.W.,
RA Hale K.K., Squires C.H., Thompson R.C., Vannice J.L.;
RT "A second tumor necrosis factor receptor gene product can shed a
RT naturally occurring tumor necrosis factor inhibitor.";
RL Proc. Natl. Acad. Sci. U.S.A. 87:8331-8335(1990).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=2160731; DOI=10.1126/science.2160731;
RA Smith C.A., Davis T., Anderson D., Solam L., Beckmann M.P., Jerzy R.,
RA Dower S.K., Cosman D., Goodwin R.G.;
RT "A receptor for tumor necrosis factor defines an unusual family of
RT cellular and viral proteins.";
RL Science 248:1019-1023(1990).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM 1).
RX PubMed=8661109; DOI=10.1006/geno.1996.0327;
RA Beltinger C.P., White P.S., Maris J.M., Sulman E.P., Jensen S.J.,
RA Lepaslier D., Stallard B.J., Goeddel D.V., Desauvage F.J.,
RA Brodeur G.M.;
RT "Physical mapping and genomic structure of the human TNFR2 gene.";
RL Genomics 35:94-100(1996).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), SUBCELLULAR LOCATION, AND
RP FUNCTION (ISOFORM 2).
RX PubMed=14688072; DOI=10.1093/intimm/dxh014;
RA Lainez B., Fernandez-Real J.M., Romero X., Esplugues E., Canete J.D.,
RA Ricart W., Engel P.;
RT "Identification and characterization of a novel spliced variant that
RT encodes human soluble tumor necrosis factor receptor 2.";
RL Int. Immunol. 16:169-177(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor
RT vector.";
RL Submitted (OCT-2004) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS MET-187; ARG-196;
RP LYS-232; THR-236; PRO-264 AND ARG-295.
RG NIEHS SNPs program;
RL Submitted (MAR-2003) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS ARG-196; LYS-232;
RP PRO-269 AND ARG-301.
RG SeattleSNPs variation discovery resource;
RL Submitted (JUL-2003) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16710414; DOI=10.1038/nature04727;
RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D.,
RA Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A.,
RA Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F.,
RA McDonald L., Evans R., Phillips K., Atkinson A., Cooper R., Jones C.,
RA Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P.,
RA Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K.,
RA Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G.,
RA Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D.,
RA Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G.,
RA Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J.,
RA Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R.,
RA Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D.,
RA Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G.,
RA Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M.,
RA Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J.,
RA Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M.,
RA Loveland J., Lovell J., Lush M.J., Lyne R., Martin S.,
RA Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S.,
RA Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C.,
RA Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z.,
RA Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E.,
RA Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A.,
RA Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R.,
RA Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V.,
RA Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence and biological annotation of human chromosome 1.";
RL Nature 441:315-321(2006).
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=PNS;
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 [11]
RP PROTEIN SEQUENCE OF 23-40; 65-69; 136-141; 300-306 AND 346-362.
RX PubMed=2173696;
RA Loetscher H., Schlaeger E.J., Lahm H.-W., Pan Y.-C.E., Lesslauer W.,
RA Brockhaus M.;
RT "Purification and partial amino acid sequence analysis of two distinct
RT tumor necrosis factor receptors from HL60 cells.";
RL J. Biol. Chem. 265:20131-20138(1990).
RN [12]
RP PROTEIN SEQUENCE OF 27-37.
RC TISSUE=Urine;
RX PubMed=8015639;
RA Suzuki J., Tomizawa S., Arai H., Seki Y., Maruyama K., Kuroume T.;
RT "Purification of two types of TNF inhibitors in the urine of the
RT patient with chronic glomerulonephritis.";
RL Nephron 66:386-390(1994).
RN [13]
RP PROTEIN SEQUENCE OF 27-31.
RC TISSUE=Urine;
RX PubMed=2153136;
RA Engelmann H., Novick D., Wallach D.;
RT "Two tumor necrosis factor-binding proteins purified from human urine.
RT Evidence for immunological cross-reactivity with cell surface tumor
RT necrosis factor receptors.";
RL J. Biol. Chem. 265:1531-1536(1990).
RN [14]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 37-461 (ISOFORM 1).
RX PubMed=1966549; DOI=10.1016/1043-4666(90)90022-L;
RA Dembic Z., Loetscher H., Gubler U., Pan Y.C., Lahm H.-W., Gentz R.,
RA Brockhaus M., Lesslauer W.;
RT "Two human TNF receptors have similar extracellular, but distinct
RT intracellular, domain sequences.";
RL Cytokine 2:231-237(1990).
RN [15]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 116-461 (ISOFORM 1), PARTIAL PROTEIN
RP SEQUENCE, AND VARIANT ARG-196.
RX PubMed=2166946; DOI=10.1073/pnas.87.16.6151;
RA Heller R.A., Song K., Onasch M.A., Fischer W.H., Chang D.,
RA Ringold G.M.;
RT "Complementary DNA cloning of a receptor for tumor necrosis factor and
RT demonstration of a shed form of the receptor.";
RL Proc. Natl. Acad. Sci. U.S.A. 87:6151-6155(1990).
RN [16]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 154-183, AND VARIANTS ARG-196 AND
RP LYS-232.
RX PubMed=11197692; DOI=10.1038/sj.gene.6363700;
RA Tsuchiya N., Komata T., Matsushita M., Ohashi J., Tokunaga K.;
RT "New single nucleotide polymorphisms in the coding region of human
RT TNFR2: association with systemic lupus erythematosus.";
RL Genes Immun. 1:501-503(2000).
RN [17]
RP CHARACTERIZATION.
RX PubMed=1328224;
RA Pennica D., Lam V.T., Mize N.K., Weber R.F., Lewis M., Fendly B.M.,
RA Lipari M.T., Goeddel D.V.;
RT "Biochemical properties of the 75-kDa tumor necrosis factor receptor.
RT Characterization of ligand binding, internalization, and receptor
RT phosphorylation.";
RL J. Biol. Chem. 267:21172-21178(1992).
RN [18]
RP INTERACTION WITH TRAF2.
RX PubMed=8069916; DOI=10.1016/0092-8674(94)90532-0;
RA Rothe M., Wong S.C., Henzel W.J., Goeddel D.V.;
RT "A novel family of putative signal transducers associated with the
RT cytoplasmic domain of the 75 kDa tumor necrosis factor receptor.";
RL Cell 78:681-692(1994).
RN [19]
RP FUNCTION, AND INTERACTION WITH BMX.
RX PubMed=12370298; DOI=10.1128/MCB.22.21.7512-7523.2002;
RA Pan S., An P., Zhang R., He X., Yin G., Min W.;
RT "Etk/Bmx as a tumor necrosis factor receptor type 2-specific kinase:
RT role in endothelial cell migration and angiogenesis.";
RL Mol. Cell. Biol. 22:7512-7523(2002).
RN [20]
RP X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 419-428 IN COMPLEX WITH
RP TRAF2.
RX PubMed=10206649; DOI=10.1038/19110;
RA Park Y.C., Burkitt V., Villa A.R., Tong L., Wu H.;
RT "Structural basis for self-association and receptor recognition of
RT human TRAF2.";
RL Nature 398:533-538(1999).
RN [21]
RP VARIANTS ARG-196 AND LYS-232.
RX PubMed=11762942;
RX DOI=10.1002/1529-0131(200112)44:12<2819::AID-ART469>3.0.CO;2-2;
RA Morita C., Horiuchi T., Tsukamoto H., Hatta N., Kikuchi Y.,
RA Arinobu Y., Otsuka T., Sawabe T., Harashima S., Nagasawa K., Niho Y.;
RT "Association of tumor necrosis factor receptor type II polymorphism
RT 196R with systemic lupus erythematosus in the Japanese: molecular and
RT functional analysis.";
RL Arthritis Rheum. 44:2819-2827(2001).
RN [22]
RP VARIANT ARG-196.
RX PubMed=12161545; DOI=10.1210/jc.87.8.3977;
RA Peral B., San Millan J.L., Castello R., Moghetti P.,
RA Escobar-Morreale H.F.;
RT "Comment: the methionine 196 arginine polymorphism in exon 6 of the
RT TNF receptor 2 gene (TNFRSF1B) is associated with the polycystic ovary
RT syndrome and hyperandrogenism.";
RL J. Clin. Endocrinol. Metab. 87:3977-3983(2002).
CC -!- FUNCTION: Receptor with high affinity for TNFSF2/TNF-alpha and
CC approximately 5-fold lower affinity for homotrimeric
CC TNFSF1/lymphotoxin-alpha. The TRAF1/TRAF2 complex recruits the
CC apoptotic suppressors BIRC2 and BIRC3 to TNFRSF1B/TNFR2. This
CC receptor mediates most of the metabolic effects of TNF-alpha.
CC Isoform 2 blocks TNF-alpha-induced apoptosis, which suggests that
CC it regulates TNF-alpha function by antagonizing its biological
CC activity.
CC -!- SUBUNIT: Binds to TRAF2. Interacts with BMX.
CC -!- INTERACTION:
CC P28799:GRN; NbExp=5; IntAct=EBI-358983, EBI-747754;
CC -!- SUBCELLULAR LOCATION: Isoform 1: Cell membrane; Single-pass type I
CC membrane protein.
CC -!- SUBCELLULAR LOCATION: Isoform 2: Secreted.
CC -!- SUBCELLULAR LOCATION: Tumor necrosis factor-binding protein 2:
CC Secreted.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P20333-1; Sequence=Displayed;
CC Name=2; Synonyms=DS-TNFR2(Delta7,8), sTNFR2;
CC IsoId=P20333-2; Sequence=VSP_011826, VSP_011827;
CC -!- PTM: Phosphorylated; mainly on serine residues and with a very low
CC level on threonine residues.
CC -!- PTM: A soluble form (tumor necrosis factor binding protein 2) is
CC produced from the membrane form by proteolytic processing.
CC -!- PHARMACEUTICAL: Available under the name Enbrel (Immunex and
CC Wyeth-Ayerst). Used to treat moderate to severe rheumatoid
CC arthritis (RA). Enbrel consist of the extracellular ligand-binding
CC portion of TNFRSF1B linked to an immunoglobulin Fc chain. It binds
CC to TNF-alpha and blocks its interactions with receptors.
CC -!- SIMILARITY: Contains 4 TNFR-Cys repeats.
CC -!- WEB RESOURCE: Name=SeattleSNPs;
CC URL="http://pga.gs.washington.edu/data/tnfrsf1b/";
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/tnfrsf1b/";
CC -!- WEB RESOURCE: Name=Enbrel; Note=Clinical information on Enbrel;
CC URL="http://www.enbrel.com/index.jspx";
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DR EMBL; M55994; AAA36755.1; -; mRNA.
DR EMBL; M32315; AAA59929.1; -; mRNA.
DR EMBL; U52165; AAC50622.1; -; Genomic_DNA.
DR EMBL; U52156; AAC50622.1; JOINED; Genomic_DNA.
DR EMBL; U52157; AAC50622.1; JOINED; Genomic_DNA.
DR EMBL; U52158; AAC50622.1; JOINED; Genomic_DNA.
DR EMBL; U52159; AAC50622.1; JOINED; Genomic_DNA.
DR EMBL; U52160; AAC50622.1; JOINED; Genomic_DNA.
DR EMBL; U52161; AAC50622.1; JOINED; Genomic_DNA.
DR EMBL; U52162; AAC50622.1; JOINED; Genomic_DNA.
DR EMBL; U52163; AAC50622.1; JOINED; Genomic_DNA.
DR EMBL; U52164; AAC50622.1; JOINED; Genomic_DNA.
DR EMBL; AY148473; AAN72434.1; -; mRNA.
DR EMBL; BT019927; AAV38730.1; -; mRNA.
DR EMBL; AY264804; AAO89076.1; -; Genomic_DNA.
DR EMBL; AY342040; AAP88939.1; -; Genomic_DNA.
DR EMBL; AL031276; CAI19225.1; -; Genomic_DNA.
DR EMBL; AL357835; CAI19225.1; JOINED; Genomic_DNA.
DR EMBL; AL357835; CAH73721.1; -; Genomic_DNA.
DR EMBL; AL031276; CAH73721.1; JOINED; Genomic_DNA.
DR EMBL; CH471130; EAW71733.1; -; Genomic_DNA.
DR EMBL; BC052977; AAH52977.1; -; mRNA.
DR EMBL; S63368; AAB19824.2; -; mRNA.
DR EMBL; M35857; AAA63262.1; -; mRNA.
DR EMBL; AB030950; BAA89053.1; -; Genomic_DNA.
DR PIR; A35356; A35356.
DR RefSeq; NP_001057.1; NM_001066.2.
DR UniGene; Hs.256278; -.
DR PDB; 1CA9; X-ray; 2.30 A; G/H=420-428.
DR PDB; 3ALQ; X-ray; 3.00 A; R/S/T/U/V/W=33-205.
DR PDBsum; 1CA9; -.
DR PDBsum; 3ALQ; -.
DR ProteinModelPortal; P20333; -.
DR SMR; P20333; 37-200.
DR DIP; DIP-78N; -.
DR IntAct; P20333; 10.
DR MINT; MINT-134958; -.
DR STRING; 9606.ENSP00000365435; -.
DR ChEMBL; CHEMBL1250356; -.
DR DrugBank; DB00005; Etanercept.
DR DrugBank; DB00065; Infliximab.
DR GuidetoPHARMACOLOGY; 1871; -.
DR PhosphoSite; P20333; -.
DR DMDM; 21264534; -.
DR PaxDb; P20333; -.
DR PeptideAtlas; P20333; -.
DR PRIDE; P20333; -.
DR DNASU; 7133; -.
DR Ensembl; ENST00000376259; ENSP00000365435; ENSG00000028137.
DR GeneID; 7133; -.
DR KEGG; hsa:7133; -.
DR UCSC; uc001att.3; human.
DR CTD; 7133; -.
DR GeneCards; GC01P012161; -.
DR HGNC; HGNC:11917; TNFRSF1B.
DR HPA; CAB013045; -.
DR HPA; HPA004796; -.
DR MIM; 191191; gene.
DR neXtProt; NX_P20333; -.
DR PharmGKB; PA36610; -.
DR eggNOG; NOG42764; -.
DR HOGENOM; HOG000132845; -.
DR HOVERGEN; HBG054237; -.
DR InParanoid; P20333; -.
DR KO; K05141; -.
DR OMA; GNASMDA; -.
DR OrthoDB; EOG786H2Q; -.
DR PhylomeDB; P20333; -.
DR EvolutionaryTrace; P20333; -.
DR GeneWiki; TNFRSF1B; -.
DR GenomeRNAi; 7133; -.
DR NextBio; 27909; -.
DR PMAP-CutDB; P20333; -.
DR PRO; PR:P20333; -.
DR ArrayExpress; P20333; -.
DR Bgee; P20333; -.
DR CleanEx; HS_TNFRSF1B; -.
DR Genevestigator; P20333; -.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR GO; GO:0016021; C:integral to membrane; IEA:UniProtKB-KW.
DR GO; GO:0045121; C:membrane raft; IDA:BHF-UCL.
DR GO; GO:0043025; C:neuronal cell body; IEA:Ensembl.
DR GO; GO:0005634; C:nucleus; IEA:Ensembl.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IEA:Ensembl.
DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0043196; C:varicosity; IEA:Ensembl.
DR GO; GO:0005031; F:tumor necrosis factor-activated receptor activity; TAS:ProtInc.
DR GO; GO:0006915; P:apoptotic process; IEA:UniProtKB-KW.
DR GO; GO:0071363; P:cellular response to growth factor stimulus; IEA:Ensembl.
DR GO; GO:0071222; P:cellular response to lipopolysaccharide; IMP:BHF-UCL.
DR GO; GO:0006955; P:immune response; IEA:Ensembl.
DR GO; GO:0006954; P:inflammatory response; IEA:Ensembl.
DR GO; GO:0050728; P:negative regulation of inflammatory response; IEA:Ensembl.
DR GO; GO:0051044; P:positive regulation of membrane protein ectodomain proteolysis; IMP:BHF-UCL.
DR GO; GO:0050779; P:RNA destabilization; IEA:Ensembl.
DR InterPro; IPR001368; TNFR/NGFR_Cys_rich_reg.
DR InterPro; IPR020411; TNFR_1B.
DR Pfam; PF00020; TNFR_c6; 2.
DR PRINTS; PR01919; TNFACTORR1B.
DR SMART; SM00208; TNFR; 4.
DR PROSITE; PS00652; TNFR_NGFR_1; 2.
DR PROSITE; PS50050; TNFR_NGFR_2; 3.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Apoptosis; Cell membrane;
KW Complete proteome; Direct protein sequencing; Disulfide bond;
KW Glycoprotein; Membrane; Pharmaceutical; Phosphoprotein; Polymorphism;
KW Receptor; Reference proteome; Repeat; Secreted; Signal; Transmembrane;
KW Transmembrane helix.
FT SIGNAL 1 22
FT CHAIN 23 461 Tumor necrosis factor receptor
FT superfamily member 1b, membrane form.
FT /FTId=PRO_0000034548.
FT CHAIN 27 ? Tumor necrosis factor-binding protein 2.
FT /FTId=PRO_0000034549.
FT TOPO_DOM 23 257 Extracellular (Potential).
FT TRANSMEM 258 287 Helical; (Potential).
FT TOPO_DOM 288 461 Cytoplasmic (Potential).
FT REPEAT 39 76 TNFR-Cys 1.
FT REPEAT 77 118 TNFR-Cys 2.
FT REPEAT 119 162 TNFR-Cys 3.
FT REPEAT 163 201 TNFR-Cys 4.
FT CARBOHYD 171 171 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 193 193 N-linked (GlcNAc...) (Potential).
FT DISULFID 40 53 By similarity.
FT DISULFID 54 67 By similarity.
FT DISULFID 57 75 By similarity.
FT DISULFID 78 93 By similarity.
FT DISULFID 96 110 By similarity.
FT DISULFID 100 118 By similarity.
FT DISULFID 120 126 By similarity.
FT DISULFID 134 143 By similarity.
FT DISULFID 137 161 By similarity.
FT DISULFID 164 179 By similarity.
FT VAR_SEQ 263 268 GLIVGV -> ASLACR (in isoform 2).
FT /FTId=VSP_011826.
FT VAR_SEQ 269 461 Missing (in isoform 2).
FT /FTId=VSP_011827.
FT VARIANT 187 187 V -> M (in dbSNP:rs2228494).
FT /FTId=VAR_017176.
FT VARIANT 196 196 M -> R (frequent polymorphism; seems to
FT be associated with hyperandrogenism,
FT polycystic ovary syndrome (PCOS) and
FT systemic lupus erythematosus;
FT dbSNP:rs1061622).
FT /FTId=VAR_015434.
FT VARIANT 232 232 E -> K (in dbSNP:rs5746026).
FT /FTId=VAR_015435.
FT VARIANT 236 236 A -> T (in dbSNP:rs5746027).
FT /FTId=VAR_017177.
FT VARIANT 264 264 L -> P (in dbSNP:rs2229700).
FT /FTId=VAR_017178.
FT VARIANT 269 269 T -> P (in dbSNP:rs17879042).
FT /FTId=VAR_017179.
FT VARIANT 295 295 Q -> R (in dbSNP:rs5746032).
FT /FTId=VAR_017180.
FT VARIANT 301 301 P -> R (in dbSNP:rs17883432).
FT /FTId=VAR_017181.
FT CONFLICT 35 37 EPG -> APT (in Ref. 12; AA sequence).
FT CONFLICT 98 98 S -> P (in Ref. 4; AAN72434).
FT CONFLICT 102 102 S -> P (in Ref. 4; AAN72434).
FT CONFLICT 141 141 R -> P (in Ref. 15; AAA63262).
FT CONFLICT 363 363 A -> T (in Ref. 15; AAA63262).
FT STRAND 44 47
FT TURN 48 51
FT STRAND 52 55
FT STRAND 61 65
FT STRAND 74 77
FT STRAND 86 88
FT STRAND 104 108
FT STRAND 112 114
FT STRAND 117 120
FT STRAND 124 129
FT STRAND 131 139
FT STRAND 147 151
FT TURN 154 156
FT STRAND 160 163
FT STRAND 174 176
FT STRAND 194 196
SQ SEQUENCE 461 AA; 48291 MW; 603D0AE1CD69ACBF CRC64;
MAPVAVWAAL AVGLELWAAA HALPAQVAFT PYAPEPGSTC RLREYYDQTA QMCCSKCSPG
QHAKVFCTKT SDTVCDSCED STYTQLWNWV PECLSCGSRC SSDQVETQAC TREQNRICTC
RPGWYCALSK QEGCRLCAPL RKCRPGFGVA RPGTETSDVV CKPCAPGTFS NTTSSTDICR
PHQICNVVAI PGNASMDAVC TSTSPTRSMA PGAVHLPQPV STRSQHTQPT PEPSTAPSTS
FLLPMGPSPP AEGSTGDFAL PVGLIVGVTA LGLLIIGVVN CVIMTQVKKK PLCLQREAKV
PHLPADKARG TQGPEQQHLL ITAPSSSSSS LESSASALDR RAPTRNQPQA PGVEASGAGE
ARASTGSSDS SPGGHGTQVN VTCIVNVCSS SDHSSQCSSQ ASSTMGDTDS SPSESPKDEQ
VPFSKEECAF RSQLETPETL LGSTEEKPLP LGVPDAGMKP S
//

MIM 191191
*RECORD*
*FIELD* NO
191191
*FIELD* TI
*191191 TUMOR NECROSIS FACTOR RECEPTOR SUBFAMILY, MEMBER 1B; TNFRSF1B
;;TUMOR NECROSIS FACTOR RECEPTOR 2; TNFR2;;
read moreTUMOR NECROSIS FACTOR, BETA RECEPTOR; TNFBR;;
TNFR, 75-KD;;
TNFR, 80-KD
*FIELD* TX

CLONING

Schall et al. (1990) isolated a cDNA corresponding to TNFR2 using
oligomer probes based on amino acid sequence from the purified protein.
The receptor encodes a predicted 415-amino acid polypeptide with a
single membrane-spanning domain and has an extracellular domain with
sequence similarity to nerve growth factor receptor (162010) and B-cell
activation protein Bp50 (164011). Recombinantly expressed receptor was
shown by Schall et al. (1990) to bind TNF-alpha (191160). Northern blots
showed expression in a variety of cell types.

GENE STRUCTURE

Beltinger et al. (1996) showed that TNFR2 contains 10 exons and spans
about 26 kb of genomic DNA. Most of the functional domains, including
the extracellular cysteine-rich motifs, occur in separate exons.
Overall, the gene structure is similar to that of TNFR1 (191190). On the
basis of a YAC contig for the region, they mapped TNFR2 to within 400 kb
of the marker D1S434 on 1p36.

Santee and Owen-Schaub (1996) characterized the complete gene structure
for human TNFR p75, which spans nearly 43 kb. The gene consists of 10
exons (ranging from 34 bp to 2.5 kb) and 9 introns (343 bp to 19 kb).
Consensus elements for transcription factors involved in T-cell
development and activation were noted in the putative promoter region.

GENE FUNCTION

TNFBR (TNFR75) is the larger of the 2 TNF receptors; see 191190. It is
present on many cell types, especially those of myeloid origin, and is
strongly expressed on stimulated T and B lymphocytes. Beltinger et al.
(1996) noted that TNFR2 is the main TNF receptor found on circulating T
cells and is the major mediator of autoregulatory apoptosis in CD8+
cells. TNFR2 may act with TNFR1 to kill nonlymphoid cells.

Preassembly or self-association of cytokine receptor dimers (e.g., IL1R,
see 147810; IL2R, 147730; and EPOR, 133171) occurs via the same amino
acid contacts that are critical for ligand binding. Chan et al. (2000)
found that, in contrast, the p60 (TNFRSF1A; 191190) and p80 (TNFRSF1B)
TNFA receptors self-assemble through a distinct functional domain in the
TNFR extracellular domain, termed the pre-ligand assembly domain (PLAD),
in the absence of ligand. Deletion of the PLAD results in monomeric
presentation of p60 or p80. Flow cytometric analysis showed that
efficient TNFA binding depends on receptor self-assembly. They also
found that other members of the TNF receptor superfamily, including the
extracellular domains of TRAIL (TNFRSF10A; 603611), CD40 (109535), and
FAS (TNFRSF6; 134637), all self-associate but do not interact with
heterologous receptors.

Using Jurkat T cells, which express TNFR1 but little TNFR2, and Jurkat
cells stably transfected with TNFR2, Li et al. (2002) confirmed that TNF
stimulation, or stimulation with a TNFR2, but not TNFR1, agonist, causes
a loss of TRAF2 (601895) in the TNFR2-expressing cells, but not the
parental cell line, through a ubiquitination- and proteasome-dependent
process. Binding analysis indicated that TRAF2 interacts with CIAP1
(601712) and CIAP2 (601721), which possess E3 ubiquitin ligase (e.g.
UBE3A, 601623) activity. Ubiquitination assays and SDS-PAGE analysis
showed that in the presence of an E2-conjugating enzyme (e.g., UBCH7,
603721), CIAP1, but not CIAP2, induces TRAF2 ubiquitination outside of
its RING domain. Both CIAPs bind but neither ubiquitinates TRAF1
(601711). CIAP1 expression fails to protect TNFR2-expressing cells from
TNF-induced apoptosis, whereas an E3-inactive CIAP1 mutant and wildtype
CIAP2 do protect cells from TRAF2 downregulation and cause a delay in
cell death. Li et al. (2002) concluded that TNFR2 stimulation causes the
ubiquitination of TRAF2 by CIAP1, which can play a proapoptotic role in
TNF signaling.

Tang et al. (2011) reported that PGRN (138945) bound directly to tumor
necrosis factor receptors (TNFR1 and TNRF2) and disturbed the TNFA-TNFR
interaction. Pgrn-deficient mice were susceptible to collagen-induced
arthritis, and administration of PGRN reversed inflammatory arthritis.
Atsttrin, an engineered protein composed of 3 PGRN fragments, exhibited
selective TNFR binding. PGRN and Atsttrin prevented inflammation in
multiple arthritis mouse models and inhibited TNFA-activated
intracellular signaling. Tang et al. (2011) concluded that PGRN is a
ligand of TNFR, an antagonist of TNFA signaling, and plays a critical
role in the pathogenesis of inflammatory arthritis in mice.

MAPPING

By Southern blot analysis of human/Chinese hamster somatic cell hybrid
DNA, Milatovich et al. (1991) mapped the TNFR2 gene to 1pter-p32. By in
situ hybridization and Southern blot analysis of a series of human/mouse
hybrid cell lines, Baker et al. (1991) refined the assignment of TNFR2
to 1p36. By nonradioactive in situ hybridization, Kemper et al. (1991)
assigned the gene to 1p36.3-p36.2. Using an SSCP polymorphism of the
TNFR2 gene, Kaufman et al. (1994) demonstrated that TNFR2 is very
closely linked to the pronatriodilatin gene (108780).

White et al. (1995) showed that TNFR2 maps outside the region of
1p36.3-p36.2 thought by loss of heterozygosity (LOH) studies to contain
the neuroblastoma tumor suppressor locus (256700).

By linkage analysis, Santee and Owen Schaub (1996) confirmed the mapping
of the TNFR2 gene to 1p36.3-p36.2.

MOLECULAR GENETICS

Glenn et al. (2000) tested markers in and near the TNFR2 gene for
linkage and association with hypertension (145500) as well as
hypercholesterolemia and plasma levels of the shed soluble receptor
(sTNF-R2). Using sib pair analysis, they reported a sharp, significant
linkage peak centered at TNFRSF1B (multipoint maximum lod score = 2.6
and 3.1 by weighted and unweighted MAPMAKER/SIBS, respectively). In a
case-control study, they demonstrated a possible association of TNFRSF1B
with hypertension by haplotype analysis. Plasma sTNF-R2 was
significantly elevated in hypertensives and showed a correlation with
systolic and diastolic blood pressure. A genotypic effect of TNFRSF1B on
plasma sTNF-R2, as well as total, low, and high density lipoprotein
cholesterol, and diastolic blood pressure was also observed. The authors
proposed a scheme for involvement of TNF and its receptors in
hypertension and hypercholesterolemia.

Geurts et al. (2000) conducted a genomic scan in 18 Dutch familial
combined hyperlipidemia (FCHL; 144250) families and identified several
loci with evidence for linkage. Linear regression analysis using 79
independent sib pairs showed linkage with a quantitative FCHL
discriminant function and the intron 4 (CA)n polymorphism of TNFRSF1B (P
= 0.032), and a case-control study demonstrated an association as well
(P = 0.029). Mutation analysis of exon 6 in 73 FCHL family members
delineated 2 TNFRSF1B alleles, coding for methionine (196M) and arginine
(196R). Complete linkage disequilibrium between CA267, CA271, and CA273
and this polymorphism was detected. In 85 hyperlipidemic FCHL subjects,
an association was demonstrated between soluble TNFRSF1B plasma
concentrations and the CA271-196M haplotype. The authors concluded that
TNFRSF1B is associated with susceptibility to FCHL.

In Japan, Sashio et al. (2002) examined polymorphisms of the tumor
necrosis factor gene (TNFA; 191160) and the TNFRSF1B gene in patients
with inflammatory bowel disease (see IBD1, 266600), including 124 with
Crohn disease and 106 with ulcerative colitis, and 111 unrelated healthy
controls. They studied 2 SNPs: 1466A-G and 1493C-T. They found a
significant difference in carrier frequency for haplotype AT (1466A,
1493T) of the TNFRSF1B gene between Crohn disease patients and the
controls (odds ratio = 2.13). Significance proved to be greater in Crohn
disease patients with both internal and external fistula, and in those
who were poor responders to treatment, which consisted of nutritional,
medical, and surgical therapy.

Peral et al. (2002) evaluated serum soluble TNF receptor-2 levels, and
several common polymorphisms in the TNFRSF1B gene, in women presenting
with polycystic ovary syndrome (PCOS; 184700) or hyperandrogenic
disorders. The 196R alleles of the M196R (676T-G) variant in exon 6 of
TNFRSF1B, which is in linkage disequilibrium with a CA repeat
microsatellite polymorphism in intron 4 of TNFRSF1B, tended to be more
frequent in hyperandrogenic patients than in controls (P = 0.056),
reaching statistical significance when the analysis was restricted to
include only PCOS patients (P less than 0.03). Extended analysis
including another 11 hyperandrogenic patients from Spain and 64 patients
and 29 controls from Italy confirmed the association between 196R
alleles of the M196R variant and hyperandrogenic disorders (P less than
0.05), which was maintained when restricting the analysis to PCOS
patients (P less than 0.02). On the contrary, the 3-prime-untranslated
region (exon 10) variants 1663G-A, 1668T-G, and 1690T-C were not
associated with hyperandrogenism. The authors concluded that the M196R
variant in exon 6 of TNFRSF1B is associated with hyperandrogenism and
PCOS, further suggesting a role for inflammatory cytokines in the
pathogenesis of these disorders.

One of the candidate loci for regulation of hip bone mineral density
(BMD) is on chromosome 1p36 (BMND3; 606928). Albagha et al. (2002)
studied several TNFRSF1B polymorphisms in a population-based cohort
study of 1,240 perimenopausal women from the UK. The authors found no
association between 676T-G (met196-to-arg) alleles and BMD at the spine
or hip. However, subjects homozygous for the A593-T598-C620 haplotype in
the 3-prime UTR region had femoral neck BMD values 5.7% lower than those
who did not carry the haplotype (P less than 0.0001). Regression
analysis showed that the ATC haplotype accounted for 1.2% of the
population variance in hip BMD and was the second strongest predictor
after body weight.

Xu et al. (2005) analyzed the (CA)n polymorphism in intron 4 of the
TNFRSF1B gene and BMD in 1,263 Chinese individuals from 402 nuclear
families composed of both parents and at least 1 daughter. Significant
within-family association was detected between the CA16 allele and BMD
at the lumbar spine (p = 0.005); about 3.14% of lumbar spine BMD
variation could be explained by the CA16 allele.

Fairfax et al. (2011) identified a haplotype marked by a SNP (dbSNP
rs522807) in the TNFR2 promoter that was strongly associated with
reduced tolerance to lipopolysaccharide (LPS). The haplotype was
associated with increased expression of TNFR2, and basal TNFR2
expression was associated with secondary TNF release. Fairfax et al.
(2011) reported that the tolerance-associated ancestral allele of dbSNP
rs522807 is present at a frequency of 8% in northern Europeans, is
absent in Asians, and is present at a frequency of approximately 50% in
equatorial Africans.

ANIMAL MODEL

Bruce et al. (1996) used targeted gene disruption to generate mice
lacking either the p55 (TNFR1) or the p75 (TNFR2) TNF receptor; mice
lacking both p55 and p75 were generated from crosses of the singly
deficient mice. The TNFR-deficient (TNFR-KO) mice exhibited no overt
phenotype under unchallenged conditions. Bruce et al. (1996) reported
that damage to neurons caused by focal cerebral ischemia and epileptic
seizures was exacerbated in the TNFR-KO mice, indicating that TNF serves
a neuroprotective function. Their studies indicated that TNF protects
neurons by stimulating antioxidative pathways. Injury-induced microglial
activation was suppressed in TNFR-KO mice. They concluded that drugs
which target TNF signaling pathways may prove beneficial in treating
stroke or traumatic brain injury.

Vielhauer et al. (2005) studied immune complex-mediated
glomerulonephritis in Tnfr1- and Tnfr2-deficient mice. Proteinuria and
renal pathology were initially milder in Tnfr1-deficient mice, but at
later time points were similar to those in wildtype controls, with
excessive renal T-cell accumulation and reduced T-cell apoptosis. In
contrast, Tnfr2-deficient mice were completely protected from
glomerulonephritis at all time points, despite an intact immune system
response. Tnfr2 expression on intrinsic renal cells, but not leukocytes,
was essential for glomerulonephritis and glomerular complement
deposition. Vielhauer et al. (2005) concluded that the proinflammatory
and immunosuppressive properties of TNF segregate at the level of its
receptors, with TNFR1 promoting systemic immune responses and renal
T-cell death and intrinsic renal cell TNFR2 playing a critical role in
complement-dependent tissue injury.

*FIELD* RF
1. Albagha, O. M. E.; Tasker, P. N.; McGuigan, F. E. A.; Reid, D.
M.; Ralston, S. H.: Linkage disequilibrium between polymorphisms
in the human TNFRSF1B gene and their association with bone mass in
perimenopausal women. Hum. Molec. Genet. 11: 2289-2295, 2002.

2. Baker, E.; Chen, L. Z.; Smith, C. A.; Callen, D. F.; Goodwin, R.;
Sutherland, G. R.: Chromosomal location of the human tumor necrosis
factor receptor genes. Cytogenet. Cell Genet. 57: 117-118, 1991.

3. Beltinger, C. P.; White, P. S.; Maris, J. M.; Sulman, E. P.; Jensen,
S. J.; LePaslier, D.; Stallard, B. J.; Goeddel, D. V.; de Sauvage,
F. J.; Brodeur, G. M.: Physical mapping and genomic structure of
the human TNFR2 gene. Genomics 35: 94-100, 1996.

4. Bruce, A. J.; Boling, W.; Kindy, M. S.; Peschon, J.; Kraemer, P.
J.; Carpenter, M. K.; Holtsberg, F. W.; Mattson, M. P.: Altered neuronal
and microglial responses to excitotoxic and ischemic brain injury
in mice lacking TNF receptors. Nature Med. 2: 788-794, 1996.

5. Chan, F. K.-M.; Chun, H. J.; Zheng, L.; Siegel, R. M.; Bui, K.
L.; Lenardo, M. J.: A domain in TNF receptors that mediates ligand-independent
receptor assembly and signaling. Science 288: 2351-2354, 2000.

6. Fairfax, B. P.; Davenport, E. E.; Makino, S.; Hill, A. V. S.; Vannberg,
F. O.; Knight, J. C.: A common haplotype of the TNF receptor 2 gene
modulates endotoxin tolerance. J. Immun. 186: 3058-3065, 2011.

7. Geurts, J. M. W.; Janssen, R. G. J. H.; van Greevenbroek, M. M.
J.; van der Kallen, C. J. H.; Cantor, R. M.; Bu, X.; Aouizerat, B.
E.; Allayee, H.; Rotter, J. I.; de Bruin, T. W. A.: Identification
of TNFRSF1B as a novel modifier gene in familial combined hyperlipidemia. Hum.
Molec. Genet. 9: 2067-2074, 2000.

8. Glenn, C. L.; Wang, W. Y. S.; Benjafield, A. V.; Morris, B. J.
: Linkage and association of tumor necrosis factor receptor 2 locus
with hypertension, hypercholesterolemia and plasma shed receptor. Hum.
Molec. Genet. 9: 1943-1949, 2000.

9. Kaufman, B. A.; White, P. S.; Steinbrueck, T.; Donis-Keller, H.;
Brodeur, G. M.: Linkage mapping of the tumor necrosis factor receptor
2 (TNFR2) gene to 1p36.2 using the single-strand conformation polymorphism
technique. Hum. Genet. 94: 418-422, 1994.

10. Kemper, O.; Derre, J.; Cherif, D.; Engelmann, H.; Wallach, D.;
Berger, R.: The gene for the type II (p75) tumor necrosis factor
receptor (TNF-RII) is localized on band 1p36.2-p36.3. Hum. Genet. 87:
623-624, 1991.

11. Li, X.; Yang, Y.; Ashwell, J. D.: TNF-RII and c-IAP1 mediate
ubiquitination and degradation of TRAF2. Nature 416: 345-349, 2002.

12. Milatovich, A.; Song, K.; Heller, R. A.; Francke, U.: Tumor necrosis
factor receptor genes, TNFR1 and TNFR2, on human chromosomes 12 and
1. Somat. Cell Molec. Genet. 17: 519-523, 1991.

13. Peral, B.; San Millan, J. L.; Castello, R.; Moghetti, P.; Escobar-Morreale,
H. F.: The methionine 196 arginine polymorphism in exon 6 of the
TNF receptor 2 gene (TNFRSF1B) is associated with the polycystic ovary
syndrome and hyperandrogenism. J. Clin. Endocr. Metab. 87: 3977-3983,
2002.

14. Santee, S. M.; Owen-Schaub, L. B.: Human tumor necrosis factor
receptor p75/80 (CD120b) gene structure and promoter characterization. J.
Biol. Chem. 271: 21151-21159, 1996.

15. Sashio, H.; Tamura, K.; Ito, R.; Yamamoto, Y.; Bamba, H.; Kosaka,
T.; Fukui, S.; Sawada, K.; Fukuda, Y.; Tamura, K.; Satomi, M.; Shimoyama,
T.; Furuyama, J.: Polymorphisms of the TNF gene and the TNF receptor
superfamily member 1B gene are associated with susceptibility to ulcerative
colitis and Crohn's disease, respectively. Immunogenetics 53: 1020-1027,
2002.

16. Schall, T. J.; Lewis, M.; Koller, K. J.; Lee, A.; Rice, G. C.;
Wong, G. H. W.; Gatanaga, T.; Granger, G. A.; Lentz, R.; Raab, H.;
Kohr, W. J.; Goeddel, D. V.: Molecular cloning and expression of
a receptor for human tumor necrosis factor. Cell 61: 361-370, 1990.

17. Tang, W.; Lu, Y.; Tian, Q.-Y.; Zhang, Y.; Guo, F.-J.; Liu, G.-Y.;
Syed, N. M.; Lai, Y.; Lin, E. A.; Kong, L.; Su, J.; Yin, F.; and
10 others: The growth factor progranulin binds to TNF receptors
and is therapeutic against inflammatory arthritis in mice. Science 332:
478-484, 2011.

18. Vielhauer, V.; Stavrakis, G.; Mayadas, T. N.: Renal cell-expressed
TNF receptor 2, not receptor 1, is essential for the development of
glomerulonephritis. J. Clin. Invest. 115: 1199-1209, 2005.

19. White, P. S.; Maris, J. M.; Beltinger, C.; Sulman, E.; Marshall,
H. N.; Fujimori, M.; Kaufman, B. A.; Biegel, J. A.; Allen, C.; Hilliard,
C.; Valentine, M. B.; Look, A. T.; Enomoto, H.; Sakiyama, S.; Brodeur,
G. M.: A region of consistent deletion in neuroblastoma maps within
human chromosome 1p36.2-36.3. Proc. Nat. Acad. Sci. 92: 5520-5524,
1995.

20. Xu, H.; Zhao, L.-J.; Lei, S.-F.; Li, M.-X.; Sun, X.; Deng, F.-Y.;
Jiang, D.-K.; Deng, H.-W.: The (CA)n polymorphism of the TNFR2 gene
is associated with peak bone density in Chinese nuclear families. J.
Hum. Genet. 50: 301-304, 2005.

*FIELD* CN
Ada Hamosh - updated: 7/8/2011
Paul J. Converse - updated: 4/21/2011
Marla J. F. O'Neill - updated: 8/30/2006
Marla J. F. O'Neill - updated: 5/20/2005
George E. Tiller - updated: 6/24/2003
John A. Phillips, III - updated: 1/28/2003
Victor A. McKusick - updated: 5/23/2002
Paul J. Converse - updated: 3/20/2002
George E. Tiller - updated: 11/17/2000
George E. Tiller - updated: 10/25/2000
Paul J. Converse - updated: 6/29/2000
Lori M. Kelman - updated: 11/13/1996
Alan F. Scott - updated: 9/19/1996
Moyra Smith - updated: 9/11/1996

*FIELD* CD
Victor A. McKusick: 8/19/1991

*FIELD* ED
alopez: 07/11/2011
terry: 7/8/2011
mgross: 5/5/2011
terry: 4/21/2011
carol: 9/21/2009
terry: 2/2/2009
carol: 10/29/2008
carol: 3/16/2007
wwang: 9/7/2006
terry: 8/30/2006
wwang: 10/27/2005
wwang: 5/23/2005
terry: 5/20/2005
cwells: 6/24/2003
alopez: 1/28/2003
cwells: 6/4/2002
terry: 5/23/2002
terry: 5/22/2002
alopez: 3/20/2002
mcapotos: 12/4/2000
mcapotos: 11/27/2000
terry: 11/17/2000
mcapotos: 11/1/2000
mcapotos: 10/25/2000
carol: 6/29/2000
carol: 12/21/1998
terry: 6/1/1998
terry: 7/10/1997
jamie: 2/5/1997
jamie: 11/13/1996
terry: 9/20/1996
mark: 9/19/1996
mark: 9/11/1996
mark: 8/27/1996
mark: 6/29/1995
terry: 12/19/1994
carol: 2/5/1993
supermim: 3/16/1992
carol: 2/23/1992
carol: 2/18/1992