RBCC Red Blood Cell Collection

ITGB3 (GP3A) [Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Integrin beta-3 (Platelet membrane glycoprotein IIIa; GPIIIa; CD61; Flags: Precursor)

UniProt P05106
ID ITB3_HUMAN Reviewed; 788 AA.
AC P05106; A0PJW2; D3DXJ8; O15495; Q12806; Q13413; Q14648; Q16499;
read moreDT 13-AUG-1987, integrated into UniProtKB/Swiss-Prot.
DT 06-FEB-2007, sequence version 2.
DT 22-JAN-2014, entry version 198.
DE RecName: Full=Integrin beta-3;
DE AltName: Full=Platelet membrane glycoprotein IIIa;
DE Short=GPIIIa;
DE AltName: CD_antigen=CD61;
DE Flags: Precursor;
GN Name=ITGB3; Synonyms=GP3A;
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 BETA-3A).
RX PubMed=3494014;
RA Fitzgerald L.A., Steiner B., Rall S.C. Jr., Lo S., Phillips D.R.;
RT "Protein sequence of endothelial glycoprotein IIIa derived from a cDNA
RT clone. Identity with platelet glycoprotein IIIa and similarity to
RT 'integrin'.";
RL J. Biol. Chem. 262:3936-3939(1987).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM BETA-3A).
RX PubMed=2452834; DOI=10.1172/JCI113478;
RA Zimrin A.B., Eisman R., Vilaire G., Schwartz E., Bennett J.S.,
RA Poncz M.;
RT "Structure of platelet glycoprotein IIIa. A common subunit for two
RT different membrane receptors.";
RL J. Clin. Invest. 81:1470-1475(1988).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM BETA-3A).
RX PubMed=2345548; DOI=10.1007/BF00422712;
RA Frachet P., Uzan G., Thevenon D., Denarier E., Prandini M.H.,
RA Marguerie G.;
RT "GPIIb and GPIIIa amino acid sequences deduced from human
RT megakaryocyte cDNAs.";
RL Mol. Biol. Rep. 14:27-33(1990).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM BETA-3C).
RC TISSUE=Osteoclastoma;
RX PubMed=9195946; DOI=10.1074/jbc.272.26.16390;
RA Kumar C.S., James I.E., Wong A., Mwangi V., Feild J.A.,
RA Nuthulaganti P., Connor J.R., Eichman C., Ali F., Hwang S.M.,
RA Rieman D.J., Drake F.H., Gowen M.;
RT "Cloning and characterization of a novel integrin beta3 subunit.";
RL J. Biol. Chem. 272:16390-16397(1997).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM BETA-3A).
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [7]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-26.
RC TISSUE=Blood;
RX PubMed=8298129;
RA Villa-Garcia M., Li L., Riely G., Bray P.F.;
RT "Isolation and characterization of a TATA-less promoter for the human
RT beta 3 integrin gene.";
RL Blood 83:668-676(1994).
RN [8]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 11-788.
RC TISSUE=Erythroleukemia;
RX PubMed=3165296;
RA Rosa J.P., Bray P.F., Gayet O., Johnston G.I., Cook R.G.,
RA Jackson K.W., Shuman M.A., McEver R.P.;
RT "Cloning of glycoprotein IIIa cDNA from human erythroleukemia cells
RT and localization of the gene to chromosome 17.";
RL Blood 72:593-600(1988).
RN [9]
RP PROTEIN SEQUENCE OF 27-37.
RC TISSUE=Platelet;
RX PubMed=1953640;
RA Catimel B., Parmentier S., Leung L.L., McGregor J.L.;
RT "Separation of important new platelet glycoproteins (GPIa, GPIc,
RT GPIc*, GPIIa and GMP-140) by F.P.L.C. Characterization by monoclonal
RT antibodies and gas-phase sequencing.";
RL Biochem. J. 279:419-425(1991).
RN [10]
RP PROTEIN SEQUENCE OF 27-34.
RC TISSUE=Platelet;
RX PubMed=12665801; DOI=10.1038/nbt810;
RA Gevaert K., Goethals M., Martens L., Van Damme J., Staes A.,
RA Thomas G.R., Vandekerckhove J.;
RT "Exploring proteomes and analyzing protein processing by mass
RT spectrometric identification of sorted N-terminal peptides.";
RL Nat. Biotechnol. 21:566-569(2003).
RN [11]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 28-788.
RX PubMed=2341395;
RA Zimrin A.B., Gidwitz S., Lord S., Schwartz E., Bennett J.S.,
RA White G.C. II, Poncz M.;
RT "The genomic organization of platelet glycoprotein IIIa.";
RL J. Biol. Chem. 265:8590-8595(1990).
RN [12]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 28-788.
RX PubMed=2145280;
RA Lanza F., Kieffer N., Phillips D.R., Fitzgerald L.A.;
RT "Characterization of the human platelet glycoprotein IIIa gene.
RT Comparison with the fibronectin receptor beta-subunit gene.";
RL J. Biol. Chem. 265:18098-18103(1990).
RN [13]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 56-120, AND VARIANTS PRO-59 AND
RP ARG-66.
RC TISSUE=Blood;
RA Pascual C., Balas A., Garcia-Sanchez F., Rodriguez de la Rua A.,
RA Vicario J.L.;
RT "A new exon II polymorphism in the platelet glycoprotein IIIa.";
RL Submitted (DEC-1993) to the EMBL/GenBank/DDBJ databases.
RN [14]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 122-204.
RX PubMed=1382574; DOI=10.1093/intimm/4.9.1031;
RA Jiang W.-M., Jenkins D., Yuan Q., Leung E., Choo K.H., Watson J.D.,
RA Krissansen G.W.;
RT "The gene organization of the human beta 7 subunit, the common beta
RT subunit of the leukocyte integrins HML-1 and LPAM-1.";
RL Int. Immunol. 4:1031-1040(1992).
RN [15]
RP PROTEIN SEQUENCE OF 218-234 AND 439-443.
RX PubMed=3801670;
RA Hiraiwa A., Matsukage A., Shiku H., Takahashi T., Naito K., Yamada K.;
RT "Purification and partial amino acid sequence of human platelet
RT membrane glycoproteins IIb and IIIa.";
RL Blood 69:560-564(1987).
RN [16]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 707-788 (ISOFORM BETA-3B).
RC TISSUE=Placenta;
RX PubMed=2787511; DOI=10.1073/pnas.86.14.5415;
RA Van Kuppevelt T.H.M.S.M., Languino L.R., Gailit J.O., Suzuki S.,
RA Ruoslahti E.;
RT "An alternative cytoplasmic domain of the integrin beta 3 subunit.";
RL Proc. Natl. Acad. Sci. U.S.A. 86:5415-5418(1989).
RN [17]
RP PARTIAL PROTEIN SEQUENCE, AND DISULFIDE BONDS.
RX PubMed=2001252;
RA Calvete J.J., Henschen A., Gonzalez-Rodriguez J.;
RT "Assignment of disulphide bonds in human platelet GPIIIa. A disulphide
RT pattern for the beta-subunits of the integrin family.";
RL Biochem. J. 274:63-71(1991).
RN [18]
RP PHOSPHORYLATION AT TYR-773 AND TYR-785 (ISOFORM BETA-3A).
RX PubMed=8631894; DOI=10.1074/jbc.271.18.10811;
RA Law D.A., Nannizzi-Alaimo L., Phillips D.R.;
RT "Outside-in integrin signal transduction. Alpha IIb beta 3-(GP IIb
RT IIIa) tyrosine phosphorylation induced by platelet aggregation.";
RL J. Biol. Chem. 271:10811-10815(1996).
RN [19]
RP INTERACTION WITH HIV-1 TAT.
RX PubMed=10397733;
RA Barillari G., Sgadari C., Fiorelli V., Samaniego F., Colombini S.,
RA Manzari V., Modesti A., Nair B.C., Cafaro A., Stuerzl M., Ensoli B.;
RT "The Tat protein of human immunodeficiency virus type-1 promotes
RT vascular cell growth and locomotion by engaging the alpha5beta1 and
RT alphavbeta3 integrins and by mobilizing sequestered basic fibroblast
RT growth factor.";
RL Blood 94:663-672(1999).
RN [20]
RP PHOSPHORYLATION AT THR-779.
RX PubMed=10896934; DOI=10.1074/jbc.M001908200;
RA Kirk R.I., Sanderson M.R., Lerea K.M.;
RT "Threonine phosphorylation of the beta 3 integrin cytoplasmic tail, at
RT a site recognized by PDK1 and Akt/PKB in vitro, regulates Shc
RT binding.";
RL J. Biol. Chem. 275:30901-30906(2000).
RN [21]
RP INTERACTION WITH SYK.
RX PubMed=11940607; DOI=10.1083/jcb.200112113;
RA Obergfell A., Eto K., Mocsai A., Buensuceso C., Moores S.L.,
RA Brugge J.S., Lowell C.A., Shattil S.J.;
RT "Coordinate interactions of Csk, Src, and Syk kinases with
RT [alpha]IIb[beta]3 initiate integrin signaling to the cytoskeleton.";
RL J. Cell Biol. 157:265-275(2002).
RN [22]
RP INTERACTION WITH FLNB.
RC TISSUE=Keratinocyte, and Skeletal muscle;
RX PubMed=11807098; DOI=10.1083/jcb.200103037;
RA van Der Flier A., Kuikman I., Kramer D., Geerts D., Kreft M.,
RA Takafuta T., Shapiro S.S., Sonnenberg A.;
RT "Different splice variants of filamin-B affect myogenesis, subcellular
RT distribution, and determine binding to integrin (beta) subunits.";
RL J. Cell Biol. 156:361-376(2002).
RN [23]
RP INTERACTION WITH MYO10.
RX PubMed=15156152; DOI=10.1038/ncb1136;
RA Zhang H., Berg J.S., Li Z., Wang Y., Lang P., Sousa A.D., Bhaskar A.,
RA Cheney R.E., Stromblad S.;
RT "Myosin-X provides a motor-based link between integrins and the
RT cytoskeleton.";
RL Nat. Cell Biol. 6:523-531(2004).
RN [24]
RP INTERACTION WITH PDIA6.
RX PubMed=15466936; DOI=10.1182/blood-2004-02-0608;
RA Jordan P.A., Stevens J.M., Hubbard G.P., Barrett N.E., Sage T.,
RA Authi K.S., Gibbins J.M.;
RT "A role for the thiol isomerase protein ERP5 in platelet function.";
RL Blood 105:1500-1507(2005).
RN [25]
RP INTERACTION WITH COMP.
RX PubMed=16051604; DOI=10.1074/jbc.M504778200;
RA Chen F.-H., Thomas A.O., Hecht J.T., Goldring M.B., Lawler J.;
RT "Cartilage oligomeric matrix protein/thrombospondin 5 supports
RT chondrocyte attachment through interaction with integrins.";
RL J. Biol. Chem. 280:32655-32661(2005).
RN [26]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-125, AND MASS
RP SPECTROMETRY.
RC TISSUE=Plasma;
RX PubMed=16335952; DOI=10.1021/pr0502065;
RA Liu T., Qian W.-J., Gritsenko M.A., Camp D.G. II, Monroe M.E.,
RA Moore R.J., Smith R.D.;
RT "Human plasma N-glycoproteome analysis by immunoaffinity subtraction,
RT hydrazide chemistry, and mass spectrometry.";
RL J. Proteome Res. 4:2070-2080(2005).
RN [27]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-125, AND MASS
RP SPECTROMETRY.
RC TISSUE=Platelet;
RX PubMed=16263699; DOI=10.1074/mcp.M500324-MCP200;
RA Lewandrowski U., Moebius J., Walter U., Sickmann A.;
RT "Elucidation of N-glycosylation sites on human platelet proteins: a
RT glycoproteomic approach.";
RL Mol. Cell. Proteomics 5:226-233(2006).
RN [28]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-773, AND MASS
RP SPECTROMETRY.
RC TISSUE=Platelet;
RX PubMed=18088087; DOI=10.1021/pr0704130;
RA Zahedi R.P., Lewandrowski U., Wiesner J., Wortelkamp S., Moebius J.,
RA Schuetz C., Walter U., Gambaryan S., Sickmann A.;
RT "Phosphoproteome of resting human platelets.";
RL J. Proteome Res. 7:526-534(2008).
RN [29]
RP INTERACTION WITH HHV-8 GLYCOPROTEIN B.
RX PubMed=18045938; DOI=10.1128/JVI.01673-07;
RA Garrigues H.J., Rubinchikova Y.E., Dipersio C.M., Rose T.M.;
RT "Integrin alphaVbeta3 Binds to the RGD motif of glycoprotein B of
RT Kaposi's sarcoma-associated herpesvirus and functions as an RGD-
RT dependent entry receptor.";
RL J. Virol. 82:1570-1580(2008).
RN [30]
RP IDENTIFICATION OF ALLOANTIGEN HPA-1A BY MASS SPECTROMETRY, AND
RP ASSOCIATION TO ALLELE HLA-DRB3*01:01.
RX PubMed=19494351; DOI=10.1182/blood-2009-04-211839;
RA Anani Sarab G., Moss M., Barker R.N., Urbaniak S.J.;
RT "Naturally processed peptides spanning the HPA-1a polymorphism are
RT efficiently generated and displayed from platelet glycoprotein by HLA-
RT DRB3*0101-positive antigen-presenting cells.";
RL Blood 114:1954-1957(2009).
RN [31]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-680, AND MASS
RP SPECTROMETRY.
RC TISSUE=Liver;
RX PubMed=19159218; DOI=10.1021/pr8008012;
RA Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H.;
RT "Glycoproteomics analysis of human liver tissue by combination of
RT multiple enzyme digestion and hydrazide chemistry.";
RL J. Proteome Res. 8:651-661(2009).
RN [32]
RP INTERACTION WITH FERMT2, AND SUBCELLULAR LOCATION.
RX PubMed=20702409; DOI=10.1074/jbc.C110.134247;
RA Bledzka K., Bialkowska K., Nie H., Qin J., Byzova T., Wu C.,
RA Plow E.F., Ma Y.Q.;
RT "Tyrosine phosphorylation of integrin beta3 regulates kindlin-2
RT binding and integrin activation.";
RL J. Biol. Chem. 285:30370-30374(2010).
RN [33]
RP X-RAY CRYSTALLOGRAPHY (3.1 ANGSTROMS) OF 27-718.
RX PubMed=11546839; DOI=10.1126/science.1064535;
RA Xiong J.P., Stehle T., Diefenbach B., Zhang R., Dunker R., Scott D.L.,
RA Joachimiak A., Goodman S.L., Arnaout M.A.;
RT "Crystal structure of the extracellular segment of integrin alpha
RT Vbeta3.";
RL Science 294:339-345(2001).
RN [34]
RP X-RAY CRYSTALLOGRAPHY (2.25 ANGSTROMS) OF 50-61 (ALLOANTIGEN HPA-1A)
RP IN COMPLEX WITH HLA-DRA/HLA-DRB3 HETERODIMER.
RX PubMed=17583734; DOI=10.1016/j.jmb.2007.05.025;
RA Parry C.S., Gorski J., Stern L.J.;
RT "Crystallographic structure of the human leukocyte antigen DRA,
RT DRB3*0101: models of a directional alloimmune response and
RT autoimmunity.";
RL J. Mol. Biol. 371:435-446(2007).
RN [35]
RP REVIEW ON GT VARIANTS.
RX PubMed=7878622;
RA Bray P.F.;
RT "Inherited diseases of platelet glycoproteins: considerations for
RT rapid molecular characterization.";
RL Thromb. Haemost. 72:492-502(1994).
RN [36]
RP VARIANT HPA-1B PRO-59, AND DESCRIPTION OF ALLOANTIGEN SYSTEM PL(A).
RX PubMed=2565345; DOI=10.1172/JCI114082;
RA Newman P.J., Derbes R.S., Aster R.H.;
RT "The human platelet alloantigens, PlA1 and PlA2, are associated with a
RT leucine33/proline33 amino acid polymorphism in membrane glycoprotein
RT IIIa, and are distinguishable by DNA typing.";
RL J. Clin. Invest. 83:1778-1781(1989).
RN [37]
RP VARIANT HPA-4B GLN-169, AND DESCRIPTION OF ALLOANTIGEN SYSTEM PEN.
RX PubMed=1430225; DOI=10.1172/JCI116084;
RA Wang R., Furihata K., McFarland J.G., Friedman K., Aster R.H.,
RA Newman P.J.;
RT "An amino acid polymorphism within the RGD binding domain of platelet
RT membrane glycoprotein IIIa is responsible for the formation of the
RT Pena/Penb alloantigen system.";
RL J. Clin. Invest. 90:2038-2043(1992).
RN [38]
RP VARIANT MO(+) ALA-433.
RX PubMed=8093349;
RA Kuijpers R.W.A.M., Simsek S., Faber N.M., Goldschmeding R.,
RA van Wermerkerken R.K.V., von Dem Borne A.E.G.K.;
RT "Single point mutation in human glycoprotein IIIa is associated with a
RT new platelet-specific alloantigen (Mo) involved in neonatal alloimmune
RT thrombocytopenia.";
RL Blood 81:70-76(1993).
RN [39]
RP VARIANT CA(+)/TU(+) GLN-515, AND DESCRIPTION OF ALLOANTIGEN SYSTEM
RP CA/TU.
RX PubMed=7694683;
RA Wang R., McFarland J.G., Kekomaki R., Newman P.J.;
RT "Amino acid 489 is encoded by a mutational 'hot spot' on the beta 3
RT integrin chain: the CA/TU human platelet alloantigen system.";
RL Blood 82:3386-3391(1993).
RN [40]
RP VARIANT SR(A) CYS-662, AND DESCRIPTION OF ALLOANTIGEN SYSTEM SR(A).
RX PubMed=8132570;
RA Santoso S., Kalb R., Kroll H., Walka M., Kiefel V.,
RA Mueller-Eckhardt C., Newman P.J.;
RT "A point mutation leads to an unpaired cysteine residue and a
RT molecular weight polymorphism of a functional platelet beta 3 integrin
RT subunit. The Sra alloantigen system of GPIIIa.";
RL J. Biol. Chem. 269:8439-8444(1994).
RN [41]
RP VARIANT GT TYR-145.
RX PubMed=2392682; DOI=10.1126/science.2392682;
RA Loftus J.C., O'Toole T.E., Plow E.F., Glass A., Frelinger A.L. III,
RA Ginsberg M.H.;
RT "A beta 3 integrin mutation abolishes ligand binding and alters
RT divalent cation-dependent conformation.";
RL Science 249:915-918(1990).
RN [42]
RP VARIANT GT GLN-240.
RX PubMed=1371279;
RA Bajt M.L., Ginsberg M.H., Frelinger A.L. III, Berndt M.C.,
RA Loftus J.C.;
RT "A spontaneous mutation of integrin alpha IIb beta 3 (platelet
RT glycoprotein IIb-IIIa) helps define a ligand binding site.";
RL J. Biol. Chem. 267:3789-3794(1992).
RN [43]
RP VARIANT GT TRP-240.
RX PubMed=1602006; DOI=10.1172/JCI115808;
RA Lanza F., Stierle A., Fournier D., Morales M., Andre G., Nurden A.T.,
RA Cazenave J.-P.;
RT "A new variant of Glanzmann's thrombasthenia (Strasbourg I). Platelets
RT with functionally defective glycoprotein IIb-IIIa complexes and a
RT glycoprotein IIIa 214Arg-->214Trp mutation.";
RL J. Clin. Invest. 89:1995-2004(1992).
RN [44]
RP VARIANT GT PRO-778.
RX PubMed=1438206; DOI=10.1073/pnas.89.21.10169;
RA Chen Y.-P., Djaffar I., Pidard D., Steiner B., Cieutat A.-M.,
RA Caen J.P., Rosa J.-P.;
RT "Ser-752-->Pro mutation in the cytoplasmic domain of integrin beta 3
RT subunit and defective activation of platelet integrin alpha IIb beta 3
RT (glycoprotein IIb-IIIa) in a variant of Glanzmann thrombasthenia.";
RL Proc. Natl. Acad. Sci. U.S.A. 89:10169-10173(1992).
RN [45]
RP VARIANT GT TYR-400.
RX PubMed=8781422;
RA Grimaldi C.M., Chen F., Scudder L.E., Coller B.S., French D.L.;
RT "A Cys374Tyr homozygous mutation of platelet glycoprotein IIIa (beta
RT 3) in a Chinese patient with Glanzmann's thrombasthenia.";
RL Blood 88:1666-1675(1996).
RN [46]
RP VARIANT GT TRP-143.
RX PubMed=9376589;
RA Basani R.B., Brown D.L., Vilaire G., Bennett J.S., Poncz M.;
RT "A Leu117-->Trp mutation within the RGD-peptide cross-linking region
RT of beta3 results in Glanzmann thrombasthenia by preventing alphaIIb
RT beta3 export to the platelet surface.";
RL Blood 90:3082-3088(1997).
RN [47]
RP VARIANTS GT ASN-145; GLN-242 AND PRO-288.
RX PubMed=9215749; DOI=10.1006/bcmd.1997.0117;
RA French D.L., Coller B.S.;
RT "Hematologically important mutations: Glanzmann thrombasthenia.";
RL Blood Cells Mol. Dis. 23:39-51(1997).
RN [48]
RP VARIANTS GT PRO-306; PHE-586; SER-598 AND SER-605.
RX PubMed=9790984; DOI=10.1006/bbrc.1998.9526;
RA Ambo H., Kamata T., Handa M., Taki M., Kuwajima M., Kawai Y., Oda A.,
RA Murata M., Takada Y., Watanabe K., Ikeda Y.;
RT "Three novel integrin beta3 subunit missense mutations (H280P, C560F,
RT and G579S) in thrombasthenia, including one (H280P) prevalent in
RT Japanese patients.";
RL Biochem. Biophys. Res. Commun. 251:763-768(1998).
RN [49]
RP VARIANT GT LEU-188.
RX PubMed=9684783;
RA Jackson D.E., White M.M., Jennings L.K., Newman P.J.;
RT "A Ser162-->Leu mutation within glycoprotein (GP) IIIa (integrin
RT beta3) results in an unstable alphaIIbbeta3 complex that retains
RT partial function in a novel form of type II Glanzmann
RT thrombasthenia.";
RL Thromb. Haemost. 80:42-48(1998).
RN [50]
RP VARIANT GT ARG-568.
RX PubMed=10233432; DOI=10.1046/j.1365-2141.1999.01376.x;
RA Ruan J., Schmugge M., Clemetson K.J., Cazes E., Combrie R., Bourre F.,
RA Nurden A.T.;
RT "Homozygous Cys542-->Arg substitution in GPIIIa in a Swiss patient
RT with type I Glanzmann's thrombasthenia.";
RL Br. J. Haematol. 105:523-531(1999).
RN [51]
RP VARIANTS PRO-59; GLN-169 AND ILE-453.
RX PubMed=10391209; DOI=10.1038/10290;
RA Cargill M., Altshuler D., Ireland J., Sklar P., Ardlie K., Patil N.,
RA Shaw N., Lane C.R., Lim E.P., Kalyanaraman N., Nemesh J., Ziaugra L.,
RA Friedland L., Rolfe A., Warrington J., Lipshutz R., Daley G.Q.,
RA Lander E.S.;
RT "Characterization of single-nucleotide polymorphisms in coding regions
RT of human genes.";
RL Nat. Genet. 22:231-238(1999).
RN [52]
RP ERRATUM.
RA Cargill M., Altshuler D., Ireland J., Sklar P., Ardlie K., Patil N.,
RA Shaw N., Lane C.R., Lim E.P., Kalyanaraman N., Nemesh J., Ziaugra L.,
RA Friedland L., Rolfe A., Warrington J., Lipshutz R., Daley G.Q.,
RA Lander E.S.;
RL Nat. Genet. 23:373-373(1999).
RN [53]
RP VARIANT GT ARG-586, AND CHARACTERIZATION OF VARIANT GT ARG-586.
RX PubMed=11588040; DOI=10.1182/blood.V98.8.2432;
RA Ruiz C., Liu C.-Y., Sun Q.-H., Sigaud-Fiks M., Fressinaud E.,
RA Muller J.-Y., Nurden P., Nurden A.T., Newman P.J., Valentin N.;
RT "A point mutation in the cysteine-rich domain of glycoprotein (GP)
RT IIIa results in the expression of a GPIIb-IIIa (alphaIIbbeta3)
RT integrin receptor locked in a high-affinity state and a Glanzmann
RT thrombasthenia-like phenotype.";
RL Blood 98:2432-2441(2001).
RN [54]
RP VARIANT ILE-166, AND CHARACTERIZATION OF VARIANT ILE-166.
RX PubMed=12036875; DOI=10.1182/blood.V99.12.4449;
RA Jallu V., Meunier M., Brement M., Kaplan C.;
RT "A new platelet polymorphism Duv(a+), localized within the RGD binding
RT domain of glycoprotein IIIa, is associated with neonatal
RT thrombocytopenia.";
RL Blood 99:4449-4456(2002).
RN [55]
RP VARIANT GT PRO-222.
RX PubMed=11897046; DOI=10.1080/09537100220122466;
RA Nurden A.T., Ruan J., Pasquet J.-M., Gauthier B., Combrie R.,
RA Kunicki T., Nurden P.;
RT "A novel 196Leu to Pro substitution in the beta3 subunit of the
RT alphaIIbbeta3 integrin in a patient with a variant form of Glanzmann
RT thrombasthenia.";
RL Platelets 13:101-111(2002).
RN [56]
RP VARIANTS GT TRP-119; VAL-243 AND ARG-601.
RX PubMed=12083483;
RA D'Andrea G., Colaizzo D., Vecchione G., Grandone E., Di Minno G.,
RA Margaglione M.;
RT "Glanzmann's thrombasthenia: identification of 19 new mutations in 30
RT patients.";
RL Thromb. Haemost. 87:1034-1042(2002).
RN [57]
RP VARIANT GT TYR-532.
RX PubMed=12353082; DOI=10.1267/THRO88030503;
RA Nair S., Li J., Mitchell W.B., Mohanty D., Coller B.S., French D.L.;
RT "Two new beta3 integrin mutations in Indian patients with Glanzmann
RT thrombasthenia: localization of mutations affecting cysteine residues
RT in integrin beta3.";
RL Thromb. Haemost. 88:503-509(2002).
RN [58]
RP VARIANT GT VAL-150, AND CHARACTERIZATION OF VARIANT GT VAL-150.
RX PubMed=15583747; DOI=10.1267/THRO04061377;
RA Gonzalez-Manchon C., Butta N., Larrucea S., Arias-Salgado E.G.,
RA Alonso S., Lopez A., Parrilla R.;
RT "A variant thrombasthenic phenotype associated with compound
RT heterozygosity of integrin beta3-subunit: (Met124Val)beta3 alters the
RT subunit dimerization rendering a decreased number of constitutive
RT active alphaIIbbeta3 receptors.";
RL Thromb. Haemost. 92:1377-1386(2004).
RN [59]
RP VARIANTS GT PRO-306 AND ASN-330, AND CHARACTERIZATION OF VARIANT GT
RP ASN-330.
RX PubMed=15634267; DOI=10.1111/j.1538-7836.2004.00990.x;
RA Tanaka S., Hayashi T., Yoshimura K., Nakayama M., Fujita T., Amano T.,
RA Tani Y.;
RT "Double heterozygosity for a novel missense mutation of Ile304 to Asn
RT in addition to the missense mutation His280 to Pro in the integrin
RT beta3 gene as a cause of the absence of platelet alphaIIbbeta3 in
RT Glanzmann's thrombasthenia.";
RL J. Thromb. Haemost. 3:68-73(2005).
RN [60]
RP VARIANTS GT CYS-141 AND LEU-321.
RX PubMed=15748237; DOI=10.1111/j.1538-7836.2005.01159.x;
RA Nair S., Ghosh K., Shetty S., Mohanty D.;
RT "Mutations in GPIIIa molecule as a cause for Glanzmann thrombasthenia
RT in Indian patients.";
RL J. Thromb. Haemost. 3:482-488(2005).
RN [61]
RP VARIANT BDPLT16 HIS-749, AND CHARACTERIZATION OF VARIANT BDPLT16
RP HIS-749.
RX PubMed=18065693; DOI=10.1182/blood-2007-09-112615;
RA Ghevaert C., Salsmann A., Watkins N.A., Schaffner-Reckinger E.,
RA Rankin A., Garner S.F., Stephens J., Smith G.A., Debili N.,
RA Vainchenker W., de Groot P.G., Huntington J.A., Laffan M., Kieffer N.,
RA Ouwehand W.H.;
RT "A nonsynonymous SNP in the ITGB3 gene disrupts the conserved
RT membrane-proximal cytoplasmic salt bridge in the alphaIIbbeta3
RT integrin and cosegregates dominantly with abnormal proplatelet
RT formation and macrothrombocytopenia.";
RL Blood 111:3407-3414(2008).
RN [62]
RP VARIANTS GT TYR-64; ARG-144; PRO-222; ASP-247 AND MET-279, AND
RP CHARACTERIZATION OF VARIANTS TYR-64; PRO-222; ASP-247 AND MET-279.
RX PubMed=20020534; DOI=10.1002/humu.21179;
RA Jallu V., Dusseaux M., Panzer S., Torchet M.F., Hezard N.,
RA Goudemand J., de Brevern A.G., Kaplan C.;
RT "AlphaIIbbeta3 integrin: new allelic variants in Glanzmann
RT thrombasthenia, effects on ITGA2B and ITGB3 mRNA splicing, expression,
RT and structure-function.";
RL Hum. Mutat. 31:237-246(2010).
CC -!- FUNCTION: Integrin alpha-V/beta-3 is a receptor for cytotactin,
CC fibronectin, laminin, matrix metalloproteinase-2, osteopontin,
CC osteomodulin, prothrombin, thrombospondin, vitronectin and von
CC Willebrand factor. Integrin alpha-IIb/beta-3 is a receptor for
CC fibronectin, fibrinogen, plasminogen, prothrombin, thrombospondin
CC and vitronectin. Integrins alpha-IIb/beta-3 and alpha-V/beta-3
CC recognize the sequence R-G-D in a wide array of ligands. Integrin
CC alpha-IIb/beta-3 recognizes the sequence H-H-L-G-G-G-A-K-Q-A-G-D-V
CC in fibrinogen gamma chain. Following activation integrin alpha-
CC IIb/beta-3 brings about platelet/platelet interaction through
CC binding of soluble fibrinogen. This step leads to rapid platelet
CC aggregation which physically plugs ruptured endothelial surface.
CC In case of HIV-1 infection, the interaction with extracellular
CC viral Tat protein seems to enhance angiogenesis in Kaposi's
CC sarcoma lesions.
CC -!- SUBUNIT: Heterodimer of an alpha and a beta subunit. Beta-3
CC associates with either alpha-IIb or alpha-V. Isoform Beta-3C
CC interacts with FLNB. Interacts with COMP. Interacts with HIV-1
CC Tat. Interacts with PDIA6 following platelet stimulation.
CC Interacts with SYK; upon activation by ITGB3 promotes platelet
CC adhesion. Interacts with MYO10. Interacts with DAB2. Interacts
CC with FERMT2. Alpha-V/beta-3 interacts with herpes virus 8/HHV-8
CC glycoprotein B and acts as a receptor for the virus.
CC -!- INTERACTION:
CC Self; NbExp=4; IntAct=EBI-702847, EBI-702847;
CC P06935:- (xeno); NbExp=4; IntAct=EBI-702847, EBI-981051;
CC P05094:ACTN1 (xeno); NbExp=2; IntAct=EBI-702847, EBI-5847257;
CC P08514:ITGA2B; NbExp=11; IntAct=EBI-702847, EBI-702693;
CC P06756:ITGAV; NbExp=11; IntAct=EBI-702847, EBI-298282;
CC P18031:PTPN1; NbExp=4; IntAct=EBI-702847, EBI-968788;
CC P05480:Src (xeno); NbExp=5; IntAct=EBI-702847, EBI-298680;
CC P54939:TLN1 (xeno); NbExp=2; IntAct=EBI-702847, EBI-1035421;
CC Q9Y490:TLN1; NbExp=4; IntAct=EBI-702847, EBI-2462036;
CC P26039:Tln1 (xeno); NbExp=3; IntAct=EBI-702847, EBI-1039593;
CC -!- SUBCELLULAR LOCATION: Cell membrane; Single-pass type I membrane
CC protein. Cell projection, lamellipodium membrane. Cell junction,
CC focal adhesion.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=Beta-3A;
CC IsoId=P05106-1; Sequence=Displayed;
CC Name=Beta-3B;
CC IsoId=P05106-2; Sequence=VSP_002745;
CC Name=Beta-3C;
CC IsoId=P05106-3; Sequence=VSP_002746;
CC -!- TISSUE SPECIFICITY: Isoform beta-3A and isoform beta-3C are widely
CC expressed. Isoform beta-3A is specifically expressed in osteoblast
CC cells; isoform beta-3C is specifically expressed in prostate and
CC testis.
CC -!- PTM: Phosphorylated on tyrosine residues in response to thrombin-
CC induced platelet aggregation. Probably involved in outside-in
CC signaling. A peptide (AA 740-762) is capable of binding GRB2 only
CC when both Tyr-773 and Tyr-785 are phosphorylated. Phosphorylation
CC of Thr-779 inhibits SHC binding.
CC -!- POLYMORPHISM: Position 59 is associated with platelet-specific
CC alloantigen HPA-1 (ZW or PL(A)). HPA-1A/ZW(A)/PL(A1) has Leu-59
CC and HPA-1B/ZW(B)/PL(A2) has Pro-59. HPA-1A is involved in fetal-
CC maternal alloimmune thromobocytopenia (FMAIT) as well as in
CC neonatal alloimmune thrombocytopenia (NAIT).
CC -!- POLYMORPHISM: Position 169 is associated with platelet-specific
CC alloantigen HPA-4 (PEN or YUK). HPA-4A/PEN(A)/YUK(A) has Arg-169
CC and HPA-4B/PEN(B)/YUK(B) has Gln-169. HPA-4B is involved in
CC neonatal alloimmune thrombocytopenia (NAIT or NATP).
CC -!- POLYMORPHISM: Position 433 is associated with platelet-specific
CC alloantigen MO. MO(-) has Pro-433 and MO(+) has Ala-433. MO(+) is
CC involved in NAIT.
CC -!- POLYMORPHISM: Position 515 is associated with platelet-specific
CC alloantigen CA/TU. CA(-)/TU(-) has Arg-515 and CA(+)/TU(+) has
CC Gln-515. CA(+) is involved in NAIT.
CC -!- POLYMORPHISM: Position 662 is associated with platelet-specific
CC alloantigen SR(A). SR(A)(-) has Arg-662 and SR(A)(+) has Cys-662.
CC -!- DISEASE: Glanzmann thrombasthenia (GT) [MIM:273800]: A common
CC inherited disease of platelet aggregation. It is characterized by
CC mucocutaneous bleeding of mild-to-moderate severity. GT has been
CC classified clinically into types I and II. In type I, platelets
CC show absence of the glycoprotein IIb-IIIa complexes at their
CC surface and lack fibrinogen and clot retraction capability. In
CC type II, the platelets express the GPIIb-IIIa complex at reduced
CC levels, have detectable amounts of fibrinogen, and have low or
CC moderate clot retraction capability. Note=The disease is caused by
CC mutations affecting the gene represented in this entry.
CC -!- DISEASE: Bleeding disorder, platelet-type 16 (BDPLT16)
CC [MIM:187800]: An autosomal dominant form of congenital
CC macrothrombocytopenia associated with platelet anisocytosis. It is
CC a disorder of platelet production. Affected individuals may have
CC no or only mildly increased bleeding tendency. In vitro studies
CC show mild platelet functional abnormalities. Note=The disease is
CC caused by mutations affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the integrin beta chain family.
CC -!- SIMILARITY: Contains 1 VWFA domain.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/ITGB3";
CC -!- WEB RESOURCE: Name=SHMPD; Note=The Singapore human mutation and
CC polymorphism database;
CC URL="http://shmpd.bii.a-star.edu.sg/gene.php?genestart=A&genename;=ITGB3";
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DR EMBL; J02703; AAA52589.1; -; mRNA.
DR EMBL; M20311; AAA60122.1; -; mRNA.
DR EMBL; M35999; AAA35927.1; -; mRNA.
DR EMBL; U95204; AAB71380.1; -; mRNA.
DR EMBL; CH471231; EAW57682.1; -; Genomic_DNA.
DR EMBL; BC127666; AAI27667.1; -; mRNA.
DR EMBL; BC127667; AAI27668.1; -; mRNA.
DR EMBL; L28832; AAA20880.2; -; Genomic_DNA.
DR EMBL; M32686; AAA67537.1; -; Genomic_DNA.
DR EMBL; M32667; AAA67537.1; JOINED; Genomic_DNA.
DR EMBL; M32672; AAA67537.1; JOINED; Genomic_DNA.
DR EMBL; M32673; AAA67537.1; JOINED; Genomic_DNA.
DR EMBL; M32674; AAA67537.1; JOINED; Genomic_DNA.
DR EMBL; M32675; AAA67537.1; JOINED; Genomic_DNA.
DR EMBL; M32680; AAA67537.1; JOINED; Genomic_DNA.
DR EMBL; M32681; AAA67537.1; JOINED; Genomic_DNA.
DR EMBL; M32682; AAA67537.1; JOINED; Genomic_DNA.
DR EMBL; M32685; AAA67537.1; JOINED; Genomic_DNA.
DR EMBL; M57494; AAA52600.1; -; Genomic_DNA.
DR EMBL; M57481; AAA52600.1; JOINED; Genomic_DNA.
DR EMBL; M57482; AAA52600.1; JOINED; Genomic_DNA.
DR EMBL; M57483; AAA52600.1; JOINED; Genomic_DNA.
DR EMBL; M57484; AAA52600.1; JOINED; Genomic_DNA.
DR EMBL; M57485; AAA52600.1; JOINED; Genomic_DNA.
DR EMBL; M57486; AAA52600.1; JOINED; Genomic_DNA.
DR EMBL; M57487; AAA52600.1; JOINED; Genomic_DNA.
DR EMBL; M57488; AAA52600.1; JOINED; Genomic_DNA.
DR EMBL; M57489; AAA52600.1; JOINED; Genomic_DNA.
DR EMBL; M57490; AAA52600.1; JOINED; Genomic_DNA.
DR EMBL; M57491; AAA52600.1; JOINED; Genomic_DNA.
DR EMBL; M57492; AAA52600.1; JOINED; Genomic_DNA.
DR EMBL; M57493; AAA52600.1; JOINED; Genomic_DNA.
DR EMBL; U03881; AAA16076.1; -; Genomic_DNA.
DR EMBL; S49379; AAB23689.2; -; Genomic_DNA.
DR EMBL; M25108; AAA36121.1; -; mRNA.
DR PIR; A26547; A26547.
DR PIR; A60798; A60798.
DR PIR; B36268; B36268.
DR PIR; I77349; I77349.
DR PIR; S14324; S14324.
DR RefSeq; NP_000203.2; NM_000212.2.
DR UniGene; Hs.218040; -.
DR PDB; 1JV2; X-ray; 3.10 A; B=27-718.
DR PDB; 1KUP; NMR; -; B=742-766.
DR PDB; 1KUZ; NMR; -; B=742-766.
DR PDB; 1L5G; X-ray; 3.20 A; B=27-718.
DR PDB; 1M1X; X-ray; 3.30 A; B=27-718.
DR PDB; 1M8O; NMR; -; B=742-788.
DR PDB; 1MIZ; X-ray; 1.90 A; A=761-769.
DR PDB; 1MK7; X-ray; 2.20 A; A/C=765-775.
DR PDB; 1MK9; X-ray; 2.80 A; A/C/E/G=765-776.
DR PDB; 1RN0; Model; -; B=135-378.
DR PDB; 1S4X; NMR; -; A=742-788.
DR PDB; 1TYE; X-ray; 2.90 A; B/D/F=27-466.
DR PDB; 1U8C; X-ray; 3.10 A; B=27-718.
DR PDB; 2INI; Model; -; B=81-460, B=558-716.
DR PDB; 2K9J; NMR; -; B=711-753.
DR PDB; 2KNC; NMR; -; B=715-788.
DR PDB; 2KV9; NMR; -; B=739-788.
DR PDB; 2L1C; NMR; -; B=762-788.
DR PDB; 2L91; NMR; -; A=711-753.
DR PDB; 2LJD; NMR; -; A=742-788.
DR PDB; 2LJE; NMR; -; A=742-788.
DR PDB; 2LJF; NMR; -; A=742-788.
DR PDB; 2Q6W; X-ray; 2.25 A; C/F=50-61.
DR PDB; 2RMZ; NMR; -; A=711-753.
DR PDB; 2RN0; NMR; -; A=711-753.
DR PDB; 2VC2; X-ray; 3.10 A; B=27-487.
DR PDB; 2VDK; X-ray; 2.80 A; B=27-487.
DR PDB; 2VDL; X-ray; 2.75 A; B=27-487.
DR PDB; 2VDM; X-ray; 2.90 A; B=27-487.
DR PDB; 2VDN; X-ray; 2.90 A; B=27-487.
DR PDB; 2VDO; X-ray; 2.51 A; B=27-487.
DR PDB; 2VDP; X-ray; 2.80 A; B=27-487.
DR PDB; 2VDQ; X-ray; 2.59 A; B=27-487.
DR PDB; 2VDR; X-ray; 2.40 A; B=27-487.
DR PDB; 3FCS; X-ray; 2.55 A; B/D=27-716.
DR PDB; 3FCU; X-ray; 2.90 A; B/D/F=27-487.
DR PDB; 3IJE; X-ray; 2.90 A; B=27-721.
DR PDB; 3NID; X-ray; 2.30 A; B/D=27-497.
DR PDB; 3NIF; X-ray; 2.40 A; B/D=27-497.
DR PDB; 3NIG; X-ray; 2.25 A; B/D=27-497.
DR PDB; 3T3M; X-ray; 2.60 A; B/D=27-498.
DR PDB; 3T3P; X-ray; 2.20 A; B/D=27-498.
DR PDB; 3ZDX; X-ray; 2.45 A; B/D=27-498.
DR PDB; 3ZDY; X-ray; 2.45 A; B/D=27-498.
DR PDB; 3ZDZ; X-ray; 2.75 A; B/D=27-498.
DR PDB; 3ZE0; X-ray; 2.95 A; B/D=27-498.
DR PDB; 3ZE1; X-ray; 3.00 A; B/D=27-498.
DR PDB; 3ZE2; X-ray; 2.35 A; B/D=27-498.
DR PDB; 4CAK; EM; 20.50 A; B=27-716.
DR PDB; 4G1E; X-ray; 3.00 A; B=27-717.
DR PDB; 4G1M; X-ray; 2.90 A; B=27-718.
DR PDBsum; 1JV2; -.
DR PDBsum; 1KUP; -.
DR PDBsum; 1KUZ; -.
DR PDBsum; 1L5G; -.
DR PDBsum; 1M1X; -.
DR PDBsum; 1M8O; -.
DR PDBsum; 1MIZ; -.
DR PDBsum; 1MK7; -.
DR PDBsum; 1MK9; -.
DR PDBsum; 1RN0; -.
DR PDBsum; 1S4X; -.
DR PDBsum; 1TYE; -.
DR PDBsum; 1U8C; -.
DR PDBsum; 2INI; -.
DR PDBsum; 2K9J; -.
DR PDBsum; 2KNC; -.
DR PDBsum; 2KV9; -.
DR PDBsum; 2L1C; -.
DR PDBsum; 2L91; -.
DR PDBsum; 2LJD; -.
DR PDBsum; 2LJE; -.
DR PDBsum; 2LJF; -.
DR PDBsum; 2Q6W; -.
DR PDBsum; 2RMZ; -.
DR PDBsum; 2RN0; -.
DR PDBsum; 2VC2; -.
DR PDBsum; 2VDK; -.
DR PDBsum; 2VDL; -.
DR PDBsum; 2VDM; -.
DR PDBsum; 2VDN; -.
DR PDBsum; 2VDO; -.
DR PDBsum; 2VDP; -.
DR PDBsum; 2VDQ; -.
DR PDBsum; 2VDR; -.
DR PDBsum; 3FCS; -.
DR PDBsum; 3FCU; -.
DR PDBsum; 3IJE; -.
DR PDBsum; 3NID; -.
DR PDBsum; 3NIF; -.
DR PDBsum; 3NIG; -.
DR PDBsum; 3T3M; -.
DR PDBsum; 3T3P; -.
DR PDBsum; 3ZDX; -.
DR PDBsum; 3ZDY; -.
DR PDBsum; 3ZDZ; -.
DR PDBsum; 3ZE0; -.
DR PDBsum; 3ZE1; -.
DR PDBsum; 3ZE2; -.
DR PDBsum; 4CAK; -.
DR PDBsum; 4G1E; -.
DR PDBsum; 4G1M; -.
DR ProteinModelPortal; P05106; -.
DR SMR; P05106; 27-788.
DR DIP; DIP-304N; -.
DR IntAct; P05106; 15.
DR MINT; MINT-209501; -.
DR STRING; 9606.ENSP00000262017; -.
DR BindingDB; P05106; -.
DR ChEMBL; CHEMBL2111443; -.
DR DrugBank; DB00054; Abciximab.
DR DrugBank; DB00775; Tirofiban.
DR PhosphoSite; P05106; -.
DR DMDM; 125987835; -.
DR PaxDb; P05106; -.
DR PRIDE; P05106; -.
DR Ensembl; ENST00000559488; ENSP00000452786; ENSG00000259207.
DR GeneID; 3690; -.
DR KEGG; hsa:3690; -.
DR UCSC; uc002ilj.3; human.
DR CTD; 3690; -.
DR GeneCards; GC17P045331; -.
DR HGNC; HGNC:6156; ITGB3.
DR HPA; CAB002501; -.
DR HPA; HPA027852; -.
DR MIM; 173470; gene+phenotype.
DR MIM; 187800; phenotype.
DR MIM; 273800; phenotype.
DR neXtProt; NX_P05106; -.
DR Orphanet; 140957; Autosomal dominant macrothrombocytopenia.
DR Orphanet; 853; Fetal and neonatal alloimmune thrombocytopenia.
DR Orphanet; 849; Glanzmann thrombasthenia.
DR PharmGKB; PA205; -.
DR eggNOG; NOG287997; -.
DR HOVERGEN; HBG006190; -.
DR InParanoid; P05106; -.
DR KO; K06493; -.
DR OMA; GHGQCSC; -.
DR OrthoDB; EOG7T7GSB; -.
DR PhylomeDB; P05106; -.
DR Reactome; REACT_111045; Developmental Biology.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_118779; Extracellular matrix organization.
DR Reactome; REACT_604; Hemostasis.
DR SignaLink; P05106; -.
DR ChiTaRS; ITGB3; human.
DR EvolutionaryTrace; P05106; -.
DR GeneWiki; CD61; -.
DR GenomeRNAi; 3690; -.
DR NextBio; 14453; -.
DR PMAP-CutDB; P05106; -.
DR PRO; PR:P05106; -.
DR ArrayExpress; P05106; -.
DR Bgee; P05106; -.
DR CleanEx; HS_ITGB3; -.
DR Genevestigator; P05106; -.
DR GO; GO:0071062; C:alphav-beta3 integrin-vitronectin complex; TAS:BHF-UCL.
DR GO; GO:0005925; C:focal adhesion; IEA:UniProtKB-SubCell.
DR GO; GO:0008305; C:integrin complex; IDA:BHF-UCL.
DR GO; GO:0031258; C:lamellipodium membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0042470; C:melanosome; IDA:UniProtKB.
DR GO; GO:0005634; C:nucleus; IDA:MGI.
DR GO; GO:0031092; C:platelet alpha granule membrane; TAS:Reactome.
DR GO; GO:0005161; F:platelet-derived growth factor receptor binding; TAS:BHF-UCL.
DR GO; GO:0003756; F:protein disulfide isomerase activity; IDA:UniProtKB.
DR GO; GO:0004872; F:receptor activity; IEA:InterPro.
DR GO; GO:0043184; F:vascular endothelial growth factor receptor 2 binding; TAS:BHF-UCL.
DR GO; GO:0032147; P:activation of protein kinase activity; IMP:BHF-UCL.
DR GO; GO:0060055; P:angiogenesis involved in wound healing; TAS:BHF-UCL.
DR GO; GO:0007411; P:axon guidance; TAS:Reactome.
DR GO; GO:0007160; P:cell-matrix adhesion; IEA:InterPro.
DR GO; GO:0007044; P:cell-substrate junction assembly; IEA:InterPro.
DR GO; GO:0030198; P:extracellular matrix organization; TAS:Reactome.
DR GO; GO:0007229; P:integrin-mediated signaling pathway; TAS:BHF-UCL.
DR GO; GO:0050900; P:leukocyte migration; TAS:Reactome.
DR GO; GO:0019048; P:modulation by virus of host morphology or physiology; IEA:UniProtKB-KW.
DR GO; GO:0010888; P:negative regulation of lipid storage; IMP:BHF-UCL.
DR GO; GO:0032369; P:negative regulation of lipid transport; IMP:BHF-UCL.
DR GO; GO:0050748; P:negative regulation of lipoprotein metabolic process; IMP:BHF-UCL.
DR GO; GO:0045715; P:negative regulation of low-density lipoprotein particle receptor biosynthetic process; IMP:BHF-UCL.
DR GO; GO:0010745; P:negative regulation of macrophage derived foam cell differentiation; IMP:BHF-UCL.
DR GO; GO:0070527; P:platelet aggregation; IMP:UniProtKB.
DR GO; GO:0002576; P:platelet degranulation; TAS:Reactome.
DR GO; GO:0010595; P:positive regulation of endothelial cell migration; IMP:BHF-UCL.
DR GO; GO:0001938; P:positive regulation of endothelial cell proliferation; IMP:BHF-UCL.
DR GO; GO:0050731; P:positive regulation of peptidyl-tyrosine phosphorylation; IMP:BHF-UCL.
DR GO; GO:0030949; P:positive regulation of vascular endothelial growth factor receptor signaling pathway; TAS:BHF-UCL.
DR GO; GO:0045124; P:regulation of bone resorption; TAS:BHF-UCL.
DR GO; GO:0014909; P:smooth muscle cell migration; IMP:BHF-UCL.
DR GO; GO:0035295; P:tube development; TAS:BHF-UCL.
DR Gene3D; 1.20.5.630; -; 1.
DR Gene3D; 3.40.50.410; -; 1.
DR InterPro; IPR027068; Integrin_beta-3.
DR InterPro; IPR015812; Integrin_bsu.
DR InterPro; IPR014836; Integrin_bsu_cyt_dom.
DR InterPro; IPR002369; Integrin_bsu_N.
DR InterPro; IPR012896; Integrin_bsu_tail.
DR InterPro; IPR016201; Plexin-like_fold.
DR InterPro; IPR002035; VWF_A.
DR PANTHER; PTHR10082; PTHR10082; 1.
DR PANTHER; PTHR10082:SF25; PTHR10082:SF25; 1.
DR Pfam; PF08725; Integrin_b_cyt; 1.
DR Pfam; PF07965; Integrin_B_tail; 1.
DR Pfam; PF00362; Integrin_beta; 1.
DR PIRSF; PIRSF002512; Integrin_B; 1.
DR PRINTS; PR01186; INTEGRINB.
DR SMART; SM00187; INB; 1.
DR SMART; SM00423; PSI; 1.
DR SMART; SM00327; VWA; 1.
DR SUPFAM; SSF103575; SSF103575; 1.
DR SUPFAM; SSF69687; SSF69687; 1.
DR PROSITE; PS00022; EGF_1; UNKNOWN_2.
DR PROSITE; PS01186; EGF_2; UNKNOWN_1.
DR PROSITE; PS00243; INTEGRIN_BETA; 3.
DR PROSITE; PS50234; VWFA; FALSE_NEG.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Cell adhesion; Cell junction;
KW Cell membrane; Cell projection; Complete proteome;
KW Direct protein sequencing; Disease mutation; Disulfide bond;
KW Glycoprotein; Host-virus interaction; Integrin; Membrane;
KW Phosphoprotein; Polymorphism; Receptor; Reference proteome; Repeat;
KW Signal; Transmembrane; Transmembrane helix.
FT SIGNAL 1 26 Potential.
FT CHAIN 27 788 Integrin beta-3.
FT /FTId=PRO_0000016344.
FT TOPO_DOM 27 718 Extracellular (Potential).
FT TRANSMEM 719 741 Helical; (Potential).
FT TOPO_DOM 742 788 Cytoplasmic (Potential).
FT DOMAIN 135 377 VWFA.
FT REPEAT 463 511 I.
FT REPEAT 512 553 II.
FT REPEAT 554 592 III.
FT REPEAT 593 629 IV.
FT REGION 463 629 Cysteine-rich tandem repeats.
FT MOD_RES 773 773 Phosphotyrosine.
FT MOD_RES 779 779 Phosphothreonine; by PDPK1 and PKB/AKT1;
FT in vitro.
FT CARBOHYD 125 125 N-linked (GlcNAc...).
FT CARBOHYD 346 346 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 397 397 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 478 478 N-linked (GlcNAc...).
FT CARBOHYD 585 585 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 680 680 N-linked (GlcNAc...).
FT DISULFID 31 461
FT DISULFID 39 49
FT DISULFID 42 75
FT DISULFID 52 64
FT DISULFID 203 210
FT DISULFID 258 299
FT DISULFID 400 412
FT DISULFID 432 681
FT DISULFID 459 463
FT DISULFID 474 486 Probable.
FT DISULFID 483 521 Probable.
FT DISULFID 488 497 Probable.
FT DISULFID 499 512 Probable.
FT DISULFID 527 532 Probable.
FT DISULFID 529 562 Probable.
FT DISULFID 534 547 Probable.
FT DISULFID 549 554
FT DISULFID 568 573 Probable.
FT DISULFID 570 601 Probable.
FT DISULFID 575 584 Probable.
FT DISULFID 586 593 Probable.
FT DISULFID 607 612 Probable.
FT DISULFID 609 657 Probable.
FT DISULFID 614 624 Probable.
FT DISULFID 627 630 Probable.
FT DISULFID 634 643 Probable.
FT DISULFID 640 713 Probable.
FT DISULFID 661 689
FT VAR_SEQ 768 788 ANNPLYKEATSTFTNITYRGT -> VRDGAGRFLKSLV
FT (in isoform Beta-3B).
FT /FTId=VSP_002745.
FT VAR_SEQ 768 788 ANNPLYKEATSTFTNITYRGT -> HYAQSLRKWNQPVSID
FT G (in isoform Beta-3C).
FT /FTId=VSP_002746.
FT VARIANT 59 59 L -> P (in alloantigen HPA-1B;
FT dbSNP:rs5918).
FT /FTId=VAR_003993.
FT VARIANT 64 64 C -> Y (in GT; the mutation prevents
FT normal ITGA2B/ITGB3 complex expression on
FT the cell surface consistent with a severe
FT type 1 phenotype).
FT /FTId=VAR_069920.
FT VARIANT 66 66 L -> R (in dbSNP:rs36080296).
FT /FTId=VAR_049633.
FT VARIANT 119 119 R -> W (in GT).
FT /FTId=VAR_030473.
FT VARIANT 141 141 Y -> C (in GT).
FT /FTId=VAR_030474.
FT VARIANT 143 143 L -> W (in GT).
FT /FTId=VAR_010649.
FT VARIANT 144 144 M -> R (in GT; the mutation prevented
FT normal ITGA2B/ITGB3 complex expression on
FT the cell surface consistent with a severe
FT type 1 phenotype).
FT /FTId=VAR_069921.
FT VARIANT 145 145 D -> N (in GT).
FT /FTId=VAR_030475.
FT VARIANT 145 145 D -> Y (in GT; type B).
FT /FTId=VAR_003998.
FT VARIANT 150 150 M -> V (in GT; may confer constitutive
FT activity to the alpha-IIb/(mutated)beta-3
FT receptor).
FT /FTId=VAR_030476.
FT VARIANT 166 166 T -> I (associated with neonatal
FT thrombocytopenia; alloantigen Duv(a+);
FT does not affect significantly the
FT integrin function).
FT /FTId=VAR_030477.
FT VARIANT 169 169 R -> Q (in alloantigen HPA-4B;
FT dbSNP:rs5917).
FT /FTId=VAR_003994.
FT VARIANT 188 188 S -> L (in GT; type II).
FT /FTId=VAR_010651.
FT VARIANT 222 222 L -> P (in GT; variant form).
FT /FTId=VAR_030478.
FT VARIANT 240 240 R -> Q (in GT; type B).
FT /FTId=VAR_003999.
FT VARIANT 240 240 R -> W (in GT; variant Strasbourg-1).
FT /FTId=VAR_004000.
FT VARIANT 242 242 R -> Q (in GT).
FT /FTId=VAR_030479.
FT VARIANT 243 243 D -> V (in GT).
FT /FTId=VAR_030480.
FT VARIANT 247 247 G -> D (in GT; the mutation prevents
FT normal ITGA2B/ITGB3 complex expression on
FT the cell surface consistent with a severe
FT type 1 phenotype; the mutation may
FT interfere with correct folding of the
FT protein).
FT /FTId=VAR_069922.
FT VARIANT 279 279 K -> M (in GT; the mutation prevents
FT normal ITGA2B/ITGB3 complex expression on
FT the cell surface consistent with a severe
FT type 1 phenotype; the mutation interupts
FT the interaction of the ITGA2B/ITGB3
FT complex).
FT /FTId=VAR_069923.
FT VARIANT 288 288 L -> P (in GT).
FT /FTId=VAR_030481.
FT VARIANT 306 306 H -> P (in GT; dbSNP:rs13306476).
FT /FTId=VAR_004001.
FT VARIANT 321 321 M -> L (in GT).
FT /FTId=VAR_030482.
FT VARIANT 330 330 I -> N (in GT; not expressed on the
FT surface and absent inside the transfected
FT cells).
FT /FTId=VAR_030483.
FT VARIANT 400 400 C -> Y (in GT).
FT /FTId=VAR_004002.
FT VARIANT 433 433 P -> A (in alloantigen MO(+); in a case
FT of neonatal alloimmune thrombocytopenia;
FT dbSNP:rs121918448).
FT /FTId=VAR_003995.
FT VARIANT 453 453 V -> I (in dbSNP:rs5921).
FT /FTId=VAR_014178.
FT VARIANT 515 515 R -> Q (in alloantigen CA(+)/TU(+);
FT dbSNP:rs13306487).
FT /FTId=VAR_003996.
FT VARIANT 532 532 C -> Y (in GT).
FT /FTId=VAR_030484.
FT VARIANT 568 568 C -> R (in GT; type I).
FT /FTId=VAR_010671.
FT VARIANT 586 586 C -> F (in GT).
FT /FTId=VAR_004003.
FT VARIANT 586 586 C -> R (in GT; gain-of-function mutation;
FT constitutively binds ligand-induced
FT binding sites antibodies and the
FT fibrinogen-mimetic antibody PAC-1).
FT /FTId=VAR_030485.
FT VARIANT 598 598 G -> S (in GT).
FT /FTId=VAR_004004.
FT VARIANT 601 601 C -> R (in GT).
FT /FTId=VAR_030486.
FT VARIANT 605 605 G -> S (in GT; type II).
FT /FTId=VAR_010672.
FT VARIANT 662 662 R -> C (in alloantigen SR(A);
FT dbSNP:rs151219882).
FT /FTId=VAR_003997.
FT VARIANT 749 749 D -> H (in BDPLT16; the mutant protein is
FT constitutively active).
FT /FTId=VAR_069924.
FT VARIANT 778 778 S -> P (in GT; variant Strasbourg-1).
FT /FTId=VAR_004005.
FT CONFLICT 12 12 A -> V (in Ref. 1; AAA52589 and 3;
FT AAA35927).
FT CONFLICT 151 151 K -> P (in Ref. 11; AAA67537 and 14;
FT AAB23689).
FT CONFLICT 205 205 D -> EY (in Ref. 11; AAA67537).
FT CONFLICT 649 653 GALHD -> EPYMT (in Ref. 1; AAA52589, 2;
FT AAA60122 and 4; AAB71380).
FT CONFLICT 716 716 G -> H (in Ref. 8).
FT CONFLICT 737 741 ALLIW -> PCSSG (in Ref. 11; AAA67537).
FT HELIX 30 33
FT HELIX 39 45
FT STRAND 50 52
FT STRAND 54 57
FT STRAND 59 61
FT STRAND 63 65
FT HELIX 67 72
FT HELIX 77 79
FT STRAND 86 91
FT STRAND 99 101
FT HELIX 103 105
FT STRAND 109 111
FT STRAND 113 118
FT STRAND 123 131
FT STRAND 138 145
FT HELIX 148 150
FT HELIX 151 156
FT TURN 157 159
FT HELIX 160 168
FT TURN 169 171
FT STRAND 175 182
FT TURN 188 190
FT HELIX 196 200
FT TURN 202 207
FT STRAND 215 224
FT HELIX 226 235
FT STRAND 242 246
FT HELIX 248 257
FT HELIX 259 262
FT STRAND 266 278
FT HELIX 285 289
FT STRAND 305 307
FT TURN 308 312
FT HELIX 318 327
FT STRAND 331 336
FT HELIX 338 340
FT HELIX 341 349
FT STRAND 355 358
FT TURN 361 363
FT HELIX 366 377
FT STRAND 381 387
FT STRAND 392 400
FT TURN 401 403
FT STRAND 404 407
FT STRAND 411 415
FT STRAND 420 429
FT STRAND 434 444
FT STRAND 451 457
FT HELIX 462 466
FT STRAND 468 470
FT TURN 472 478
FT STRAND 479 482
FT STRAND 485 488
FT STRAND 489 491
FT TURN 494 497
FT STRAND 500 504
FT STRAND 513 518
FT HELIX 520 523
FT STRAND 524 527
FT STRAND 529 534
FT STRAND 538 540
FT STRAND 542 544
FT STRAND 549 552
FT STRAND 556 561
FT HELIX 562 564
FT STRAND 565 569
FT STRAND 572 575
FT STRAND 579 584
FT TURN 591 593
FT STRAND 598 600
FT STRAND 602 604
FT STRAND 606 608
FT STRAND 611 613
FT TURN 616 618
FT STRAND 620 624
FT STRAND 628 630
FT TURN 633 635
FT HELIX 639 641
FT TURN 642 646
FT STRAND 649 655
FT TURN 658 660
FT STRAND 664 666
FT STRAND 669 671
FT STRAND 674 678
FT STRAND 680 684
FT STRAND 688 694
FT STRAND 698 700
FT STRAND 704 706
FT STRAND 707 710
FT STRAND 715 717
FT TURN 743 759
FT TURN 761 765
FT STRAND 767 770
FT HELIX 771 774
FT HELIX 776 779
FT TURN 782 786
SQ SEQUENCE 788 AA; 87058 MW; F246623608E05F9E CRC64;
MRARPRPRPL WATVLALGAL AGVGVGGPNI CTTRGVSSCQ QCLAVSPMCA WCSDEALPLG
SPRCDLKENL LKDNCAPESI EFPVSEARVL EDRPLSDKGS GDSSQVTQVS PQRIALRLRP
DDSKNFSIQV RQVEDYPVDI YYLMDLSYSM KDDLWSIQNL GTKLATQMRK LTSNLRIGFG
AFVDKPVSPY MYISPPEALE NPCYDMKTTC LPMFGYKHVL TLTDQVTRFN EEVKKQSVSR
NRDAPEGGFD AIMQATVCDE KIGWRNDASH LLVFTTDAKT HIALDGRLAG IVQPNDGQCH
VGSDNHYSAS TTMDYPSLGL MTEKLSQKNI NLIFAVTENV VNLYQNYSEL IPGTTVGVLS
MDSSNVLQLI VDAYGKIRSK VELEVRDLPE ELSLSFNATC LNNEVIPGLK SCMGLKIGDT
VSFSIEAKVR GCPQEKEKSF TIKPVGFKDS LIVQVTFDCD CACQAQAEPN SHRCNNGNGT
FECGVCRCGP GWLGSQCECS EEDYRPSQQD ECSPREGQPV CSQRGECLCG QCVCHSSDFG
KITGKYCECD DFSCVRYKGE MCSGHGQCSC GDCLCDSDWT GYYCNCTTRT DTCMSSNGLL
CSGRGKCECG SCVCIQPGSY GDTCEKCPTC PDACTFKKEC VECKKFDRGA LHDENTCNRY
CRDEIESVKE LKDTGKDAVN CTYKNEDDCV VRFQYYEDSS GKSILYVVEE PECPKGPDIL
VVLLSVMGAI LLIGLAALLI WKLLITIHDR KEFAKFEEER ARAKWDTANN PLYKEATSTF
TNITYRGT
//

MIM 173470
*RECORD*
*FIELD* NO
173470
*FIELD* TI
+173470 INTEGRIN, BETA-3; ITGB3
;;PLATELET GLYCOPROTEIN IIIa; GP3A;;
GP IIIa;;
PLATELET FIBRINOGEN RECEPTOR, BETA SUBUNIT;;
read moreCD61
THROMBOCYTOPENIA, NEONATAL ALLOIMMUNE, INCLUDED; NAIT, INCLUDED;;
POSTTRANSFUSION PURPURA, INCLUDED; PTP, INCLUDED
*FIELD* TX

DESCRIPTION

The ITGB3 gene encodes glycoprotein IIIa (GP IIIa), the beta subunit of
the platelet membrane adhesive protein receptor complex GP IIb/IIIa. The
alpha subunit, GP IIb, is encoded by the ITGA2B gene (607759). The GP
IIb/IIIa complex belongs to the integrin class of cell adhesion molecule
receptors that share a common heterodimeric structure with alpha and
beta subunits.

Glycoprotein IIIa is also the beta subunit of 2 other integrins,
fibronectin receptor (FNRB; 135630) and vitronectin receptor (193210),
which have distinctive alpha subunits.

CLONING

Zimrin et al. (1988) described the structure of GP IIIa deduced from an
analysis of 4 kb of overlapping cDNA sequences isolated from a human
erythroleukemia cell cDNA expression library. A continuous open reading
frame encoding all 788 amino acids was present. The deduced amino acid
sequence included a 26-residue N-terminal signal peptide, a 29-residue
transmembrane domain near the C terminus, and 4 tandemly repeated
cysteine-rich domains of 33 to 38 residues. Zimrin et al. (1988) found
38% similarity with the beta subunit of LFA1 (600065) and virtual
identity with human endothelial cell GP IIIa. Northern blot analysis
using RNA from both human erythroleukemia cells and endothelial cells
showed 2 GP IIIa transcripts of 5.9 and 4.1 kb. However, erythroleukemia
RNA, but not endothelial cell RNA, contained a transcript for GP IIb.
This indicated that the GP IIIa-containing heterodimers in platelets and
endothelial cells are not identical structures but are members of a
subfamily within the family of human adhesion protein receptors sharing
an identical beta subunit. Hynes (1987) proposed that there are 3
subfamilies within the family of human adhesion protein receptor
heterodimers based on the number of different beta subunits. The
platelet and endothelial cell heterodimers use GP IIIa as the beta
subunit; the leukocyte heterodimers contain a beta subunit with a
molecular mass of 95 kD that is homologous to GP IIIa but is clearly a
different protein (600065); and the fibronectin receptors contain a beta
subunit that appears to be analogous to band 3 of integrin (135630).
Burk et al. (1988) described a RFLP of the GP3A gene.

Rosa et al. (1988) derived cDNAs for platelet GP IIIa peptide from a
cDNA library which was constructed by use of an RNA purified from human
erythroleukemia cells. The sequence matched a previously reported
endothelial cell cDNA sequence except for 8 nucleotides. Five of these
were silent changes consistent with genetic polymorphism.

Lanza et al. (1990) isolated genomic clones for the beta subunit of the
fibronectin receptor. Of the 8 splice sites identified in FNRB, 6
occurred at the same amino acid residue as in GP3A. They interpreted
these results as indicating a common evolutionary origin of GP3A and
FNRB within the integrin family.

GENE STRUCTURE

Lanza et al. (1990) demonstrated that the GP3A gene has 14 exons. The
3-prime exon is larger than 1,700 nucleotides and contains the 3-prime
untranslated region.

Weiss et al. (2006) stated that the ITGB3 gene contains 15 exons and
spans 60 kb.

BIOCHEMICAL FEATURES

- Crystal Structure

Xiong et al. (2001) determined the crystal structure of the
extracellular portion of integrin alpha-V-beta-3 at 3.1-angstrom
resolution. Its 12 domains assemble into an ovoid head and 2 tails. In
the crystal, alpha-V-beta-3 is severely bent at a defined region in its
tails, reflecting an unusual flexibility that may be linked to integrin
regulation. Xiong et al. (2002) determined the crystal structure of the
extracellular segment of integrin alpha-V-beta-3 in complex with a
cyclic peptide presenting the arg-gly-asp sequence. The ligand binds at
the major interface between the alpha-V and beta-3 subunits and makes
extensive contacts with both. Both tertiary and quaternary changes were
observed in the presence of ligand. The tertiary rearrangements take
place in beta-A, the ligand-binding domain of beta-3; in the complex,
beta-A acquires 2 cations, 1 of which contacts the ligand asp directly
and the other stabilizes the ligand-binding surface. Ligand binding
induces small changes in the orientation of alpha-V relative to beta-3.

Xiao et al. (2004) defined with crystal structures the atomic basis for
allosteric regulation of the conformation and affinity for ligand of the
integrin ectodomain, and how fibrinogen-mimetic therapeutics bind to
platelet integrin alpha-IIb-beta-3. Allostery in the beta-3 I domain
alters 3 metal binding sites, associated loops, and alpha-1- and
alpha-7-helices. Piston-like displacement of the alpha-7-helix causes a
62-degree reorientation between the beta-3 I and hybrid domains.
Transmission through the rigidly connected plexin/semaphorin/integrin
(PSI) domain in the upper beta-3 leg causes a 70-angstrom separation
between the knees of the alpha and beta legs. Allostery in the head thus
disrupts interaction between the legs in a previously described
low-affinity bent integrin conformation, and leg extension positions the
high-affinity head far above the cell surface.

MAPPING

Rosa et al. (1988) localized the GP3A gene to chromosome 17 by
hybridization to DNA from sorted chromosomes and by hybridization to DNA
from mouse-human somatic hybrids.

Letellier et al. (1988) demonstrated linkage between the
platelet-specific alloantigens Pl(A) and BAK, an epitope of GP IIb, and
showed linkage disequilibrium in unrelated Caucasian subjects. By
somatic cell hybrid and in situ hybridization studies, Sosnoski et al.
(1988) found close physical location of the GP2B and GP3A genes in the
segment 17q21-q23. Because of close physical proximity of the genes with
resulting linkage disequilibrium, the authors suggested that it may be
difficult to use RFLPs in family studies to assign the defect through
either the GP2B or the GP3A gene in cases of thrombasthenia. Bray et al.
(1988) demonstrated that both GP2B and GP3A are situated close to the
TK1 gene (188300) on chromosome 17 and, furthermore, that GP2B and GP3A
are physically linked within the same 260-kb pulsed field gel
electrophoresis (PFGE) fragment. The findings suggested that GP2B is
located on the 3-prime side of GP3A. Coordinate expression of these 2
genes may depend on physical proximity.

Van Cong et al. (1989) assigned the GP3A gene to chromosome 17 by
somatic cell hybridization and to 17q21.1-q21.3 by in situ
hybridization. By genetic linkage studies using multiple DNA markers in
the 17q12-q21 region, Anderson et al. (1993) placed the GP3A gene on the
genetic map of the region.

In a study of large kindreds with mutations in either ITGA2B or ITGB3,
Thornton et al. (1999) developed a genetic linkage map between the THRA1
(190120) and ITGB3 genes as follows: cen--THRA1--BRCA1
(113705)--D17S579/ITGA2B--ITGB3--qter, with a distance of 1.3 cM between
ITGA2B and ITGB3, and the 2 genes being oriented in the same direction.
PFGE genomic and YAC clone analysis showed that the ITGB3 gene is distal
and 365 kb or more upstream of ITGA2B. Additional restriction mapping
showed that ITGA2B is linked to the EPB3 gene (SLC4A1; 109270), and
ITGB3 to the HOX2B gene (HOXB6; 142961). Further analysis confirmed that
the EPB3 gene is approximately 110 kb downstream of the ITGA2B gene.
Sequencing the region surrounding the ITGA2B gene showed that the
granulin gene (GRN; 138945) is located approximately 18 kb downstream to
ITGA2B. Thornton et al. (1999) found that this organization is conserved
in the murine sequence. These studies showed that the ITGA2B and ITGB3
genes are not closely linked, with ITGA2B flanked by nonmegakaryotic
genes, and implied that the genes are unlikely to share common
regulatory domains during megakaryopoiesis.

GENE FUNCTION

The GP IIb/IIIa complex mediates platelet aggregation by acting as a
receptor for fibrinogen. The complex also acts as a receptor for von
Willebrand factor and fibronectin (Prandini et al., 1988).

Lefkovits et al. (1995) reviewed the role of platelet glycoprotein
IIb/IIIa receptors and their agonists in cardiovascular medicine. Since
this receptor is involved in platelet aggregation, which is the final
common pathway of platelet plug formation, the study of receptor
inhibitors was considered a logical pharmaceutical strategy.

Stupack et al. (2001) demonstrated that cells adherent within a
3-dimensional extracellular matrix undergo apoptosis due to expression
of unligated integrins, the beta subunit cytoplasmic domain, or its
membrane proximal sequence KLLITIHDRKEF. Integrin-mediated death
requires initiator, but not stress, caspase activity and is distinct
from anoikis, which is caused by the loss of adhesion per se. Stupack et
al. (2001) demonstrated that unligated integrin or beta-integrin tails
recruit caspase-8 (601763) to the membrane, where it becomes activated
in a death receptor-independent manner. Integrin ligation disrupts this
integrin-caspase-containing complex and increases survival, revealing an
unexpected role for integrins in the regulation of apoptosis and tissue
remodeling.

While studying thrombus formation in mice lacking CD40L (300386), Andre
et al. (2002) observed that recombinant soluble CD40L (rsCD40L) carrying
a mutation changing the KGD motif sequence to KGE failed to restore
thrombus stability. Flow cytometric analysis demonstrated that rsCD40L
binds to activated platelets of wildtype as well as of CD40 (109535) -/-
mice but that this binding can be inhibited by a peptide interfering
with GP IIb/IIa binding. Plate-binding analysis indicated specific
saturable binding of rsCD40L for GP IIb/IIa. Fluorescence microscopy
showed that human platelets spread on but did not adhere to an
rsCD40L-coated glass surface only in the absence of an inhibitor of
ITGA2B/ITGB3. Andre et al. (2002) concluded that CD40L is a GP IIb/IIa
ligand.

Transmembrane helices of integrin alpha and beta subunits have been
implicated in the regulation of integrin activity. Li et al. (2003)
showed that 2 mutations, gly708 to asn and met701 to asn, in the
transmembrane helix of the beta-3 subunit enabled integrin
alpha-IIB/beta-3 (273800) to bind soluble fibrinogen constitutively.
Further characterization of the gly708-to-asn mutant revealed that it
induced alpha-IIB/beta-3 clustering and constitutive phosphorylation of
focal adhesion kinase (600758). This mutation also enhanced the tendency
of the transmembrane helix to form homotrimers. The findings of Li et
al. (2003) suggested that homomeric associations involving transmembrane
domains provide a driving force for integrin activation and suggested a
structural basis for the coincidence of integrin activation and
clustering.

In a patient with features of Glanzmann thrombasthenia and leukocyte
adhesion deficiency-1 (116920), McDowall et al. (2003) identified a
novel form of integrin dysfunction involving ITGB1 (135630), ITGB2
(600065), and ITGB3. ITGB2 and ITGB3 were constitutively clustered.
Although all 3 integrins were expressed on the cell surface at normal
levels and were capable of function following extracellular stimulation,
they could not be activated via the 'inside-out' signaling pathways.

Mechanical forces on matrix-integrin-cytoskeleton linkages are crucial
for cell viability, morphology, and organ function. The production of
force depends on the molecular connections from
extracellular-matrix-integrin complexes to the cytoskeleton. The minimal
matrix complex causing integrin-cytoskeleton connections is a trimer of
fibronectin's (135600) integrin-binding domain FNIII7-10. Jiang et al.
(2003) reported a specific, molecular slip bond that was repeatedly
broken by a force of 2 pN at the cellular loading rate of 60 nm/second;
this occurred with single trimer beads but not with the monomer. Talin-1
(186745), which binds to integrins and actin filaments in vitro, is
required for the 2-pN slip bond and rapid cytoskeleton binding.
Furthermore, Jiang et al. (2003) showed that inhibition of fibronectin
binding to alpha-v-beta-3 integrin and deletion of beta-3 markedly
decreased the 2-pN force peak. They suggested that talin-1 initially
forms a molecular slip bond between closely packed fibronectin-integrin
complexes and the actin cytoskeleton, which can apply a low level of
force to fibronectin until many bonds form or a signal is received to
activate a force response.

Faccio et al. (2003) retrovirally transduced ITGB3 -/- osteoclast
precursors with chimeric colony-stimulating factor-1 receptor (CSF1R;
164770) constructs containing various cytoplasmic domain mutations and
found that CSF1R tyr697 was required for normalization of
osteoclastogenesis and ERK activation (see 176948). Overexpression of
FOS (164810) normalized the number of ITGB3 -/- osteoclasts in vitro but
not their ability to resorb dentin. Faccio et al. (2003) concluded that
whereas CSF1R and alpha-V-beta-3 integrin collaborate in the
osteoclastogenic process through shared activation of the ERK/FOS
signaling pathway, the integrin is essential for matrix degradation.

Wang et al. (2003) showed that epidermal growth factor receptor (EGFR;
131550) serves as a receptor for cytomegalovirus (CMV). Given the broad
tropism of CMV, Wang et al. (2005) sought additional receptors.
Antibody-mediated infection-blocking experiments indicated that CMV also
uses alpha-V-beta-3 integrin, but not other integrins, as a coreceptor.
Upon infection, CMV glycoproteins gB and gH independently bound to EGFR
and alpha-V-beta-3, respectively, to initiate viral entry and signaling.
CMV infection induced phosphorylation of beta-3 and EGFR and activated
SRC (190090) and PI3K (see PIK3CG; 601232) signaling pathways,
respectively. Activated alpha-V-beta-3 translocated to lipid rafts,
where it interacted with activated EGFR to induce coordinated signaling.
This coordination was essential for viral entry, RhoA (ARHA; 165390)
downregulation, stress fiber disassembly, and viral nuclear trafficking.

Raymond et al. (2005) noted that crystal structure and electron
microscopy analyses had demonstrated dramatically different active and
inactive conformations of alpha-V-beta-3 integrin. Manganese ions direct
the conformation of the extended, activated form, which binds ligands
through adjacent globular heads, whereas calcium ions direct the bent,
inactive structure, which is folded in a manner that masks the
ligand-binding site (Takagi et al., 2002). By mutation analysis, Raymond
et al. (2005) found that pathogenic forms of hantavirus required asp39
in the PSI domain of beta-3 for infection. Infection of cells by
pathogenic strains was enhanced by calcium and inhibited by manganese,
suggesting that hantavirus interacts with apical PSI domains exposed on
the surface of bent alpha-V-beta-3 integrins. Cells expressing the
extended form of alpha-V-beta-3 were resistant to hantavirus infection,
whereas cells expressing the bent form were susceptible. Raymond et al.
(2005) proposed that viral interaction with inactive integrin restricts
alpha-V-beta-3 functions that regulate vascular permeability.

Gong et al. (2010) found that the heterotrimeric guanine
nucleotide-binding protein G-alpha-13 (604406) directly binds to the
integrin beta-3 cytoplasmic domain and that G-alpha-13-integrin
interaction is promoted by ligand binding to the integrin alpha-IIb
(607759)-beta-3 and by GTP loading of G-alpha-13. Interference of
G-alpha-13 expression or a myristoylated fragment of G-alpha-13 that
inhibited interaction of alpha-IIb-beta-3 with G-alpha-13 diminished
activation of protein kinase c-Src (124095) and stimulated the small
guanosine triphosphatase RhoA (165390), consequently inhibiting cell
spreading and accelerating cell retraction. Gong et al. (2010) concluded
that integrins are noncanonical G-alpha-13-coupled receptors that
provide a mechanism for dynamic regulation of RhoA.

Shen et al. (2013) demonstrated that G-alpha-13 and talin (186745) bind
to mutually exclusive but distinct sites within the integrin beta-3
cytoplasmic domain in opposing waves. The first talin-binding wave
mediates inside-out signaling and also ligand-induced integrin
activation, but is not required for outside-in signaling. Integrin
ligation induces transient talin dissociation and G-alpha-13 binding to
an EXE motif (in which X denotes any residue), which selectively
mediates outside-in signaling and platelet spreading. The second
talin-binding wave is associated with clot retraction. An
EXE-motif-based inhibitor of G-alpha-13-integrin interaction selectively
abolishes outside-in signaling without affecting integrin ligation, and
suppresses occlusive arterial thrombosis without affecting bleeding
time. Shen et al. (2013) concluded that they discovered a mechanism for
the directional switch of integrin signaling and, on the basis of this
mechanism, designed a potent antithrombotic drug that does not cause
bleeding.

- Platelet-specific Antigens and Alloimmune Thrombocytopenia

There are 2 serologically defined allelic forms of the platelet-specific
alloantigen Pl(A): Pl(A1) and Pl(A2), both of which have been localized
to the GP IIIa molecule. The gene frequency for Pl(A1) is about 85% and
for Pl(A2) about 15% in U.S. Caucasians (Newman et al., 1989). Newman et
al. (1989) demonstrated that the Pl(A1) and Pl(A2) diallelic difference
depends on the presence of leucine or proline, respectively, as amino
acid 33 of the GP IIIa molecule (see 173470.0006). The amino acid
substitution was produced by a C-to-T polymorphism at base 196, which
created a unique restriction enzyme cleavage site in the Pl(A2) cDNA.
The platelet antigen system is of clinical significance because
alloimmunization can occur. Maternofetal incompatibility in relation to
Pl(A) is responsible for neonatal alloimmune thrombocytopenia (NAIT).
Immunization against Pl(A1) is responsible for posttransfusion
thrombocytopenia, a disorder limited almost entirely to women who have
acquired sensitization during pregnancy.

Shibata et al. (1986) reported a novel platelet antigen, YUK(b),
involved in a case of neonatal alloimmune thrombocytopenia. They
considered this antigen to be a product of an allele of the YUK gene,
another allele of which codes for YUK(a), which had been involved in
other cases of neonatal alloimmune thrombocytopenia. YUK(a) and YUK(b)
antigens are not expressed on platelets from patients with Glanzmann
thrombasthenia, suggesting that these antigens are present on platelet
glycoprotein IIb and/or IIIa. The gene frequencies for YUK(a) and YUK(b)
in the Japanese population were estimated to be 0.0083 and 0.9917,
respectively. YUK(b) and YUK(a) are the same as PEN(a) and PEN(b),
respectively. See 173470.0005 for a description of the molecular basis
of this polymorphism. Furihata et al. (1987) determined that the Pen(a)
alloantigen is associated with GP IIIa but is distinct from Pl(A). (See
also NOMENCLATURE below).

Kekomaki et al. (1991) concluded that a 50-kD cysteine-rich region of GP
IIIa is a frequent target of autoantibodies in idiopathic
thrombocytopenia.

Transplanted organs, particularly livers and kidneys, carry passenger
lymphocytes that can transmit autoimmune diseases or initiate alloimmune
disorders in the recipient. West et al. (1999) described 3 unrelated
patients with severe alloimmune thrombocytopenia that developed as a
result of antibodies against the HPA-1a (Pl(A1)) alloantigen. In these
patients the thrombocytopenia was refractory to all medical maneuvers
except the transfusion of HPA-1a-negative platelets. In 1 patient the
thrombocytopenia contributed to death. In another patient the
thrombocytopenia was cured by splenectomy, and in the third patient the
thrombocytopenia resolved after an episode of severe graft rejection.
All 3 organs were from the same donor, the kidney in 2 cases and the
liver in the third. The donor was homozygous for HPA-1b; the 3
recipients were homozygous for HPA-1a. The results of nested PCR with a
set of primers specific for the HLA-DR4 allele showed that DNA from the
donor was present in the spleen of the patient who responded to
splenectomy, but not in peripheral blood.

MOLECULAR GENETICS

Data on gene frequencies of allelic variants were tabulated by
Roychoudhury and Nei (1988).

- Glanzmann Thrombasthenia

In Glanzmann thrombasthenia (273800), both GP IIIa and the platelet
allotype are deficient or lacking. Kunicki et al. (1981) concluded that
the lack of expression of the Pl(A1) antigen on thrombasthenic platelets
results from the decrease or absence of GP IIIa.

In a child with Glanzmann thrombasthenia, Bray and Shuman (1989, 1990)
found compound heterozygosity for a defect in GP IIIa. The child had
inherited from the father a gene with a large rearrangement detected by
Southern blot analysis.

Newman et al. (1991) demonstrated that the form of Glanzmann
thrombasthenia frequent in Iraqi Jews is due to a truncated GP IIIa
lacking a transmembrane domain as a result of an 11-bp deletion within
exon 12 of the ITGB3 gene (173470.0014), whereas the form of the disease
frequent in Arabs in Israel is due to a 13-bp deletion that spans the
intron/exon boundary of exon 4 of the ITGA2B gene (607759.0002).

Rosenberg et al. (1997) stated that most mutations in the ITGA2B and
ITGB3 genes are point mutations: 10 in ITGB3 and 12 in ITGA2B. In
addition, 9 are small or large rearrangements: 5 in ITGB3 and 4 in
ITGA2B. They added a large deletion mutation of the ITGB3 gene
(173470.0011) to the list.

In a patient with Glanzmann thrombasthenia, Jin et al. (1996) identified
homozygosity for a mutation upstream of the GP IIIa exon 9 splice donor
site. Patient platelet GP IIIa transcripts lacked exon 9 despite normal
DNA sequence in all of the cis-acting sequences known to regulate splice
site selection. In vitro analysis of transcripts generated from
mini-gene constructs demonstrated that exon skipping occurred only when
the mutation was cis to a polymorphism 116 bp upstream, providing
precedence that 2 sequence variations in the same exon which do not
alter consensus splice sites and do not generate missense or nonsense
mutations can affect splice site selection. The mutant transcript
resulted from utilization of a cryptic splice acceptor site and returned
the open reading frame. These data supported the hypothesis that
pre-mRNA secondary structure and allelic sequence variants can influence
splicing and provided new insight into the regulated control of RNA
processing. In addition, haplotype analysis suggested that the patient
had 2 identical copies of chromosome 17. Markers studied on 3 other
chromosomes suggested that this finding was not due to consanguinity.
Jin et al. (1996) stated that the restricted phenotype in this patient
may provide information regarding the expression of potentially
imprinted genes on chromosome 17. Jin et al. (1996) ruled out the
possibility of a large gene deletion. They believed this to be the first
reported example of chromosomal 17 uniparental disomy, in this case
maternal disomy. The patient's father was not available for study to
definitively eliminate the possibility of consanguinity in this case.

Among 24 patients with Glanzmann thrombasthenia and 2 asymptomatic
carriers of the disorder, Jallu et al. (2010) identified 20 different
mutations in the ITGA2B gene (see, e.g., 607759.0015-607759.0016) in 18
individuals and 10 different mutations in the ITGB3 gene (see, e.g.,
173470.0016-173470.0017) in 8 individuals. There were 17 novel mutations
described. Four mutations in the ITGB3 gene were examined for
pathogenicity and all were found to decrease cell surface expression of
the IIb/IIIa complex, consistent with the severe type I phenotype. One
in particular, K253M (173470.0016), defined a key role for the lys253
residue in the interaction of the alpha-IIb propeller and the beta-I
domain of IIIa, and loss of lys253 would interrupt complex formation.

- Platelet-Type Bleeding Disorder 16, Autosomal Dominant

In 5 members of a family with autosomal dominant platelet-type bleeding
disorder-16 (BDPLT16; 187800) manifest as congenital
macrothrombocytopenia, Ghevaert et al. (2008) identified a heterozygous
mutation in the ITGB3 gene (D723H; 173470.0018). Molecular modeling
indicated that the mutation changed the electrostatic surface potential,
consistent with the disruption of a conserved salt bridge with R995 in
the ITGA2B gene (607759). In vitro functional expression assays in CHO
cells showed that the mutant protein was constitutively active. The
mutant protein also led to the formation of large proplatelet-like
protrusions in CHO cells and in patient megakaryocytes in the presence
of fibrinogen. The findings suggested that constitutive partial
activation by the mutant receptor caused abnormal sizing of platelets
during formation, resulting in thrombocytopenia due to increased
platelet turnover. GPIIb/IIIa expression on platelets was normal, and
none of the affected individuals had bleeding abnormalities; the defect
in the proband was an incidental finding.

In affected members of 2 unrelated Italian families with autosomal
dominant BDPLT16, Gresele et al. (2009) identified a heterozygous
mutation in the ITGB3 gene (173740.0019). Haplotype analysis suggested a
founder effect. Clinical features included lifelong bleeding tendency,
particularly mucosal bleeding, and macrothrombocytopenia.

Kobayashi et al. (2013) identified a heterozygous mutation in the ITGB3
gene (L718P; 173740.0020) in affected members of a 4-generation Japanese
family with BDPLT16. Studies of patient platelets showed decreased
expression of the GPIIb/IIIa complex and evidence of spontaneous partial
activation, including increased PAC-1 binding and increased fibrinogen
binding potential. In CHO cells, the mutation promoted the generation of
proplatelet-like protrusions by downregulation of RhoA (165390)
activity. The findings suggested that this mutation contributes to
thrombocytopenia through a gain of function.

- Heritability of Normal Blood Parameters

In a study of 2,413 participants in the Framingham Heart Study,
O'Donnell et al. (2001) found evidence for the heritability of platelet
aggregation responses to epinephrine and ADP and collagen lag time. The
estimated heritabilities were 0.48, 0.44, and 0.62, respectively.
Measured covariates accounted for only 4 to 7% of the overall variance
in platelet aggregation, and heritable factors accounted for 20 to 30%.
However, the Pl(A2) variant of platelet glycoprotein IIIa and the
fibrinogen HindIII beta-148 polymorphism (134830.0014) contributed less
than 1% of the overall variance.

In 567 Hutterite individuals, Weiss et al. (2004) found suggestive
evidence for linkage between whole blood serotonin and the ITGB3 gene:
genomewide linkage analysis yielded a lod score of 1.87 near ITGB3, and
allele-specific association tests showed that the leu33 allele was
associated with lower levels of serotonin (pointwise p = 0.000098).
Weiss et al. (2004) noted that more than 99% of whole blood serotonin is
contained in the platelet, and whole blood serotonin correlated with
serotonin per unit mass of platelet protein. The authors suggested that
polymorphisms in the ITGB3 gene may act as a recessive quantitative
trait locus (QTL) for whole blood serotonin. By sex stratification
analysis of the data obtained by Weiss et al. (2004), Weiss et al.
(2005) found that the serotonin QTL associated with the ITGB3 gene
influenced serotonin blood levels only in males.

- Association with Autism

See 610676 for a discussion of a possible association between autism
susceptibility and variation in the ITGB3 gene.

NOMENCLATURE

According to a report on nomenclature of platelet-specific alloantigens,
HPA-1 is the designation for Zw and Pl(A), and HPA-4 is the designation
for Pen and Yuk (von dem Borne and Decary, 1990). The allele of high
frequency is called 'a' and that of low frequency 'b.' Newman (1994)
pointed out that unfortunately the HPA nomenclature system was conceived
just before the discovery of the molecular basis of platelet membrane GP
polymorphisms, and he illustrated the fact that it does not seem to be
capable, in its original form, of serving the nomenclature needs while
remaining scientifically accurate. For illustration purposes, he
discussed the HPA nomenclature of GP IIIa, because it represented the
'worst case scenario.' He provided an ingenious diagram in which it
could be seen that the HPA-1a, HPA-4a, HPA-7a, HPA-6a, and HPA-8a
antigens are actually 5 different names for the same molecular species,
i.e., a single GP IIIa allele with a gene frequency of 0.85 in the
Caucasian population and the amino acid constitution
leu33-arg143-pro407-arg489-arg636.

Newman (1994) proposed a modified HPA nomenclature in which the 5
identical allelic forms of GP IIIa have only 1 HPA designation, HPA-1a.
A departure from the HPA nomenclature used GP IIIa as the designation
for the most frequent allele and the alloantigen it encodes, whereas
Pl(A2) becomes pro33-GP IIIa; Pen(b), gln143-GP IIIa; Mo(a), ala407-GP
IIIa; Ca/Tu(a), gln489-GP IIIa; and Sr(a), cys636-GP IIIa.

ANIMAL MODEL

Beta-3 integrins have been implicated in a wide variety of functions,
including platelet aggregation and thrombosis and implantation,
placentation, angiogenesis, bone remodeling, and tumor progression.
Glanzmann thrombasthenia can result from defects in the genes for either
the alpha-IIb (273800) or the beta-3 subunit. To develop a mouse model
of Glanzmann thrombasthenia and to further studies of hemostasis,
thrombosis, or other suggested roles of beta-3 integrins, Hodivala-Dilke
et al. (1999) generated a strain of beta-3 null mice. The mice were
viable and fertile, and showed all the cardinal features of Glanzmann
thrombasthenia. Implantation appeared to be unaffected, but placental
defects did occur and led to fetal mortality. Postnatal hemorrhage led
to anemia and reduced survival.

Reynolds et al. (2002) reported that mice lacking beta-3 integrins or
both beta-3 and beta-5 integrins not only support tumorigenesis but have
enhanced tumor growth as well. The tumors in these integrin-deficient
mice display enhanced angiogenesis, strongly suggesting that neither
beta-3 nor beta-5 integrins are essential for neovascularization.
Reynolds et al. (2002) also observed that angiogenic responses to
hypoxia and vascular endothelial growth factor (VEGF; 192240) are
augmented significantly in the absence of beta-3 integrins. Reynolds et
al. (2002) found no evidence that the expression or functions of other
integrins were altered as a consequence of the beta-3 deficiency, but
did observe elevated levels of VEGF receptor-2 (191306) in beta-3
null-endothelial cells. Reynolds et al. (2002) concluded that
alpha-5-beta-3 and alpha-5-beta-5 integrins are not essential for
vascular development or pathologic angiogenesis.

Reynolds et al. (2005) found that mice lacking Itgb3 showed enhanced
wound healing with reepithelialization complete several days earlier
than in wildtype mice. The effect was due to increased Tgfb1 (190180)
and enhanced dermal fibroblast infiltration into wounds of Itgb3-null
mice. Specifically, Itgb3 deficiency was associated with elevated Tgfbr1
(190181) and Tgfbr2 (190182) expression, reduced Smad3 (603109) levels,
sustained Smad2 (601366) and Smad4 (600993) nuclear localization, and
enhanced Tgfb1-mediated dermal fibroblast migration. Reynolds et al.
(2005) concluded that alpha-5-beta-3 integrin can control the rate of
wound healing by suppressing Tgfb1-mediated signaling.

*FIELD* AV
.0001
GLANZMANN THROMBASTHENIA
ITGB3, ARG214GLN

In a patient with Glanzmann thrombasthenia (273800), Bajt et al. (1992)
identified a G-to-A transition in the ITGB3 gene, resulting in an
arg214-to-gln (R214Q) substitution. The patient's platelets failed to
aggregate in response to stimuli. Bajt et al. (1992) concluded that the
point mutation involved a putative ligand-binding domain of the beta-3
subunit.

.0002
GLANZMANN THROMBASTHENIA
ITGB3, ASP119TYR

The Cam variant of Glanzmann thrombasthenia (273800) (Ginsberg et al.,
1986) is an autosomal recessive hereditary disorder of the GP IIb-IIIa
complex that is associated with the inability of this integrin to
recognize macromolecular or synthetic peptide ligands. Loftus et al.
(1990) determined that the disorder was due to a G-to-T transversion in
the ITGB3 gene, resulting in an asp119-to-tyr (D119Y) substitution. Two
affected sibs were studied.

.0003
GLANZMANN THROMBASTHENIA
ITGB3, ARG214TRP

In a patient with Glanzmann thrombasthenia (273800), Lanza et al. (1992)
found a C-to-T transition in exon D of ITGB3 resulting in an
arg214-to-trp (R214W) substitution. The patient was a 19-year-old
Caucasian female who from birth had had bleeding episodes consisting
mainly of unprovoked bruising. She had a traumatic intracerebral
hematoma at the age of 6 years. The parents, who were first cousins
('direct cousins'), were each heterozygous for the same mutation. The
patient showed an absence of platelet aggregation to ADP, thrombin, and
collagen, and a decreased clot retraction. Platelet fibrinogen was about
20% of normal. ADP-stimulated platelets bound markedly reduced amounts
of soluble fibrinogen, and platelet adhesion to surface-bound fibrinogen
was defective. The substitution involved an amino acid critical to the
region of GP IIIa involved in the binding of fibrinogen. Arg214 in the
protein encoded by the ITGB3 gene is substituted also in another form of
Glanzmann thrombasthenia (173470.0001).

.0004
GLANZMANN THROMBASTHENIA
ITGB3, SER752PRO

Chen et al. (1992) described a form of Glanzmann thrombasthenia (273800)
in which chemical and genetic analyses were consistent with the idea
that the functional defect was due to a ser752-to-pro (S752P)
substitution in the cytoplasmic domain of beta-3. This mutation was
predicted to impair the coupling between cellular activation and
upregulation of affinity of the alpha-IIb/beta-3 complex for fibrinogen.
This appeared to be the first point mutation reported that affects
integrin activation.

.0005
PEN(a)/PEN(b) ALLOANTIGEN POLYMORPHISM
THROMBOCYTOPENIA, NEONATAL ALLOIMMUNE, INCLUDED;;
POSTTRANSFUSION PURPURA, INCLUDED
ITGB3, ARG143GLN

The Pen(a)/Pen(b) alloantigen system has been implicated in 2 clinical
syndromes, neonatal alloimmune thrombocytopenic purpura and
posttransfusion purpura. Wang et al. (1992) identified a 526G-A
transition in the ITGB3 gene, resulting in an arg143-to-gln (R143Q)
substitution that correlated with the Pen serologic phenotype. The
polymorphic residue is located within the 63-amino acid region (residues
109-171) that interacts with the tripeptide sequence, RGD (arg-gly-asp),
that is present in many adhesive protein ligands, including fibrinogen,
fibronectin, and von Willebrand factor. Wang et al. (1992) found that
the anti-Pen(a) alloantibodies could recognize only the arg143
recombinant form and anti-Pen(b) alloantibodies were reactive only with
the gln143 isoform.

.0006
PL(A1)/(A2) ALLOANTIGEN POLYMORPHISM
THROMBOCYTOPENIA, NEONATAL ALLOIMMUNE, INCLUDED;;
POSTTRANSFUSION PURPURA, INCLUDED;;
MYOCARDIAL INFARCTION, SUSCEPTIBILITY TO, INCLUDED;;
FRACTURE, HIP, SUSCEPTIBILITY TO, INCLUDED
ITGB3, LEU33PRO

The molecular basis of the platelet-specific alloantigen system Pl(A) is
a 1565T-C transition in exon 2 of the ITGB3 gene, resulting in a
leu33-to-pro (L33P) substitution which corresponds to Pl(A1) and Pl(A2),
respectively (Newman et al., 1989). Known also as alloantigen Zw, Pl(A)
is the one most frequently implicated in syndromes of immune-mediated
platelet destruction, particularly neonatal alloimmune thrombocytopenia
and posttransfusion purpura.

Kim et al. (1995) determined the allelic frequencies of Pl(A1) and
Pl(A2) in African Americans, whites, and Koreans living in the
metropolitan Baltimore area.

Using a monoclonal antibody that specifically distinguished Pl(A1) from
Pl(A2), Weiss et al. (1995) observed an unexpected high frequency of
family members homozygous for the A2 allele in kindreds with a high
prevalence of acute coronary events at a relatively young age (under 60
years). In a case-control study, Weiss et al. (1996) found that the A2
allele was 2.1 times more prevalent among 71 patients with myocardial
infarction (608446) or unstable angina than among controls (39.4% vs
19.1%, respectively; P = 0.01). In a subgroup of patients whose disease
began before the age of 60 years, the prevalence of the A2 allele was
50%, a value that was 3.6 times that among control subjects under 60
years of age (13.9%; P = 0.002), yielding an odds ratio (OR) of 2.8 for
those with the A2 allele. In patients less than 60 years of age at the
onset of disease, the OR was 6.2.

Goldschmidt-Clermont et al. (1996) reported without supporting data that
the other major polymorphisms were not associated with myocardial
infarction: Ko(a), Ko(b), Bak(a), Bak(b), Pen(a), Pen(b), Br(a), and
Br(b).

Goldschmidt-Clermont et al. (1996) presented evidence that Sergei
Grinkov, twice Olympic pairs figure skating gold medalist, was
heterozygous for the A1/A2 polymorphism and suggested that this may have
been related to his precocious coronary artery disease. Grinkov, aged
28, collapsed suddenly while training on the ice rink in Lake Placid,
New York, and could not be resuscitated. Necropsy showed severe coronary
artery disease and a recent (4- to 6-hour-old) anteroseptal myocardial
infarction (MI). He had never sought medical attention for a heart
problem. He was not a smoker, did not use drugs or medications, did not
have hypertension or diabetes mellitus, his total cholesterol and lipid
profiles were unremarkable, and he trained for several hours daily.
Significantly, his father died suddenly at the age of 52 years. See the
lay account by Grinkov's widow, Ekaterina Gordeeva (1996).

Goldschmidt-Clermont et al. (1999) genotyped 116 asymptomatic sibs (60
Caucasians, 56 Afro-Caribbeans) of patients with coronary heart disease
manifested before the age of 60 years for the Pl(A) polymorphism. A
control cohort consisted of 268 individuals (168 Caucasians, 100
Afro-Caribbeans) who were matched for race and geographic area but were
free of coronary heart disease. The authors also characterized the sib
cohort for other atherogenic and thrombogenic risk factors. The results
supported the hypothesis that the prevalence of Pl(A2)-positive
individuals is high in kindreds with premature coronary heart disease.
Hence, like the established risk factors that tend to cluster in
families with premature coronary heart disease and contribute strongly
to the accelerated atherosclerotic process affecting these individuals,
the Pl(A2) polymorphism of GP IIIa may represent an inherited risk that
promotes the thromboembolic complications of coronary heart disease.
That these asymptomatic sibs had overall less-established risk factors
than their Pl(A1) counterparts may provide an explanation for why they
remained asymptomatic despite their Pl(A2) positivity.

In a cross-sectional study of patients with a history of myocardial
infarction and in matched controls from the Finnish population, Pastinen
et al. (1998) analyzed common variants of 8 genes implicated previously
as risk factors for coronary heart disease or MI. The most common low
density lipoprotein receptor (LDLR; 606945) mutations in Finland were
also included in the analysis. Multiplex genotyping of the target genes
was performed using a specific and efficient array-based minisequencing
system. The 4G allele of the PAI1 (173360) gene (P less than 0.05) and
the Pl(A2) allele of the glycoprotein IIIa gene (P less than 0.01) were
associated with an increased risk of MI in the Finnish study population.
They found that the combined effect of these risk alleles conferred a
high risk for the development of MI (OR = 4.5, P = 0.001), which was
particularly prominent in male subjects (OR = 6.4, P = 0.0005). The
observation of 2 separate genes contributing an additive risk of
developing MI exemplified the advantages of multiplex analysis of
genetic variation.

Undas et al. (2001) reported studies in healthy, male, nonsmoking
medical students aged 21 to 24 years using a controlled method for
producing microvascular injury. They found that the Pl(A2) variant was
associated with enhanced thrombin generation and impaired antithrombotic
action of aspirin at the site of microvascular injury.

Tofteng et al. (2007) analyzed the L33P polymorphism in 9,233 randomly
selected Danish individuals, of whom 267 had a hip fracture (see 166710)
during a 25-year follow-up period. Individuals homozygous for L33P had a
2-fold greater risk of hip fracture compared to noncarriers (p = 0.02),
with risk confined primarily to postmenopausal women, in whom the hazard
ratio was 2.6 after adjustment for age at menopause and use of hormone
replacement therapy.

.0007
Mo ALLOANTIGEN POLYMORPHISM
THROMBOCYTOPENIA, NEONATAL ALLOIMMUNE, INCLUDED
ITGB3, PRO407ALA

In a case of neonatal alloimmune thrombocytopenia, Kroll et al. (1990)
identified a private antigen on GP IIIa. Kuijpers et al. (1993)
identified a 1267C-G transversion in the ITGB3 gene, resulting in a
pro407-to-ala (P407A) substitution. The antigen was provisionally called
'Mo' after the name of the family. All family members, including those
who were Mo antigen positive, were healthy; heterozygotes appeared to
have no significant platelet dysfunction in vivo since none of them
suffered from increased tendency to bleeding or thrombosis. One of 45
random healthy blood donors was found to be positive for the Mo antigen.

.0008
GLANZMANN THROMBASTHENIA
ITGB3, IVSiDS, G-T, EXiDEL

Simsek et al. (1993) found homozygosity for a splice mutation in the
ITGB3 gene in a 29-year-old woman with Glanzmann thrombasthenia
(273800), the offspring of first-cousin parents. From childhood she had
suffered from a severe hemorrhagic diathesis, manifesting as epistaxis,
gingival bleeding, and menorrhagia and requiring regular transfusions of
whole blood and/or platelets. A G-to-T transversion eliminated the GT
splice donor site at the boundary of exon i with intron i. Both parents
were heterozygous and the proposita was homozygous for the mutation
which resulted in skipping of exon i.

.0009
Ca/Tu ALLOANTIGEN POLYMORPHISM
THROMBOCYTOPENIA, NEONATAL ALLOIMMUNE, INCLUDED
ITGB3, ARG489GLN

In a Filipino family living in Canada, Wang et al. (1993) demonstrated
that neonatal alloimmune thrombocytopenia, resulting from a platelet
alloantigen termed Ca, had its basis in a 1564G-A transition in the
ITGB3 gene, resulting in an arg489-to-gln (R489Q) substitution. At least
3 different codons resulting in the wildtype arg489 were identified in
the general population: CGG (63%), CGA (37%), and CGC (less than 1%).
Wang et al. (1993) demonstrated that the Ca alloantigen is identical to
the Tu platelet alloantigen defined in the Finnish population (Kekomaki
et al., 1993).

.0010
GLANZMANN THROMBASTHENIA
ITGB3, CYS374TYR

In a Chinese patient with Glanzmann thrombasthenia (273800), Chen et al.
(1993) identified a cys374-to-tyr (C374Y) substitution in the product of
the ITGB3 gene.

.0011
GLANZMANN THROMBASTHENIA
ITGB3, 11.2-KB DEL

In 3 unrelated Iraqi-Jewish families with Glanzmann thrombasthenia
(273800), Rosenberg et al. (1997) identified an 11.2-kb deletion between
an Alu sequence in intron 9 and exon 13 in the GP3A gene. They showed
that in the general Iraqi-Jewish population living in Israel, the
frequency of heterozygotes for an 11-bp deletion (173470.0014) is 1 in
114 and that for the 11.2-kb deletion is less than 1 in 700. Haplotype
analyses indicated that each mutation originated in a distinct founder.

.0012
GLANZMANN THROMBASTHENIA
ITGB3, ARG724TER

Wang et al. (1997) studied a thrombasthenic variant in a patient whose
platelets failed to aggregate in response to physiologic agonists,
despite the fact that they contained abundant levels of alpha-IIb/beta-3
on their surface. Binding of soluble fibrinogen or fibrinogen mimetic
antibodies to patient's platelets did not occur, except in the presence
of ligand-induced binding site antibodies that transformed the patient's
integrin complex into an active conformation from outside the cell.
Sequence analysis revealed a 2268C-T substitution in the ITGB3 gene that
resulted in an arg724-to-ter (R724X) substitution, producing a truncated
protein containing only the first 8 of the 47 amino acids normally
present in the cytoplasmic domain. Functional analysis of both the
patient's platelets and Chinese hamster ovary cells stably expressing
this truncated integrin revealed that the complex with the mutation was
able to mediate binding to immobilized fibrinogen, although downstream
events, including cytoskeletally-mediated cell spreading and tyrosine
phosphorylation of focal adhesion kinase (600758), failed to occur. The
studies of Wang et al. (1997) established the importance of the
membrane-distal portion of the integrin beta-3 cytoplasmic domain in
bidirectional transmembrane signaling in human platelets, and the role
of integrin signaling in maintaining normal hemostasis in vivo. The
patient was a 10-year-old African American with normal platelet counts
but with severe bleeding from birth. The bleeding time was greater than
20 minutes.

.0013
GLANZMANN THROMBASTHENIA
ITGB3, GLU616TER

Ferrer et al. (1998) described a novel mutation of the ITGB3 gene in a
20-year-old Caucasian woman clinically diagnosed as having Glanzmann
thrombasthenia (273800) when referred with a history of mucocutaneous
bleeding episodes and unprovoked bruising that started soon after birth,
as well as copious menstrual hemorrhages. The parents were unaffected
and not known to be related. The patient was found to be homozygous for
a 1846G-T transversion in exon 11 of the ITGB3 gene, resulting in a
glu616-to-ter (E616X) substitution. Cytometric and immunochemical
analysis indicated that platelet GP IIb-IIIa was absent in the proband
but present at normal levels in the heterozygous relatives. Pulse-chase
and immunoprecipitation analysis of GP IIb-IIIa complexes in cells
transiently cotransfected with cDNAs encoding normal GP IIb and
(T1846)GP IIIa showed neither maturation of GP IIb nor complex formation
and surface exposure of GPIIb-delGPIIIa. These observations indicated
that the sequence from glu616 to thr762 in GP IIIa is essential for
heterodimerization with GP IIb. PCR-based analysis demonstrated the
presence of normal levels of full-length GP IIIa mRNA in the proband and
in heterozygous relatives. In addition, a shortened transcript, with a
324-nucleotide deletion resulting from in-frame skipping of exons 10 and
11, was detectable upon reamplification of the DNA. Thus, unlike other
nonsense mutations, (T1846)GP IIIa does not lead to abnormal processing
or reduction in the number of transcripts with the termination codon.

.0014
GLANZMANN THROMBASTHENIA
ITGB3, 11-BP DEL, EX12

In 6 unrelated Iraqi-Jewish patients with Glanzmann thrombasthenia
(273800), Newman et al. (1991) identified an 11-bp deletion in exon 12
of the GP3A gene.

.0015
GLANZMANN THROMBASTHENIA
ITGB3, LEU117TRP

In a study of 40 families with Glanzmann thrombasthenia (273800) in
southern India, Peretz et al. (2006) found that 12 families carried a
428T-G transversion in exon 4 of the ITGB3 gene, resulting in a
leu143-to-trp substitution (L143W; L117W in the mature glycoprotein).
Evidence of a founder effect was detected. This mutation had been
described by Basani et al., (1997).

.0016
GLANZMANN THROMBASTHENIA
ITGB3, LYS253MET

In a patient with Glanzmann thrombasthenia (273800), Jallu et al. (2010)
identified compound heterozygosity for 2 mutations in the ITGB3 gene: an
836A-T transversion in exon 6, resulting in a lys253-to-met (K253M)
substitution in the mature protein, and G221D (173470.0017). Both
mutations are located in the beta-I domain. Flow cytometric studies of
the mutant protein expressed in COS-7 cells showed that the mutation
prevented normal GPIIb/IIIa complex expression on the cell surface
consistent with a severe type 1 phenotype. However, specific antibodies
detected some residual expression of the IIIa protein. Structural and
free energy analyses of the IIb/IIIa complex showed that the side chain
of lys253 protrudes from the IIIa beta-I domain and is involved with the
beta-propeller of alpha-IIb (607759). The K253M mutation would interrupt
this interaction.

.0017
GLANZMANN THROMBASTHENIA
ITGB3, GLY221ASP

In a patient with Glanzmann thrombasthenia (273800), Jallu et al. (2010)
identified compound heterozygosity for 2 mutations in the ITGB3 gene: a
740G-A transition in exon 5, resulting in a gly221-to-asp (G221D)
substitution in the mature protein, and K253M (173470.0016). Both
mutations are located in the beta-I domain. Flow cytometric studies of
the mutant protein expressed in COS-7 cells showed that the mutation
prevented normal GPIIb/IIIa complex expression on the cell surface
consistent with a severe type 1 phenotype. However, specific antibodies
detected some residual expression of the IIIa protein. Jallu et al.
(2010) postulated that the mutation interferes with correct folding of
the protein.

.0018
BLEEDING DISORDER, PLATELET-TYPE, 16
ITGB3, ASP723HIS

In 5 members of a family with autosomal dominant platelet-type bleeding
disorder-16 (BDPLT16; 187800) manifest as congenital
macrothrombocytopenia, Ghevaert et al. (2008) identified a heterozygous
c.2245G-C transversion in exon 14 of the ITGB3 gene, resulting in an
asp723-to-his (D723H) substitution in the membrane proximal cytoplasmic
segment of the protein. Molecular modeling indicated that the mutation
changed the electrostatic surface potential, consistent with the
disruption of a conserved salt bridge with R995 in the ITGA2B gene
(607759). The D723H mutation was not found in unaffected family members
or in 1,639 controls. In vitro functional expression assays in CHO cells
showed that the mutant protein was constitutively active. There was
spontaneously increased binding of the PAC-1 antibody, which
specifically recognizes the activated form of the GPIIb/IIIa complex, as
well as increased adhesion to von Willebrand factor (VWF) in static
conditions and increased binding to fibrinogen under shear stress
compared to wildtype. The mutant protein also led to the formation of
large proplatelet-like protrusions in CHO cells and in patient
megakaryocytes in the presence of fibrinogen. The findings suggested
that constitutive partial activation of the mutant receptor caused
abnormal sizing of platelets during formation, resulting in
thrombocytopenia due to increased platelet turnover. GPIIb/IIIa
expression on platelets was normal, and none of the affected individuals
had bleeding abnormalities; the defect in the proband was an incidental
finding.

.0019
BLEEDING DISORDER, PLATELET-TYPE, 16
ITGB3, IVS13DS, G-C, +1

In affected members of 2 unrelated Italian families with autosomal
dominant BDPLT16 (187800), Gresele et al. (2009) identified a
heterozygous G-to-C transversion in intron 13 of the ITGB3 gene
(c.2134+1G-C), resulting in an in-frame 120-bp deletion in exon 13, with
loss of 40 residues from the extracellular domain (asp647_glu686del).
The mutation segregated with the phenotype in the family and was not
found in 150 unrelated controls. Haplotype analysis suggested a founder
effect. Clinical features included lifelong bleeding tendency,
particularly mucosal bleeding, and macrothrombocytopenia. Patient
platelets showed decreased expression of the GPIIb/IIIa complex.
Functional studies showed several abnormalities, including impaired
platelet aggregation to physiologic agonists but not to ristocetin,
normal clot retraction, reduced fibrinogen binding and reduced
expression of activated GPIIb/IIIa upon stimulation, normal platelet
adhesion to immobilized fibrinogen but reduced platelet spreading, and
decreased tyrosine phosphorylation, indicating defective outside-in
signaling. Spontaneous aggregation was absent. The concomitant presence
of both the normal and a mutant ITGB3 allele in patient platelet lysates
suggested a loss-of-function hypothesis with a dominant-negative effect.

.0020
BLEEDING DISORDER, PLATELET-TYPE, 16
ITGB3, LEU718PRO

In a Spanish woman with BDPLT15 (187800), Jayo et al. (2010) identified
a de novo heterozygous c.2231T-C transition in the ITGB3 gene, resulting
in a leu718-to-pro (L718P) substitution in the membrane proximal region
of the cytoplasmic domain, which plays a role in maintaining the
GPIIb/IIIa complex in a low affinity state. The mutation was not found
in more than 50 control DNA samples and was not present in the
unaffected parents. Immunofluorescence studies showed that mutant
protein was retained intracellularly, consistent with reduced surface
expression of the GPIIb/IIIa complex on patient platelets. Cells
transfected with the mutation showed increased PAC-1 binding, increased
fibrinogen binding, and increased cell aggregation compared to controls,
suggesting that the mutation causes constitutive activation of the
integrin complex. Fibrinogen-adherent cells showed a peculiar spreading
phenotype with long protrusions. Cells with the mutation showed an
abnormal pattern of integrin clusters and integrin-free patches that was
associated with disruption of ordered lipid domains within the plasma
membrane. This aberrant distribution was thought to result in altered
outside-in signaling and to cause abnormal platelet adhesion.

Kobayashi et al. (2013) identified a heterozygous L718P substitution in
affected members of a 4-generation Japanese family with BDPLT16. The
mutation was identified by exome sequencing, was not found in control
databases, and segregated with the disorder in the family. Studies of
patient platelets showed decreased expression of the GPIIb/IIIa complex
and evidence of spontaneous partial activation, including increased
PAC-1 binding and increased fibrinogen binding potential. After
treatment with the agonist ADP, patient platelets did not show
significantly increased fibrinogen binding potential compared to
controls, suggesting that they cannot be fully activated in the presence
of such signals. In CHO cells, the mutation promoted the generation of
proplatelet-like protrusions by downregulation of RhoA (165390)
activity. The findings suggested that this mutation contributes to
thrombocytopenia through a gain of function.

*FIELD* SA
Newman et al. (1990); Saunders et al. (1985)
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P.; Boucheix, C.; Marguerie, G.; Frezal, J.: Assignment of GP3A gene
to chromosome 17 (somatic cell hybrid analysis), region q21.1-q21.3
(in situ hybridization). (Abstract) Cytogenet. Cell Genet. 51: 1096-1097,
1989.

66. von dem Borne, A. E. G.; Decary, F.: Nomenclature of platelet
specific antigens. Brit. J. Haemat. 74: 239-240, 1990.

67. Wang, R.; Furihata, K.; McFarland, J. G.; Friedman, K.; Aster,
R. H.; Newman, P. J.: An amino acid polymorphism within the RGD binding
domain of platelet membrane glycoprotein IIIa is responsible for the
formation of the Pen(a)/Pen(b) alloantigen system. J. Clin. Invest. 90:
2038-2043, 1992.

68. Wang, R.; McFarland, J. G.; Kekomaki, R.; Newman, P. J.: Amino
acid 489 is encoded by a mutational 'hot spot' on the beta-3 integrin
chain: the CA/TU human platelet alloantigen system. Blood 82: 3386-3391,
1993.

69. Wang, R.; Shattil, S. J.; Ambruso, D. R.; Newman, P. J.: Truncation
of the cytoplasmic domain of beta-3 in a variant form of Glanzmann
thrombasthenia abrogates signaling through the integrin alpha(IIIb)-beta(3)
complex. J. Clin. Invest. 100: 2393-2403, 1997.

70. Wang, X.; Huang, D. Y.; Huong, S.-M.; Huang, E.-S.: Integrin
alpha-v-beta-3 is a coreceptor for human cytomegalovirus. Nature
Med. 11: 515-521, 2005.

71. Wang, X.; Huong, S.-M.; Chiu, M. L.; Raab-Traub, N.; Huang, E.-S.
: Epidermal growth factor receptor is a cellular receptor for human
cytomegalovirus. Nature 424: 456-461, 2003.

72. Weiss, E. J.; Bray, P. F.; Tayback, M.; Schulman, S. P.; Kickler,
T. S.; Becker, L. C.; Weiss, J. L.; Gerstenblith, G.; Goldschmidt-Clermont,
P. J.: A polymorphism of a platelet glycoprotein receptor as an inherited
risk factor for coronary thrombosis. New Eng. J. Med. 334: 1090-1094,
1996.

73. Weiss, E. J.; Goldschmidt-Clermont, P. J.; Grigoryev, D.; Yin,
Y.; Kickler, T. S.; Bray, P. F.: A monoclonal antibody (SZ21) specific
for platelet GPIIIa distinguishes PlA1 from PlA2. Tissue Antigens 46:
374-381, 1995.

74. Weiss, L. A.; Abney, M.; Cook, E. H., Jr.; Ober, C.: Sex-specific
genetic architecture of whole blood serotonin levels. Am. J. Hum.
Genet. 76: 33-41, 2005.

75. Weiss, L. A.; Ober, C.; Cook, E. H., Jr.: ITGB3 shows genetic
and expression interaction with SLC6A4. Hum. Genet. 120: 93-100,
2006.

76. Weiss, L. A.; Veenstra-VanderWeele, J.; Newman, D. L.; Kim, S.-J.;
Dytch, H.; McPeek, M. S.; Cheng, S.; Ober, C.; Cook, E. H., Jr.; Abney,
M.: Genome-wide association study identifies ITGB3 as a QTL for whole
blood serotonin. Europ. J. Hum. Genet. 12: 949-954, 2004.

77. West, K. A.; Anderson, D. R.; McAlister, V. C.; Hewlett, T. J.
C.; Belitsky, P.; Smith, J. W.; Kelton, J. G.: Alloimmune thrombocytopenia
after organ transplantation. New Eng. J. Med. 341: 1504-1507, 1999.

78. Xiao, T.; Takagi, J.; Coller, B. S.; Wang, J.-H.; Springer, T.
A.: Structural basis for allostery in integrins and binding to fibrinogen-mimetic
therapeutics. Nature 432: 59-67, 2004.

79. Xiong, J.-P.; Stehle, T.; Diefenbach, B.; Zhang, R.; Dunker, R.;
Scott, D. L.; Joachimiak, A.; Goodman, S. L.; Arnaout, M. A.: Crystal
structure of the extracellular segment of integrin alpha-V-beta-3. Science 294:
339-345, 2001.

80. Xiong, J.-P.; Stehle, T.; Zhang, R.; Joachimiak, A.; Frech, M.;
Goodman, S. L.; Arnaout, M. A.: Crystal structure of the extracellular
segment of integrin alpha-V-beta-3 in complex with an Arg-Gly-Asp
ligand. Science 296: 151-155, 2002.

81. Zimrin, A. B.; Eisman, R.; Vilaire, G.; Schwartz, E.; Bennett,
J. S.; Poncz, M.: Structure of platelet glycoprotein IIIa: a common
subunit for two different membrane receptors. J. Clin. Invest. 81:
1470-1475, 1988.

*FIELD* CS
INHERITANCE:
Autosomal recessive

HEAD AND NECK:
[Nose];
Epistaxis;
[Mouth];
Gingival bleeding

ABDOMEN:
[Gastrointestinal];
Gastrointestinal hemorrhage

GENITOURINARY:
[Internal genitalia, female];
Menorrhagia

SKIN, NAILS, HAIR:
[Skin];
Unprovoked bruising;
Purpura

NEUROLOGIC:
[Central nervous system];
Intracranial hemorrhage

HEMATOLOGY:
Glanzmann thrombasthenia;
Neonatal alloimmune thrombocytopenia (NAIT);
Post-transfusion thrombocytopenia;
Bleeding tendency

LABORATORY ABNORMALITIES:
Platelet glycoprotein IIIa deficiency;
Decreased clot retraction;
Platelet aggregation defect;
Normal platelet count

MISCELLANEOUS:
See also Glanzmann thrombasthenia due to mutations in integrin alpha
2B (273800)

MOLECULAR BASIS:
Caused by mutations in the platelet glycoprotein IIIa gene (ITGB3,
173470.0001)

*FIELD* CN
Kelly A. Przylepa - updated: 12/5/2001
Kelly A. Przylepa - revised: 4/18/2001

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

*FIELD* ED
joanna: 07/23/2013
joanna: 12/5/2001
joanna: 4/18/2001

*FIELD* CN
Ada Hamosh - updated: 11/21/2013
Cassandra L. Kniffin - updated: 4/25/2013
Cassandra L. Kniffin - updated: 4/8/2010
Ada Hamosh - updated: 2/1/2010
Marla J. F. O'Neill - updated: 1/7/2008
Cassandra L. Kniffin - updated: 3/12/2007
Victor A. McKusick - updated: 6/6/2006
Paul J. Converse - updated: 5/5/2006
Patricia A. Hartz - updated: 7/6/2005
Paul J. Converse - updated: 5/23/2005
Marla J. F. O'Neill - updated: 2/17/2005
Ada Hamosh - updated: 9/30/2004
Victor A. McKusick - updated: 11/3/2003
Victor A. McKusick - updated: 7/24/2003
Cassandra L. Kniffin - reorganized: 5/14/2003
Ada Hamosh - updated: 5/6/2003
Denise L. M. Goh - updated: 4/16/2003
Ada Hamosh - updated: 4/9/2002
Ada Hamosh - updated: 4/2/2002
Paul J. Converse - updated: 2/28/2002
Ada Hamosh - updated: 10/23/2001
Victor A. McKusick - updated: 2/17/2000
Victor A. McKusick - updated: 1/6/2000
Victor A. McKusick - updated: 11/22/1999
Victor A. McKusick - updated: 3/16/1999
Victor A. McKusick - updated: 2/1/1999
Victor A. McKusick - updated: 9/17/1998
Victor A. McKusick - updated: 1/20/1998
Victor A. McKusick - updated: 6/21/1997
Victor A. McKusick - updated: 2/7/1997
Stylianos E. Antonarakis - updated: 7/5/1996

*FIELD* CD
Victor A. McKusick: 5/27/1988

*FIELD* ED
carol: 12/23/2013
alopez: 11/21/2013
carol: 11/14/2013
carol: 5/3/2013
ckniffin: 4/25/2013
carol: 5/30/2012
carol: 11/2/2011
ckniffin: 4/8/2011
carol: 11/12/2010
wwang: 4/12/2010
ckniffin: 4/8/2010
alopez: 2/2/2010
terry: 2/1/2010
terry: 12/17/2009
wwang: 11/5/2008
carol: 1/16/2008
carol: 1/8/2008
carol: 1/7/2008
terry: 1/7/2008
carol: 5/15/2007
carol: 5/14/2007
ckniffin: 5/10/2007
ckniffin: 3/12/2007
ckniffin: 3/8/2007
terry: 11/15/2006
alopez: 6/13/2006
terry: 6/6/2006
mgross: 5/12/2006
terry: 5/5/2006
mgross: 7/7/2005
terry: 7/6/2005
mgross: 6/17/2005
terry: 5/23/2005
wwang: 2/23/2005
terry: 2/17/2005
alopez: 11/5/2004
alopez: 10/29/2004
alopez: 10/1/2004
tkritzer: 9/30/2004
carol: 3/17/2004
mgross: 11/3/2003
tkritzer: 7/25/2003
terry: 7/24/2003
carol: 5/14/2003
ckniffin: 5/13/2003
alopez: 5/8/2003
terry: 5/6/2003
carol: 4/16/2003
ckniffin: 6/5/2002
cwells: 4/11/2002
terry: 4/9/2002
carol: 4/8/2002
alopez: 4/4/2002
terry: 4/2/2002
alopez: 2/28/2002
carol: 10/24/2001
terry: 10/23/2001
alopez: 3/6/2000
mcapotos: 3/3/2000
mcapotos: 3/1/2000
terry: 2/17/2000
mgross: 1/14/2000
terry: 1/6/2000
carol: 11/23/1999
terry: 11/22/1999
carol: 3/16/1999
terry: 3/16/1999
carol: 2/22/1999
terry: 2/19/1999
carol: 2/15/1999
terry: 2/1/1999
carol: 9/21/1998
terry: 9/17/1998
mark: 1/23/1998
terry: 1/20/1998
terry: 11/11/1997
terry: 11/10/1997
jenny: 7/9/1997
terry: 6/24/1997
terry: 6/21/1997
mark: 6/14/1997
mark: 6/12/1997
alopez: 6/4/1997
jamie: 3/5/1997
mark: 2/7/1997
jamie: 1/7/1997
terry: 1/6/1997
terry: 7/24/1996
carol: 7/5/1996
terry: 7/3/1996
mark: 6/8/1995
mimadm: 1/14/1995
carol: 11/11/1994
terry: 4/27/1994
warfield: 3/4/1994
carol: 9/22/1993

MIM 187800
*RECORD*
*FIELD* NO
187800
*FIELD* TI
#187800 BLEEDING DISORDER, PLATELET-TYPE, 16; BDPLT16
;;GLANZMANN THROMBASTHENIA, AUTOSOMAL DOMINANT;;
read moreTHROMBASTHENIA OF GLANZMANN AND NAEGELI, AUTOSOMAL DOMINANT
*FIELD* TX
A number sign (#) is used with this entry because platelet-type bleeding
disorder-16 (BDPLT16) is caused by heterozygous mutation in the gene
encoding platelet glycoprotein alpha-IIb (ITGA2B; 607759) on chromosome
17q21.31 or the gene encoding platelet glycoprotein IIIa (ITGB3; 173470)
on chromosome 17q21.32. Together these 2 proteins form an integrin,
known as platelet glycoprotein GPIIb/IIIa, that is expressed on
platelets.

Biallelic mutations in either of these 2 genes cause autosomal recessive
Glanzmann thrombasthenia (273800).

DESCRIPTION

BDPLT16 is an autosomal dominant form of congenital
macrothrombocytopenia associated with platelet anisocytosis. It is a
disorder of platelet production. Affected individuals may have no or
only mildly increased bleeding tendency. In vitro studies show mild
platelet functional abnormalities (summary by Kunishima et al., 2011 and
Nurden et al., 2011).

CLINICAL FEATURES

Gross et al. (1960) reported a family in which affected members over 3
generations had petechiae, bleeding from mucous membranes, prolonged
bleeding after injury, and severe anemia. Studies revealed prolonged
bleeding time, abnormal capillary fragility, and a normal or an
increased number of platelets, with giant platelets. Alteration in the
concentration of several platelet enzymes was found.

Hardisty et al. (1992) reported a young Italian man with a lifelong
history of bleeding from gums and mucocutaneous tissues. Laboratory
studies showed modest thrombocytopenia, platelet anisocytosis, and large
platelets. Platelet aggregation was decreased, but clot retraction was
normal. His platelets had decreased levels of the GPIIb/IIIa complex
compared to controls (40-50% by crossed immunoelectrophoresis), and
further decreased surface expression (12-20% using monocloncal
antibodies). Surface expression of GPIIb/IIIa increased upon platelet
stimulation, suggesting a substantial amount of these proteins in the
internal platelet store. His father also showed platelet anisocytosis
and large platelets. This family was also studied by Peyruchaud et al.
(1998) and Nurden et al. (2011).

Ghevaert et al. (2008) reported a family in which 5 individuals had
macrothrombocytopenia. GPIIb/IIIa expression on platelets was normal,
and none of the affected individuals had bleeding abnormalities; the
defect in the proband was an incidental finding.

Gresele et al. (2009) reported 2 unrelated Italian families with
autosomal dominant BDPLT16. Clinical features included lifelong bleeding
tendency, particularly mucosal bleeding, and macrothrombocytopenia.
Patient platelets showed decreased expression of the GPIIb/IIIa complex.
Functional studies showed several abnormalities, including impaired
platelet aggregation to physiologic agonists but not to ristocetin,
normal clot retraction, reduced fibrinogen binding and expression of
activated GPIIb/IIIa upon stimulation, normal platelet adhesion to
immobilized fibrinogen but reduced platelet spreading, and decreased
tyrosine phosphorylation, indicating defective outside-in signaling.

Jayo et al. (2010) reported a Spanish woman with a lifelong history of
mucocutaneous bleeding tendency associated with moderate
thrombocytopenia and platelet anisocytosis. Functional studies showed
decreased platelet agglutination to physiologic agonists and impaired
spreading on fibrinogen. There was no family history of a similar
disorder.

Kunishima et al. (2011) reported 11 patients from 4 unrelated Japanese
families with congenital macrothrombocytopenia. Bleeding tendency was
mild or absent. Platelet aggregation was decreased, but bleeding time
was normal, and platelet spreading on fibrinogen was partially impaired.
Patient platelets showed decreased surface expression of GPIIb/IIIa
(50-70% of controls).

Kobayashi et al. (2013) reported a 4-generation Japanese kindred in
which 10 individuals had mild bleeding tendencies, such as nasal
bleeding and purpura, associated with macrothrombocytopenia and platelet
anisocytosis. Laboratory studies showed decreased platelet aggregation
by physiologic agonists. Studies of patient platelets showed decreased
expression of the GPIIb/IIIa complex and evidence of spontaneous partial
activation, including increased PAC-1 binding and increased fibrinogen
binding potential. After treatment with the agonist ADP, patient
platelets did not show significantly increased fibrinogen binding
potential compared to controls, suggesting that they could not be fully
activated in the presence of such signals.

INHERITANCE

Of 13 families with Glanzmann thrombasthenia studied by Caen et al.
(1966), only 1 seemed to have dominant inheritance with probable
transmission through 4 generations with male-to-male transmission.

The transmission pattern in the families with macrothrombocytopenia
reported by Gresele et al. (2009), Ghevaert et al. (2008), and Kunishima
et al. (2011) was consistent with autosomal dominant inheritance.

MOLECULAR GENETICS

- Mutations in the ITGA2B Gene

In an Italian man with macrothrombocytopenia reported by Hardisty et al.
(1992), Peyruchaud et al. (1998) identified a heterozygous mutation in
the ITGA2B gene (R995Q; 607759.0017). In vitro functional expression
studies in CHO cells indicated that the R995Q mutation would give rise
to an integrin complex that is more easily activatable compared to
wildtype.

In 11 patients from 4 Japanese families with BDPLT16, Kunishima et al.
(2011) identified a heterozygous mutation in the ITGA2B gene (R995W;
607759.0018). The disease haplotype was unique in each family,
indicating independent occurrence. In vitro studies indicated that
mutant protein assumed a constitutive, activated conformation, but did
not induce platelet activation. Transfection of the mutation into CHO
cells and mouse liver-derived megakaryocytes resulted in abnormal
membrane ruffling and cytoplasmic protrusions, as well as defect
proplatelet formation. The findings were reminiscent of the activating
D723H mutation in ITGB3 (173470.0018), and Kunishima et al. (2011)
concluded that activating mutations in ITGA2B and ITGB3 are responsible
for a subset of congenital macrothrombocytopenias.

- Mutations in the ITGB3 Gene

In 5 members of a family with autosomal dominant BDPLT16 manifest as
macrothrombocytopenia, Ghevaert et al. (2008) identified a heterozygous
mutation in the ITGB3 gene (D723H; 173470.0018). Molecular modeling
indicated that the mutation changed the electrostatic surface potential,
causing disruption of a conserved salt bridge between D723 in ITGB3 and
residue R995 in the ITGA2B gene. In vitro functional expression assays
showed that the mutant protein was constitutively active. Cells
transfected with the mutation exhibited spontaneous and specific
increased binding of the antibody PAC-1, increased adhesion to von
Willebrand factor (VWF) in static conditions, and increased binding to
fibrinogen under shear stress compared to wildtype, all consistent with
a gain of function. The mutant protein also led to the formation of
large proplatelet-like protrusions in CHO cells and in patient
megakaryocytes in the presence of fibrinogen. The findings suggested
that constitutive partial activation of the mutant receptor caused
incorrect sizing of platelets during formation, resulting in
thrombocytopenia due to increased platelet turnover.

In affected members of 2 unrelated Italian families with autosomal
dominant BDPLT16, Gresele et al. (2009) identified a heterozygous splice
site mutation in the ITGB3 gene (173470.0019). Haplotype analysis
suggested a founder effect. In vitro studies suggested defective
GPIIb/IIIa outside-in signaling. The concomitant presence of both the
normal and a mutant ITGB3 allele in patient platelet lysates suggested a
loss-of-function hypothesis with a dominant-negative effect.

In a Spanish woman with a bleeding disorder, thrombocytopenia, platelet
anisocytosis, and reduced platelet aggregation, Jayo et al. (2010)
identified a de novo heterozygous mutation in the ITGB3 gene (L718P;
173470.0020).

Kobayashi et al. (2013) identified a heterozygous L718P mutation in the
ITGB3 gene in affected members of a 4-generation Japanese family with
BDPLT16. In CHO cells, the mutation promoted the generation of
proplatelet-like protrusions by downregulation of RhoA (165390)
activity. The findings suggested that this mutation contributes to
thrombocytopenia through a gain of function.

HISTORY

In von Willebrand disease (193400), factor VIII is low and the platelets
show faulty adhesion to glass. In hereditary thrombopathy, availability
of platelet factor-3 is reduced and platelets do not aggregate on
exposure to collagen. Crowell and Eisner (1972) described a family with
a combination of these abnormalities in affected persons in several
successive generations without male-to-male transmission.

*FIELD* SA
Ruggeri et al. (1982)
*FIELD* RF
1. Caen, J. P.; Castaldi, P. A.; Leclerc, J. C.; Inceman, S.; Larrieu,
M. J.; Probst, M.; Bernard, J.: Congenital bleeding disorders with
long bleeding time and normal platelet count. I. Glanzmann's thrombasthenia
(report of fifteen patients). Am. J. Med. 41: 4-26, 1966.

2. Crowell, E. B., Jr.; Eisner, E. V.: Familial association of thrombopathia
and antihemophilic factor (AHF, factor VIII) deficiency. Blood 40:
227-233, 1972.

3. Ghevaert, C.; Salsmann, A.; Watkins, N. A.; Schaffner-Reckinger,
E.; Rankin, A.; Garner, S. F.; Stephens, J.; Smith, G. A.; Debili,
N.; Vainchenker, W.; de Groot, P. G.; Huntington, J. A.; Laffan, M.;
Kieffer, N.; Ouwehand, W. H.: A nonsynonymous SNP in the ITGB3 gene
disrupts the conserved membrane-proximal cytoplasmic salt bridge in
the alphaIIb/beta3 integrin and cosegregates dominantly with abnormal
proplatelet formation and macrothrombocytopenia. Blood 111: 3407-3414,
2008.

4. Gresele, P.; Falcinelli, E.; Giannini, S.; D'Adamo, P.; D'Eustacchio,
A.; Corazzi, T.; Mezzasoma, A. M.; Di Bari, F.; Guglielmini, G.; Cecchetti,
L.; Noris, P.; Balduini, C. L.; Savoia, A.: Dominant inheritance
of a novel integrin beta3 mutation associated with a hereditary macrothrombocytopenia
and platelet dysfunction in two Italian families. Haematologica 94:
663-669, 2009.

5. Gross, R.; Gerok, W.; Lohr, G. W.; Vogell, W.; Walker, H. D.; Theopold,
W.: Ueber die Natur der Thrombasthenie: Thrombopathie Glanzmann Naegeli. Klin.
Wschr. 38: 193-206, 1960.

6. Hardisty, R.; Pidard, D.; Cox, A.; Nokes, T.; Legrand, C.; Bouillot,
C.; Pannocchia, A.; Heilmann, E.; Hourdille, P.; Bellucci, S.; Nurden,
A.: A defect of platelet aggregation associated with an abnormal
distribution of glycoprotein IIb-IIIa complexes within the platelet:
the cause of a lifelong bleeding disorder. Blood 80: 696-708, 1992.

7. Jayo, A.; Conde, I.; Lastres, P.; Martinez, C.; Rivera, J.; Vicente,
V.; Gonzalez-Manchon, C.: L718P mutation in the membrane-proximal
cytoplasmic tail of beta3 promotes abnormal alphaIIb/beta3 clustering
and lipid microdomain coalescence, and associates with a thrombasthenia-like
phenotype. Haematologica 95: 1158-1166, 2010.

8. Kobayashi, Y.; Matsui, H.; Kanai, A.; Tsumura, M.; Okada, S.; Miki,
M.; Nakamura, K.; Kunishima, S.; Inaba, T.; Kobayashi, M.: Identification
of the integrin beta3 L718P mutation in a pedigree with autosomal
dominant thrombocytopenia with anisocytosis. Brit. J. Haemat. 160:
521-529, 2013.

9. Kunishima, S.; Kashiwagi, H.; Otsu, M.; Takayama, N.; Eto, K.;
Onodera, M.; Miyajima, Y.; Takamatsu, Y.; Suzumiya, J.; Matsubara,
K.; Tomiyama, Y.; Saito, H.: Heterozygous ITGA2B R995W mutation inducing
constitutive activation of the alphaIIb/beta3 receptor affects proplatelet
formation and causes congenital macrothrombocytopenia. Blood 117:
5479-5484, 2011.

10. Nurden, A. T.; Pillois, X.; Fiore, M.; Heilig, R.; Nurden, P.
: Glanzmann thrombasthenia-like syndromes associated with macrothrombocytopenias
and mutations in the genes encoding the alphaIIb/beta3 integrin. Semin.
Thromb. Hemost. 37: 698-706, 2011.

11. Peyruchaud, O.; Nurden, A. T.; Milet, S.; Macchi, L.; Pannochia,
A.; Bray, P. F.; Kieffer, N.; Bourre, F.: R to Q amino acid substitution
in the GFFKR sequence of the cytoplasmic domain of the integrin alphaIIb
subunit in a patient with a Glanzmann's thrombasthenia-like syndrome. Blood 92:
4178-4187, 1998.

12. Ruggeri, Z. M.; Bader, R.; de Marco, L.: Glanzmann thrombasthenia:
deficient binding of von Willebrand factor to thrombin-stimulated
platelets. Proc. Nat. Acad. Sci. 79: 6038-6041, 1982.

*FIELD* CS
INHERITANCE:
Autosomal dominant

HEMATOLOGY:
Macrothrombocytopenia;
Bleeding tendency, mild, mucocutaneous;
Platelet anisocytosis;
Variable platelet functional defects

MISCELLANEOUS:
Some patients show no bleeding abnormalities

MOLECULAR BASIS:
Caused by mutation in the integrin, alpha-2b gene (ITGA2B, 607759.0017);
Caused by mutation in the integrin, beta-3 gene (ITGB3, 173470.0018)

*FIELD* CN
Cassandra L. Kniffin - revised: 4/25/2013

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

*FIELD* ED
joanna: 06/04/2013
ckniffin: 4/25/2013

*FIELD* CN
Cassandra L. Kniffin - updated: 4/25/2013
Cassandra L. Kniffin - updated: 5/14/2003

*FIELD* CD
Victor A. McKusick: 6/2/1986

*FIELD* ED
carol: 05/03/2013
ckniffin: 4/25/2013
carol: 5/14/2003
ckniffin: 5/13/2003
alopez: 6/3/1997
mimadm: 5/10/1995
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/27/1989
marie: 3/25/1988
reenie: 10/18/1986

MIM 273800
*RECORD*
*FIELD* NO
273800
*FIELD* TI
#273800 GLANZMANN THROMBASTHENIA; GT
;;BLEEDING DISORDER, PLATELET-TYPE, 2; BDPLT2;;
read moreTHROMBASTHENIA OF GLANZMANN AND NAEGELI;;
PLATELET GLYCOPROTEIN IIb-IIIa DEFICIENCY;;
GP IIb-IIIa COMPLEX, DEFICIENCY OF;;
PLATELET FIBRINOGEN RECEPTOR, DEFICIENCY OF;;
GLYCOPROTEIN COMPLEX IIb-IIIa, DEFICIENCY OF
*FIELD* TX
A number sign (#) is used with this entry because Glanzmann
thrombasthenia (GT) can be caused by mutation in the gene encoding
platelet glycoprotein alpha-IIb (ITGA2B; 607759) on chromosome 17q21.31
or the gene encoding platelet glycoprotein IIIa (ITGB3; 173470) on
chromosome 17q21.32.

DESCRIPTION

Glanzmann thrombasthenia is an autosomal recessive bleeding disorder
characterized by failure of platelet aggregation and by absent or
diminished clot retraction. The abnormalities are related to
quantitative or qualitative abnormalities of the GPIIb/IIIa platelet
surface fibrinogen receptor complex resulting from mutations in either
the GPIIb or GPIIIa genes (Rosenberg et al., 1997).

See 187800 for discussion of a possible dominant form.

CLINICAL FEATURES

Glanzmann thrombasthenia has been classified clinically into types I and
II. In type I, platelets show absence of the glycoprotein IIb-IIIa
complexes at their surface and lack fibrinogen and clot retraction
capability. In type II, the platelets express the GPIIb-IIIa complex at
reduced levels (5-20% controls), have detectable amounts of fibrinogen,
and have low or moderate clot retraction capability. The platelets of GT
'variants' have normal or near normal (60-100%) expression of
dysfunctional receptors (Ferrer et al., 1998).

The disorder is manifest soon after birth with episodic mucocutaneous
bleeding and unprovoked bruising. Epistaxis frequently occurs and, in
women, copious menstrual hemorrhage. Intracranial bleeding may also
occur. Bleeding time is prolonged, with normal platelet count, normal
platelet morphology, and normal coagulation times. Platelets fail to
aggregate, either spontaneously or in response to agonists, such as ADP,
thrombin, or epinephrine, although there may be a transient response to
ristocetin (Ferrer et al., 1998; Poncz et al., 1994).

Early cases were reported by Lelong (1960) and Marx and Jean (1962).
Friedman et al. (1964) described the disease in a boy and girl who were
double first cousins (the mother of one was a sister of the father of
the other and vice versa). An apparently unique congenital platelet
disorder was described by Bowie et al. (1964). Absent platelet
aggregation and defective hemostatic plug formation in the disorder was
emphasized by Caen et al. (1966).

Cronberg et al. (1967) described a kindred in which 3 persons in 2
sibships had a severe clotting defect, whereas others, including all 4
parents of the affected sibships, had a minor defect. The most
impressive abnormality in vitro was complete absence of ability of the
platelets to aggregate or adhere to glass. The same was observed by
Zaizov et al. (1968) in brother and sister whose parents were first
cousins once removed. Papayannis and Israels (1970) concluded that the
heterozygote can be identified by the clot retraction test. Some
heterozygotes are mild bleeders.

The difficult nosology of the heterogeneous category of platelet
disorders was discussed by Kanska et al. (1963) and by Alagille et al.
(1964). A classification of hereditary thrombopathies into 3 major
categories was given by Bowie and Owen (1968): (1) thrombopathy
(deficient or ineffective platelet factor-3); (2) thrombasthenia
(diminished clot retraction); and (3) compound platelet defects (those
associated with deficiency of either factor VIII or factor IX).

Corby et al. (1971) reported a brother and sister who had bleeding
diathesis, normal platelet counts, prolonged bleeding times, deficient
platelet factor 3 and absent platelet aggregation in response to ADP,
collagen and epinephrine. Hathaway (1971) reviewed disorders of platelet
function. Awidi (1983) described 12 Jordanian patients in 9 families.
The parents were consanguineous in all instances. All patients were
children with mucosal bleeding. Awidi (1983) concluded that Glanzmann
disease is the second most frequent bleeding disorder in Jordan.

Poncz et al. (1994) reported an infant who presented at 2 days of age
with subdural bleeding and extensive ecchymoses. She had a normal
platelet count, prolonged bleeding time, and absent platelet
aggregation.

BIOCHEMICAL FEATURES

Gross et al. (1960) found that the platelets of affected patients had
greatly reduced glyceraldehydephosphate dehydrogenase (GAPDH) and
pyruvate kinase (PK) activity. The platelets showed reduced
adhesiveness; on blood smears there was notable absence of platelet
aggregation, and by electron microscopy there were 'round' platelets.

Moser et al. (1968) found severe deficiency of glutathione reductase in
platelets in 2 sibs. Karpatkin and Weiss (1972) found markedly decreased
glutathione peroxidase activity of platelets in 3 patients.

Booyse et al. (1972) found that microquantitation of thrombosthenin by
radial immunodiffusion and a specific immunohistochemical antibody
staining technique indicated absence of the surface-localized
thrombosthenin in platelets from patients with Glanzmann thrombasthenia.
In addition, ADP- and ATP-induced changes of the surface of normal
platelets could not be demonstrated.

PATHOGENESIS

Dautigny et al. (1975) used an IgG antibody derived from a
multitransfused patient with thrombasthenia to test platelets in vitro.
Platelets of all normal subjects reacted with it in fixing complement.
Platelets of the patient of origin and 8 others with thrombasthenia did
not react. The authors took this as evidence that a specific molecule of
the platelet is lacking or structurally modified in this disease.
Phillips and Agin (1977) found deficiency of 2 platelet membrane
glycoproteins in this disorder.

McEver et al. (1980) used the hybridoma technique to characterize
further the platelet glycoprotein abnormality in Glanzmann
thrombasthenia. Spleen cells from mice immunized with human platelets
were fused to mouse myeloma cells with HGPRT deficiency. Hybridoma lines
producing a variety of antiplatelet antibodies were isolated by HAT
selection and cloned. Purified monoclonal IgG from 6 lines was prepared.
One of these bound to a protein (called Tab) on normal platelets but not
on thrombasthenic platelets. The protein was isolated by affinity
chromatography on Tab-Sepharose. SDS polyacrylamide gel electrophoresis
showed the protein to be a complex of glycoproteins IIb and IIIa.
Platelets of heterozygotes had intermediate Tab-binding. The platelet
alloantigen Pl(A1) (see 173470) was not recognized by Tab, because
platelets from 3 Pl(A1)-negative subjects bound Tab normally. Thus, a
platelet membrane protein that may be required for platelet aggregation
and clot retraction was demonstrated. The 2 bands shown to be deficient
in thrombasthenia were glycoproteins GPIIb and GPIIIa. Following up on
the work of McEver et al. (1980), McEver et al. (1982) separated the
polypeptide subunits IIb and IIIa of the glycoprotein isolated by
affinity chromatography using the specific monoclonal antibody, and they
compared their structures. The peptide maps were found to be completely
different, suggesting that they are products of 2 separate genes or
cleaved from a single proprotein.

Montgomery et al. (1983) demonstrated that an assay using monoclonal
antibodies raised in the mouse can recognize the deficiency of
glycoprotein Ib in the Bernard-Soulier syndrome (BSS; 231200) and of the
glycoprotein IIb/IIIa in Glanzmann thrombasthenia. They studied 3
patients with BSS and 6 with GT. Of the GT patients, 3 had negligible
binding to the antibody (type I GT) and 3 had greatly reduced binding
(type II GT). The platelets in GT are aggregation-defective; those in
BSS are adhesion-defective.

Levy et al. (1971) and Tongio et al. (1982) studied GT in 2 large
families belonging to the Manouche Gypsy tribe. In studies of these
cases, Kunicki et al. (1981) showed that the molecular expression of
type I thrombasthenia, absence of GPIIb and IIa, was controlled by a
different gene from that determining the platelet antigen Pl(A1). This
suggested that the lack of expression of Pl(A1) antigen on
thrombasthenic platelets is the result of absence of GPIIIa, the
glycoprotein carrier of the Pl(A1) determinant. A deletion of the
platelet antigen Pl(A1) on platelets from 5 patients with GT was
demonstrated by Kunicki and Aster (1978) and confirmed by others.

Nurden et al. (1987) described a patient with Glanzmann thrombasthenia
whose platelets contained unstable GPIIb/IIIa complexes unable to
support fibrinogen binding. Giltay et al. (1987) found that endothelial
cells from patients with Glanzmann disease were normal in their ability
to synthesize and express a GPIIb/IIIa complex. This suggested that the
defect in platelets may be caused by a defect in a regulatory element
affecting the transcription of these 2 genes in megakaryocytes, as
proposed by Bray et al. (1986). Alternatively, some evidence suggested
that platelet and endothelial GPIIb/IIIa are not identical. The
electrophoretic mobility of the complexes and their subunits is
different, and not all monoclonal antibodies directed against platelet
GPIIb/IIIa crossreact with endothelial GPIIb/IIIa. The surface protein
deficient in Glanzmann disease is related to the family that includes
LFA1A (153370) and MAC1 (120980). Coller et al. (1987) found that
immunoblot patterns of glycoprotein IIIa could distinguish the defect
present in most Iraqi-Jewish cases from that in Arab cases in Israel.

To explain why both GPIIb and GPIIIa are deficient in Glanzmann disease,
Bray et al. (1986) suggested that there may be a defect in a common
regulatory element, or that a molecular defect in either protein may
result in instability or improper processing of the other.

In a patient with features of Glanzmann thrombasthenia (see 173470) and
leukocyte adhesion deficiency-1, McDowall et al. (2003) identified a
novel form of integrin dysfunction involving ITGB1 (135630), ITGB2, and
ITGB3 (173470). ITGB2 and ITGB3 were constitutively clustered. Although
all 3 integrins were expressed on the cell surface at normal levels and
were capable of function following extracellular stimulation, they could
not be activated via the 'inside-out' signaling pathways.

DIAGNOSIS

Seligsohn et al. (1985) demonstrated that in the form of Glanzmann
thrombasthenia frequent in Iraqi Jews, prenatal diagnosis is possible by
means of a monoclonal antibody against GPIIb/IIIa applied to fetal blood
obtained by fetoscopic venipuncture. The method would not be applicable
in the rare instances of variant thrombasthenia due to a functional
rather than a quantitative defect of GPIIb/IIIa. They tested an
earlier-born child in this family who was found to have had facial
purpura soon after delivery by cesarean section, excessive bleeding with
circumcision, and repeated episodes of gingival bleeding, epistaxis, and
pharyngeal bleeding from 'injury caused by sweets.' The diagnosis of
Glanzmann disease was based on lack of clot retraction, isolated
(nonaggregated) platelets on blood smear, and failure of ADP-induced
platelet aggregation.

Bray (1994) reviewed the inherited diseases of platelet glycoproteins
and made recommendations of general strategy for rapid molecular
characterization of those disorders.

MOLECULAR GENETICS

Newman et al. (1991) demonstrated that the form of Glanzmann
thrombasthenia frequent in Iraqi Jews is due to a truncated GPIIIa as a
result of an 11-bp deletion within the GP3A gene (173470.0014), whereas
the form of the disease frequent in Arabs in Israel is due to a 13-bp
deletion in the GP2B gene (607759.0002).

In 2 kindreds from Israel with Glanzmann thrombasthenia, Russell et al.
(1988) could find no major insertions, deletions, or rearrangements in
either the GP2B or the GP3A gene.

In a patient with Glanzmann thrombasthenia, Bajt et al. (1992)
identified a mutation in the ITGB3 gene (173470.0001). The patient's
platelets failed to aggregate in response to stimuli. In an Ashkenazi
Jewish female infant with Glanzmann thrombasthenia, born of a
consanguineous marriage, Poncz et al. (1994) identified a homozygous
mutation in the ITGA2B gene (607759.0007).

Peretz et al. (2006) investigated the molecular basis of Glanzmann
thrombasthenia in 40 families from southern India. Of 23 identified
mutations, 13 in the ITGA2B gene and 10 in the ITGB3 gene, 20 were
novel. A founder effect was observed for 2 mutations. Alternative
splicing was predicted in silico for the normal variant and a missense
variant of the ITGB3 gene, and for 10 of 11 frameshift or nonsense
mutations in ITGA2B or ITGB3.

Among 24 patients with Glanzmann thrombasthenia and 2 asymptomatic
carriers of the disorder, Jallu et al. (2010) identified 20 different
mutations in the ITGA2B gene (see, e.g., 607759.0015-607759.0016) in 18
individuals and 10 different mutations in the ITGB3 (see, e.g.,
173470.0016-173470.0017) gene in 8 individuals. There were 17 novel
mutations described. Four mutations in the ITGB3 gene were examined for
pathogenicity and all were found to decrease cell surface expression of
the IIb/IIIa complex, consistent with the severe type I phenotype. One
in particular, K253M (173470.0016), defined a key role for the lys253
residue in the interaction of the alpha-IIb propeller and the beta-I
domain of IIIa, and loss of lys253 would interrupt complex formation.

POPULATION GENETICS

A splice site mutation in the ITGA2B gene (607759.0008) has been
identified exclusively in patients with Glanzmann thrombasthenia from
the French Gypsy Manouche community. By genotyping and haplotype
analysis of 23 individuals, including 9 patients with Glanzmann
thrombasthenia, from 16 families from the French Manouche community,
Fiore et al. (2011) identified a 4-Mb ancestral common core haplotype,
indicating a founder effect. The mutation was estimated to have occurred
about 300 to 400 years ago. Gypsies are believed to be a population with
Indian origins with an initial exodus into the Byzantine Empire during
the 11th century. Fiore et al. (2011) suggested that the Manouche
families moved from Germany to the north of France between the 17th and
18th centuries.

HISTORY

Stevens and Meyer (2002) reviewed the work of 2 Swiss pioneer
hematologists, Eduard Glanzmann (1887-1959) and Guido Fanconi
(1892-1979).

*FIELD* SA
Bellucci et al. (1985); Beutler (1972); Degos et al. (1975); Herrmann
et al. (1983); Herrmann et al. (1982); Khanduri et al. (1981); Meyer
and Herrmann (1985); Nachman (1966); Nurden and Caen (1974); Nurden
et al. (1985); Pittman and Graham (1964); Ruggeri et al. (1982); Waller
and Gross (1964)
*FIELD* RF
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2. Awidi, A. S.: Increased incidence of Glanzmann's thrombasthenia
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3. Bajt, M. L.; Ginsberg, M. H.; Frelinger, A. L., III; Berndt, M.
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7. Bowie, E. J. W.; Owen, C. A., Jr.: Thrombopathy. Seminars Hemat. 5:
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8. Bowie, E. J. W.; Thompson, J. H., Jr.; Owen, C. A., Jr.: A new
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9. Bray, P. F.: Inherited diseases of platelet glycoproteins: considerations
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10. Bray, P. F.; Rosa, J.-P.; Lingappa, V. R.; Kan, Y. W.; McEver,
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17. Ferrer, M.; Tao, J.; Iruin, G.; Sanchez-Ayuso, M.; Gonzalez-Rodriguez,
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18. Fiore, M.; Pillois, X.; Nurden, P.; Nurden, A. T.; Austerlitz,
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20. Giltay, J. C.; Leeksma, O. C.; Breederveld, C.; van Mourik, J.
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21. Gross, R.; Gerok, W.; Lohr, G. W.; Vogell, W.; Waller, H. D.;
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24. Herrmann, F. H.; Meyer, M.; Ihle, E.: Protein and glycoprotein
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26. Kanska, B.; Niewiarowski, S.; Ostrowski, L.; Poplawski, A.; Prokopowicz,
J.: Macrothrombocytic thrombopathia. Clinical, coagulation and hereditary
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27. Karpatkin, S.; Weiss, H. J.: Deficiency of glutathione peroxidase
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28. Khanduri, U.; Pulimood, R.; Sudarsanam, A.; Carman, R. H.; Jadhav,
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29. Kunicki, T. J.; Aster, R. H.: Deletion of the platelet-specific
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30. Kunicki, T. J.; Pidard, D.; Cazenave, J.-P.; Nurden, A. T.; Caen,
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1981.

31. Lelong, J. C.: La thrombopathie de Glanzmann-Naegeli. Paris:
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32. Levy, J. M.; Mayer, G.; Sacrez, R.; Ruff, R.; Francfort, J. J.;
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33. Marx, R.; Jean, G.: Studien zur Pathogenese der Thrombasthenie
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34. McDowall, A.; Inwald, D.; Leitinger, B.; Jones, A.; Liesner, R.;
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35. McEver, R. P.; Baenziger, J. U.; Majerus, P. W.: Isolation and
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36. McEver, R. P.; Baenziger, N. L.; Majerus, P. W.: Isolation and
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37. Meyer, M.; Herrmann, F. H.: Diversity of glycoprotein deficiencies
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38. Montgomery, R. R.; Kunicki, T. J.; Taves, C.; Pidard, D.; Corcoran,
M.: Diagnosis of Bernard-Soulier syndrome and Glanzmann's thrombasthenia
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1983.

39. Moser, K.; Lechner, K.; Vinazzer, H.: A hitherto not described
enzyme defect in thrombasthenia: glutathione reductase deficiency. Thromb.
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40. Nachman, R. L.: Thrombasthenia: immunologic evidence of a platelet
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*FIELD* CS
INHERITANCE:
Autosomal recessive

HEAD AND NECK:
[Nose];
Epistaxis;
[Mouth];
Gingival bleeding

ABDOMEN:
[Gastrointestinal];
GI hemorrhage

GENITOURINARY:
[Internal genitalia, female];
Menorrhagia

SKIN, NAILS, HAIR:
[Skin];
Easy bruisability;
Purpura

NEUROLOGIC:
[Central nervous system];
Intracranial hemorrhage

HEMATOLOGY:
Glanzmann thrombasthenia;
Normal platelet count;
Abnormal platelet aggregation

LABORATORY ABNORMALITIES:
Prolonged bleeding time;
Deficiency of glycoprotein (GP)IIb-IIIa complex

MISCELLANEOUS:
Increased frequency in Iraqi Jews, selected Arab populations, French
gypsies, and natives of Southern India;
Autosomal dominant inheritance has been rarely reported (187800)

MOLECULAR BASIS:
Caused by mutation in the integrin, alpha-2b gene (ITGA2B, 607759.0002);
Caused by mutation in the integrin, beta-3 gene (ITGB3, 173470.0001)

*FIELD* CN
Kelly A. Przylepa - revised: 2/8/2002

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

*FIELD* ED
ckniffin: 03/08/2007
joanna: 2/8/2002

*FIELD* CN
Cassandra L. Kniffin - updated: 9/22/2011
Cassandra L. Kniffin - updated: 4/8/2010
Victor A. McKusick - updated: 6/6/2006
Cassandra L. Kniffin - reorganized: 5/14/2003
Ada Hamosh - updated: 5/6/2003
Victor A. McKusick - updated: 2/5/2003
Paul J. Converse - updated: 2/28/2002
Victor A. McKusick - updated: 1/14/2000
Ada Hamosh - updated: 5/11/1999
Victor A. McKusick - updated: 2/19/1999
Jennifer P. Macke - updated: 8/27/1996
Stylianos E. Antonarakis - updated: 7/4/1996

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

*FIELD* ED
carol: 09/23/2011
ckniffin: 9/22/2011
carol: 9/21/2011
carol: 9/12/2011
ckniffin: 9/8/2011
wwang: 4/12/2010
ckniffin: 4/8/2010
terry: 3/25/2009
alopez: 6/13/2006
terry: 6/6/2006
ckniffin: 6/28/2004
terry: 6/25/2004
carol: 5/14/2003
ckniffin: 5/13/2003
alopez: 5/8/2003
terry: 5/6/2003
tkritzer: 2/11/2003
terry: 2/5/2003
carol: 4/8/2002
alopez: 2/28/2002
mgross: 1/14/2000
alopez: 5/14/1999
terry: 5/11/1999
carol: 2/22/1999
terry: 2/19/1999
terry: 6/24/1997
mark: 6/12/1997
alopez: 6/5/1997
alopez: 5/8/1997
mark: 3/17/1997
jenny: 12/9/1996
terry: 11/25/1996
terry: 7/24/1996
carol: 7/22/1996
carol: 7/4/1996
terry: 7/2/1996
mark: 2/9/1996
terry: 1/30/1996
mark: 7/6/1995
terry: 1/5/1995
mimadm: 5/18/1994
warfield: 3/10/1994
carol: 3/5/1994
carol: 11/18/1993