RBCC

Full text data of ITGA2B

ITGA2B (GP2B, ITGAB) [Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Integrin alpha-IIb (GPalpha IIb; GPIIb; Platelet membrane glycoprotein IIb; CD41; Integrin alpha-IIb heavy chain; Integrin alpha-IIb light chain, form 1; Integrin alpha-IIb light chain, form 2; Flags: Precursor)

UniProt P08514
ID ITA2B_HUMAN Reviewed; 1039 AA.
AC P08514; B2RCY8; O95366; Q14443; Q17R67;
DT 01-AUG-1988, integrated into UniProtKB/Swiss-Prot.
read moreDT 14-APR-2009, sequence version 3.
DT 22-JAN-2014, entry version 182.
DE RecName: Full=Integrin alpha-IIb;
DE AltName: Full=GPalpha IIb;
DE Short=GPIIb;
DE AltName: Full=Platelet membrane glycoprotein IIb;
DE AltName: CD_antigen=CD41;
DE Contains:
DE RecName: Full=Integrin alpha-IIb heavy chain;
DE Contains:
DE RecName: Full=Integrin alpha-IIb light chain, form 1;
DE Contains:
DE RecName: Full=Integrin alpha-IIb light chain, form 2;
DE Flags: Precursor;
GN Name=ITGA2B; Synonyms=GP2B, ITGAB;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND VARIANT ALA-313.
RX PubMed=2439501;
RA Poncz M., Eisman R., Heidenreich R., Silver S.M., Vilaire G.,
RA Surrey S., Schwartz E., Bennett J.S.;
RT "Structure of the platelet membrane glycoprotein IIb. Homology to the
RT alpha subunits of the vitronectin and fibronectin membrane
RT receptors.";
RL J. Biol. Chem. 262:8476-8482(1987).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND VARIANT ALA-313.
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 [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM 1).
RX PubMed=2322558; DOI=10.1021/bi00457a020;
RA Heidenreich R., Eisman R., Surrey S., Delgrosso K., Bennett J.S.,
RA Schwartz E., Poncz M.;
RT "Organization of the gene for platelet glycoprotein IIb.";
RL Biochemistry 29:1232-1244(1990).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Spleen;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16625196; DOI=10.1038/nature04689;
RA Zody M.C., Garber M., Adams D.J., Sharpe T., Harrow J., Lupski J.R.,
RA Nicholson C., Searle S.M., Wilming L., Young S.K., Abouelleil A.,
RA Allen N.R., Bi W., Bloom T., Borowsky M.L., Bugalter B.E., Butler J.,
RA Chang J.L., Chen C.-K., Cook A., Corum B., Cuomo C.A., de Jong P.J.,
RA DeCaprio D., Dewar K., FitzGerald M., Gilbert J., Gibson R.,
RA Gnerre S., Goldstein S., Grafham D.V., Grocock R., Hafez N.,
RA Hagopian D.S., Hart E., Norman C.H., Humphray S., Jaffe D.B.,
RA Jones M., Kamal M., Khodiyar V.K., LaButti K., Laird G., Lehoczky J.,
RA Liu X., Lokyitsang T., Loveland J., Lui A., Macdonald P., Major J.E.,
RA Matthews L., Mauceli E., McCarroll S.A., Mihalev A.H., Mudge J.,
RA Nguyen C., Nicol R., O'Leary S.B., Osoegawa K., Schwartz D.C.,
RA Shaw-Smith C., Stankiewicz P., Steward C., Swarbreck D.,
RA Venkataraman V., Whittaker C.A., Yang X., Zimmer A.R., Bradley A.,
RA Hubbard T., Birren B.W., Rogers J., Lander E.S., Nusbaum C.;
RT "DNA sequence of human chromosome 17 and analysis of rearrangement in
RT the human lineage.";
RL Nature 440:1045-1049(2006).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Lung;
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 PARTIAL NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Erythroleukemia;
RX PubMed=2351656;
RA Bray P.F., Leung C.S.-I., Shuman M.A.;
RT "Human platelets and megakaryocytes contain alternately spliced
RT glycoprotein IIb mRNAs.";
RL J. Biol. Chem. 265:9587-9590(1990).
RN [8]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 392-1039 (ISOFORM 1).
RX PubMed=3422188; DOI=10.1111/j.1432-1033.1988.tb13762.x;
RA Uzan G., Frachet P., Lajmanovich A., Prandini M.-H., Denarier E.,
RA Duperray A., Loftus J., Ginsberg M., Plow E., Marguerie G.;
RT "cDNA clones for human platelet GPIIb corresponding to mRNA from
RT megakaryocytes and HEL cells. Evidence for an extensive homology to
RT other Arg-Gly-Asp adhesion receptors.";
RL Eur. J. Biochem. 171:87-93(1988).
RN [9]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 868-1039 (ISOFORM 1).
RX PubMed=3479442; DOI=10.1172/JCI113277;
RA Bray P.F., Rosa J.P., Johnston G.I., Shiu D.T., Cook R.G., Lau C.,
RA Kan Y.W., McEver R.P., Shuman M.A.;
RT "Platelet glycoprotein IIb. Chromosomal localization and tissue
RT expression.";
RL J. Clin. Invest. 80:1812-1817(1987).
RN [10]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-62 AND 1021-1039.
RX PubMed=2845986; DOI=10.1016/S0006-291X(88)80884-2;
RA Prandini M.H., Denarier E., Frachet P., Uzan G., Marguerie G.;
RT "Isolation of the human platelet glycoprotein IIb gene and
RT characterization of the 5' flanking region.";
RL Biochem. Biophys. Res. Commun. 156:595-601(1988).
RN [11]
RP PROTEIN SEQUENCE OF 32-56 AND 903-917.
RX PubMed=3534886; DOI=10.1073/pnas.83.21.8351;
RA Charo I.F., Fitzgerald L.A., Steiner B., Rall S.C., Bekeart L.S.,
RA Phillips D.R.;
RT "Platelet glycoproteins IIb and IIIa: evidence for a family of
RT immunologically and structurally related glycoproteins in mammalian
RT cells.";
RL Proc. Natl. Acad. Sci. U.S.A. 83:8351-8355(1986).
RN [12]
RP PROTEIN SEQUENCE OF 32-42.
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 [13]
RP PROTEIN SEQUENCE OF 32 AND 872.
RX PubMed=8620874; DOI=10.1111/j.1432-1033.1996.0205n.x;
RA Makogonenko E.M., Yakubenko V.P., Ingham K.C., Medved L.V.;
RT "Thermal stability of individual domains in platelet glycoprotein
RT IIbIIIa.";
RL Eur. J. Biochem. 237:205-211(1996).
RN [14]
RP PROTEIN SEQUENCE OF 487-501 AND 1026-1038.
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 [15]
RP PROTEIN SEQUENCE OF 903-922 AND 934-939.
RX PubMed=2476117;
RA Calvete J.J., Alvarez M.V., Rivas G., Hew C.L., Henschen A.,
RA Gonzalez-Rodriguez J.;
RT "Interchain and intrachain disulphide bonds in human platelet
RT glycoprotein IIb. Localization of the epitopes for several monoclonal
RT antibodies.";
RL Biochem. J. 261:551-560(1989).
RN [16]
RP PARTIAL PROTEIN SEQUENCE, DISULFIDE BONDS, AND GLYCOSYLATION AT
RP ASN-46; ASN-280; ASN-601 AND ASN-711.
RX PubMed=2775232;
RA Calvete J.J., Henschen A., Gonzalez-Rodriguez J.;
RT "Complete localization of the intrachain disulphide bonds and the N-
RT glycosylation points in the alpha-subunit of human platelet
RT glycoprotein IIb.";
RL Biochem. J. 261:561-568(1989).
RN [17]
RP PARTIAL PROTEIN SEQUENCE, AND GLYCOSYLATION AT SER-878.
RX PubMed=7688323; DOI=10.1016/0014-5793(93)80959-X;
RA Calvete J.J., Muniz-Diaz E.;
RT "Localization of an O-glycosylation site in the alpha-subunit of the
RT human platelet integrin GPIIb/IIIa involved in Baka (HPA-3a)
RT alloantigen expression.";
RL FEBS Lett. 328:30-34(1993).
RN [18]
RP PARTIAL NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3).
RX PubMed=9809974;
RA Trikha M., Cai Y., Grignon D., Honn K.V.;
RT "Identification of a novel truncated alphaIIb integrin.";
RL Cancer Res. 58:4771-4775(1998).
RN [19]
RP PROTEOLYTIC CLEAVAGE, AND PYROGLUTAMATE FORMATION AT GLN-891.
RX PubMed=2226834; DOI=10.1016/0014-5793(90)80443-M;
RA Calvete J.J., Schafer W., Henschen A., Gonzalez-Rodriguez J.;
RT "Characterization of the beta-chain N-terminus heterogeneity and the
RT alpha-chain C-terminus of human platelet GPIIb. Posttranslational
RT cleavage sites.";
RL FEBS Lett. 272:37-40(1990).
RN [20]
RP MUTAGENESIS OF 1029-PRO-PRO-1030.
RX PubMed=10212286; DOI=10.1074/jbc.274.18.12945;
RA Leisner T.M., Wencel-Drake J.D., Wang W., Lam S.C.;
RT "Bidirectional transmembrane modulation of integrin alphaIIbbeta3
RT conformations.";
RL J. Biol. Chem. 274:12945-12949(1999).
RN [21]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-601, 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 [22]
RP INTERACTION WITH RNF181.
RX PubMed=18331836; DOI=10.1016/j.bbrc.2008.02.142;
RA Brophy T.M., Raab M., Daxecker H., Culligan K.G., Lehmann I.,
RA Chubb A.J., Treumann A., Moran N.;
RT "RN181, a novel ubiquitin E3 ligase that interacts with the KVGFFKR
RT motif of platelet integrin alpha(IIb)beta3.";
RL Biochem. Biophys. Res. Commun. 369:1088-1093(2008).
RN [23]
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 [24]
RP VARIANT HPA-3 (BAK).
RX PubMed=2350579;
RA Lyman S., Aster R.H., Visentin G.P., Newman P.J.;
RT "Polymorphism of human platelet membrane glycoprotein IIb associated
RT with the Baka/Bakb alloantigen system.";
RL Blood 75:2343-2348(1990).
RN [25]
RP VARIANT GT ASP-273.
RX PubMed=8282784; DOI=10.1172/JCI116942;
RA Poncz M., Rifat S., Coller B.S., Newman P.J., Shattil S.J.,
RA Parrella T., Fortina P., Bennett J.S.;
RT "Glanzmann thrombasthenia secondary to a Gly273-->Asp mutation
RT adjacent to the first calcium-binding domain of platelet glycoprotein
RT IIb.";
RL J. Clin. Invest. 93:172-179(1994).
RN [26]
RP VARIANT GT ASP-449.
RX PubMed=7508443;
RA Wilcox D.A., Wautier J.-L., Pidard D., Newman P.J.;
RT "A single amino acid substitution flanking the fourth calcium binding
RT domain of alpha IIb prevents maturation of the alpha IIb beta 3
RT integrin complex.";
RL J. Biol. Chem. 269:4450-4457(1994).
RN [27]
RP VARIANT GT HIS-358.
RX PubMed=7706461; DOI=10.1172/JCI117828;
RA Wilcox D.A., Paddock C.M., Lyman S., Gill J.C., Newman P.J.;
RT "Glanzmann thrombasthenia resulting from a single amino acid
RT substitution between the second and third calcium-binding domains of
RT GPIIb. Role of the GPIIb amino terminus in integrin subunit
RT association.";
RL J. Clin. Invest. 95:1553-1560(1995).
RN [28]
RP VARIANT GT VAL-456-457-ASP DEL, AND CHARACTERIZATION OF VARIANT GT
RP VAL-456-457-ASP DEL.
RX PubMed=8704171;
RA Basani R.B., Vilaire G., Shattil S.J., Kolodziej M.A., Bennett J.S.,
RA Poncz M.;
RT "Glanzmann thrombasthenia due to a two amino acid deletion in the
RT fourth calcium-binding domain of alpha IIb: demonstration of the
RT importance of calcium-binding domains in the conformation of alpha IIb
RT beta 3.";
RL Blood 88:167-173(1996).
RN [29]
RP VARIANTS GT ILE-207; THR-596 AND GLN-1026.
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 [30]
RP VARIANT GT PRO-214, AND CHARACTERIZATION OF VARIANT GT PRO-214.
RX PubMed=9473221;
RA Grimaldi C.M., Chen F., Wu C., Weiss H.J., Coller B.S., French D.L.;
RT "Glycoprotein IIb Leu214Pro mutation produces Glanzmann thrombasthenia
RT with both quantitative and qualitative abnormalities in GPIIb/IIIa.";
RL Blood 91:1562-1571(1998).
RN [31]
RP VARIANT GT PRO-778.
RX PubMed=9763559;
RA Tadokoro S., Tomiyama Y., Honda S., Arai M., Yamamoto N., Shiraga M.,
RA Kosugi S., Kanakura Y., Kurata Y., Matsuzawa Y.;
RT "A Gln747-->Pro substitution in the IIb subunit is responsible for a
RT moderate IIbbeta3 deficiency in Glanzmann thrombasthenia.";
RL Blood 92:2750-2758(1998).
RN [32]
RP VARIANT BDPLT16 GLN-1026, AND CHARACTERIZATION OF VARIANT BDPLT16
RP GLN-1026.
RX PubMed=9834222;
RA Peyruchaud O., Nurden A.T., Milet S., Macchi L., Pannochia A.,
RA Bray P.F., Kieffer N., Bourre F.;
RT "R to Q amino acid substitution in the GFFKR sequence of the
RT cytoplasmic domain of the integrin IIb subunit in a patient with a
RT Glanzmann's thrombasthenia-like syndrome.";
RL Blood 92:4178-4187(1998).
RN [33]
RP VARIANTS GT SER-320; LYS-355 AND PRO-778.
RX PubMed=9722314; DOI=10.1046/j.1365-2141.1998.00824.x;
RA Ambo H., Kamata T., Handa M., Kawai Y., Oda A., Murata M., Takada Y.,
RA Ikeda Y.;
RT "Novel point mutations in the alphaIIb subunit (Phe289-->Ser,
RT Glu324-->Lys and Gln747-->Pro) causing thrombasthenic phenotypes in
RT four Japanese patients.";
RL Br. J. Haematol. 102:829-840(1998).
RN [34]
RP VARIANTS GT LYS-355 AND THR-596.
RX PubMed=9734640; DOI=10.1046/j.1365-2141.1998.00852.x;
RA Ruan J., Peyruchaud O., Alberio L., Valles G., Clemetson K.,
RA Bourre F., Nurden A.T.;
RT "Double heterozygosity of the GPIIb gene in a Swiss patient with
RT Glanzmann's thrombasthenia.";
RL Br. J. Haematol. 102:918-925(1998).
RN [35]
RP VARIANTS ILE-40; SER-874 AND ASN-968.
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 [36]
RP VARIANT GT ARG-705, AND CHARACTERIZATION OF VARIANT GT ARG-705.
RX PubMed=9920835;
RA Gonzalez-Manchon C., Fernandez-Pinel M., Arias-Salgado E.G.,
RA Ferrer M., Alvarez M.-V., Garcia-Munoz S., Ayuso M.S., Parrilla R.;
RT "Molecular genetic analysis of a compound heterozygote for the
RT glycoprotein (GP) IIb gene associated with Glanzmann's thrombasthenia:
RT disruption of the 674-687 disulfide bridge in GPIIb prevents surface
RT exposure of GPIIb-IIIa complexes.";
RL Blood 93:866-875(1999).
RN [37]
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 [38]
RP VARIANTS GT ALA-176 AND LEU-176.
RX PubMed=10607701;
RA Basani R.B., French D.L., Vilaire G., Brown D.L., Chen F.,
RA Coller B.S., Derrick J.M., Gartner T.K., Bennett J.S., Poncz M.;
RT "A naturally occurring mutation near the amino terminus of alphaIIb
RT defines a new region involved in ligand binding to alphaIIbbeta3.";
RL Blood 95:180-188(2000).
RN [39]
RP VARIANTS GT TRP-161; LEU-222; ARG-412 AND PRO-847.
RX PubMed=11798398; DOI=10.1080/095371001317126383;
RA Vinciguerra C., Bordet J.C., Beaune G., Grenier C., Dechavanne M.,
RA Negrier C.;
RT "Description of 10 new mutations in platelet glycoprotein IIb
RT (alphaIIb) and glycoprotein IIIa (beta3) genes.";
RL Platelets 12:486-495(2001).
RN [40]
RP VARIANT GT PRO-86, AND CHARACTERIZATION OF VARIANT GT PRO-86.
RX PubMed=12181054; DOI=10.1046/j.1365-2141.2002.03678.x;
RA Tanaka S., Hayashi T., Hori Y., Terada C., Han K.S., Ahn H.S.,
RA Bourre F., Tani Y.;
RT "A Leu55 to Pro substitution in the integrin alphaIIb is responsible
RT for a case of Glanzmann's thrombasthenia.";
RL Br. J. Haematol. 118:833-835(2002).
RN [41]
RP VARIANTS GT VAL-139; ALA-176; GLU-267; ASP-380; THR-405; ASP-581;
RP ARG-705; VAL-752 AND PRO-755.
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 [42]
RP VARIANTS GT PHE-329 AND THR-405, AND CHARACTERIZATION OF VARIANTS GT
RP PHE-329 AND THR-405.
RX PubMed=12424194; DOI=10.1182/blood-2002-07-2266;
RA Mitchell W.B., Li J.H., Singh F., Michelson A.D., Bussel J.,
RA Coller B.S., French D.L.;
RT "Two novel mutations in the alpha IIb calcium-binding domains identify
RT hydrophobic regions essential for alpha IIbbeta 3 biogenesis.";
RL Blood 101:2268-2276(2003).
RN [43]
RP VARIANT GT HIS-174, AND CHARACTERIZATION OF VARIANT GT HIS-174.
RX PubMed=12506038; DOI=10.1182/blood-2002-07-2144;
RA Kiyoi T., Tomiyama Y., Honda S., Tadokoro S., Arai M., Kashiwagi H.,
RA Kosugi S., Kato H., Kurata Y., Matsuzawa Y.;
RT "A naturally occurring Tyr143His alpha IIb mutation abolishes alpha
RT IIb beta 3 function for soluble ligands but retains its ability for
RT mediating cell adhesion and clot retraction: comparison with other
RT mutations causing ligand-binding defects.";
RL Blood 101:3485-3491(2003).
RN [44]
RP VARIANT GT MET-982, CHARACTERIZATION OF VARIANT GT MET-982, AND
RP VARIANT THR-989.
RX PubMed=15099289; DOI=10.1046/j.1538-7836.2004.00711.x;
RA Nurden A.T., Breillat C., Jacquelin B., Combrie R., Freedman J.,
RA Blanchette V.S., Schmugge M., Rand M.L.;
RT "Triple heterozygosity in the integrin alphaIIb subunit in a patient
RT with Glanzmann's thrombasthenia.";
RL J. Thromb. Haemost. 2:813-819(2004).
RN [45]
RP VARIANT GT CYS-202, AND CHARACTERIZATION OF VARIANT GT CYS-202.
RX PubMed=15219201; DOI=10.1111/j.1538-7836.2004.00758.x;
RA Rosenberg N., Landau M., Luboshitz J., Rechavi G., Seligsohn U.;
RT "A novel Phe171Cys mutation in integrin alpha causes Glanzmann
RT thrombasthenia by abrogating alphaIIbbeta3 complex formation.";
RL J. Thromb. Haemost. 2:1167-1175(2004).
RN [46]
RP VARIANT GT LEU-943, AND CHARACTERIZATION OF VARIANT GT LEU-943.
RX PubMed=17018384;
RA Jayo A., Pabon D., Lastres P., Jimenez-Yuste V., Gonzalez-Manchon C.;
RT "Type II Glanzmann thrombasthenia in a compound heterozygote for the
RT alpha IIb gene. A novel missense mutation in exon 27.";
RL Haematologica 91:1352-1359(2006).
RN [47]
RP VARIANTS GT THR-405; THR-596; ARG-705; PRO-778; PHE-934; LEU-957;
RP MET-982 AND THR-989, AND CHARACTERIZATION OF VARIANTS GT PHE-934 AND
RP LEU-957.
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).
RN [48]
RP VARIANT BDPLT16 TRP-1026, AND CHARACTERIZATION OF VARIANT BDPLT16
RP TRP-1026.
RX PubMed=21454453; DOI=10.1182/blood-2010-12-323691;
RA Kunishima S., Kashiwagi H., Otsu M., Takayama N., Eto K., Onodera M.,
RA Miyajima Y., Takamatsu Y., Suzumiya J., Matsubara K., Tomiyama Y.,
RA Saito H.;
RT "Heterozygous ITGA2B R995W mutation inducing constitutive activation
RT of the alphaIIbbeta3 receptor affects proplatelet formation and causes
RT congenital macrothrombocytopenia.";
RL Blood 117:5479-5484(2011).
CC -!- FUNCTION: Integrin alpha-IIb/beta-3 is a receptor for fibronectin,
CC fibrinogen, plasminogen, prothrombin, thrombospondin and
CC vitronectin. It recognizes the sequence R-G-D in a wide array of
CC ligands. It recognizes the sequence H-H-L-G-G-G-A-K-Q-A-G-D-V in
CC 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 cell
CC surface.
CC -!- SUBUNIT: Heterodimer of an alpha and a beta subunit. The alpha
CC subunit is composed of a heavy and a light chain linked by a
CC disulfide bond. Alpha-IIb associates with beta-3. Directly
CC interacts with RNF181.
CC -!- INTERACTION:
CC Self; NbExp=7; IntAct=EBI-702693, EBI-702693;
CC P05106:ITGB3; NbExp=11; IntAct=EBI-702693, EBI-702847;
CC -!- SUBCELLULAR LOCATION: Membrane; Single-pass type I membrane
CC protein.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=P08514-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P08514-2; Sequence=VSP_002737;
CC Name=3;
CC IsoId=P08514-3; Sequence=VSP_002736;
CC -!- TISSUE SPECIFICITY: Isoform 1 and isoform 2 were identified in
CC platelets and megakaryocytes, but not in reticulocytes or in
CC Jurkat and U-937 white blood cell line. Isoform 3 is expressed by
CC leukemia, prostate adenocarcinoma and melanoma cells but not by
CC platelets or normal prostate or breast epithelial cells.
CC -!- POLYMORPHISM: Position 874 is associated with platelet-specific
CC alloantigen HPA-3/BAK/LEK. HPA-3A/BAK(A)/LEK(A) has Ile-874 and
CC HPA-3B/BAK(B)/LEK(B) has Ser-874. HPA-3B is involved in neonatal
CC alloimmune thrombocytopenia (NAIT or NATP).
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 alpha chain family.
CC -!- SIMILARITY: Contains 7 FG-GAP repeats.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/ITGA2B";
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DR EMBL; J02764; AAA60114.1; -; mRNA.
DR EMBL; M34480; AAA35926.1; -; mRNA.
DR EMBL; M34344; AAA53150.1; -; Genomic_DNA.
DR EMBL; M33319; AAA53150.1; JOINED; Genomic_DNA.
DR EMBL; M33320; AAA53150.1; JOINED; Genomic_DNA.
DR EMBL; M54799; AAA52599.1; -; Genomic_DNA.
DR EMBL; X06831; CAA29987.1; -; mRNA.
DR EMBL; M18085; AAA52597.1; -; mRNA.
DR EMBL; M22568; AAA52587.1; -; Genomic_DNA.
DR EMBL; M22569; AAA52588.1; -; Genomic_DNA.
DR EMBL; AF098114; AAC98507.1; -; mRNA.
DR EMBL; AK315335; BAG37735.1; -; mRNA.
DR EMBL; AC003043; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC117443; AAI17444.1; -; mRNA.
DR EMBL; BC126442; AAI26443.1; -; mRNA.
DR PIR; A34269; A34269.
DR RefSeq; NP_000410.2; NM_000419.3.
DR UniGene; Hs.411312; -.
DR PDB; 1DPK; NMR; -; A=1020-1039.
DR PDB; 1DPQ; NMR; -; A=1020-1039.
DR PDB; 1JX5; Model; -; A=32-483.
DR PDB; 1KUP; NMR; -; A=1018-1028.
DR PDB; 1KUZ; NMR; -; A=1018-1028.
DR PDB; 1M8O; NMR; -; A=1020-1039.
DR PDB; 1RN0; Model; -; A=32-482.
DR PDB; 1S4W; NMR; -; A=1020-1039.
DR PDB; 1TYE; X-ray; 2.90 A; A/C/E=32-483.
DR PDB; 1UV9; Model; -; A=32-973.
DR PDB; 2K1A; NMR; -; A=989-1029.
DR PDB; 2K9J; NMR; -; A=989-1029.
DR PDB; 2KNC; NMR; -; A=991-1039.
DR PDB; 2VC2; X-ray; 3.10 A; A=32-483.
DR PDB; 2VDK; X-ray; 2.80 A; A=32-483.
DR PDB; 2VDL; X-ray; 2.75 A; A=32-483.
DR PDB; 2VDM; X-ray; 2.90 A; A=32-483.
DR PDB; 2VDN; X-ray; 2.90 A; A=32-483.
DR PDB; 2VDO; X-ray; 2.51 A; A=32-483.
DR PDB; 2VDP; X-ray; 2.80 A; A=32-483.
DR PDB; 2VDQ; X-ray; 2.59 A; A=32-483.
DR PDB; 2VDR; X-ray; 2.40 A; A=32-483.
DR PDB; 3FCS; X-ray; 2.55 A; A/C=32-989.
DR PDB; 3FCU; X-ray; 2.90 A; A/C/E=32-488.
DR PDB; 3NID; X-ray; 2.30 A; A/C=32-488.
DR PDB; 3NIF; X-ray; 2.40 A; A/C=32-488.
DR PDB; 3NIG; X-ray; 2.25 A; A/C=32-488.
DR PDB; 3T3M; X-ray; 2.60 A; A/C=32-488.
DR PDB; 3T3P; X-ray; 2.20 A; A/C=32-488.
DR PDB; 3ZDX; X-ray; 2.45 A; A/C=32-488.
DR PDB; 3ZDY; X-ray; 2.45 A; A/C=32-488.
DR PDB; 3ZDZ; X-ray; 2.75 A; A/C=32-488.
DR PDB; 3ZE0; X-ray; 2.95 A; A/C=32-488.
DR PDB; 3ZE1; X-ray; 3.00 A; A/C=32-488.
DR PDB; 3ZE2; X-ray; 2.35 A; A/C=32-488.
DR PDB; 4CAK; EM; 20.50 A; A=32-989.
DR PDBsum; 1DPK; -.
DR PDBsum; 1DPQ; -.
DR PDBsum; 1JX5; -.
DR PDBsum; 1KUP; -.
DR PDBsum; 1KUZ; -.
DR PDBsum; 1M8O; -.
DR PDBsum; 1RN0; -.
DR PDBsum; 1S4W; -.
DR PDBsum; 1TYE; -.
DR PDBsum; 1UV9; -.
DR PDBsum; 2K1A; -.
DR PDBsum; 2K9J; -.
DR PDBsum; 2KNC; -.
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; 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 ProteinModelPortal; P08514; -.
DR SMR; P08514; 32-989, 991-1039.
DR DIP; DIP-68N; -.
DR IntAct; P08514; 1.
DR STRING; 9606.ENSP00000262407; -.
DR BindingDB; P08514; -.
DR ChEMBL; CHEMBL2111443; -.
DR DrugBank; DB00775; Tirofiban.
DR PhosphoSite; P08514; -.
DR DMDM; 226694183; -.
DR OGP; P08514; -.
DR PaxDb; P08514; -.
DR PRIDE; P08514; -.
DR Ensembl; ENST00000262407; ENSP00000262407; ENSG00000005961.
DR Ensembl; ENST00000353281; ENSP00000340536; ENSG00000005961.
DR GeneID; 3674; -.
DR KEGG; hsa:3674; -.
DR UCSC; uc002igt.1; human.
DR CTD; 3674; -.
DR GeneCards; GC17M042460; -.
DR HGNC; HGNC:6138; ITGA2B.
DR HPA; CAB018611; -.
DR HPA; HPA031168; -.
DR HPA; HPA031169; -.
DR HPA; HPA031170; -.
DR HPA; HPA031171; -.
DR MIM; 187800; phenotype.
DR MIM; 273800; phenotype.
DR MIM; 607759; gene.
DR neXtProt; NX_P08514; -.
DR Orphanet; 853; Fetal and neonatal alloimmune thrombocytopenia.
DR Orphanet; 849; Glanzmann thrombasthenia.
DR PharmGKB; PA29938; -.
DR eggNOG; NOG26407; -.
DR HOGENOM; HOG000231603; -.
DR HOVERGEN; HBG006186; -.
DR InParanoid; P08514; -.
DR KO; K06476; -.
DR OMA; CFNIQMC; -.
DR OrthoDB; EOG7TMZQZ; -.
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; P08514; -.
DR EvolutionaryTrace; P08514; -.
DR GeneWiki; ITGA2B; -.
DR GenomeRNAi; 3674; -.
DR NextBio; 14381; -.
DR PMAP-CutDB; Q17R67; -.
DR PRO; PR:P08514; -.
DR ArrayExpress; P08514; -.
DR Bgee; P08514; -.
DR CleanEx; HS_ITGA2B; -.
DR Genevestigator; P08514; -.
DR GO; GO:0009897; C:external side of plasma membrane; IEA:Ensembl.
DR GO; GO:0005925; C:focal adhesion; IEA:Ensembl.
DR GO; GO:0005887; C:integral to plasma membrane; TAS:ProtInc.
DR GO; GO:0008305; C:integrin complex; IEA:InterPro.
DR GO; GO:0031092; C:platelet alpha granule membrane; TAS:Reactome.
DR GO; GO:0050840; F:extracellular matrix binding; IEA:Ensembl.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0007411; P:axon guidance; TAS:Reactome.
DR GO; GO:0007155; P:cell adhesion; TAS:ProtInc.
DR GO; GO:0007160; P:cell-matrix adhesion; IEA:Ensembl.
DR GO; GO:0030198; P:extracellular matrix organization; TAS:Reactome.
DR GO; GO:0007229; P:integrin-mediated signaling pathway; IEA:UniProtKB-KW.
DR GO; GO:0030168; P:platelet activation; TAS:Reactome.
DR GO; GO:0002576; P:platelet degranulation; TAS:Reactome.
DR InterPro; IPR013517; FG-GAP.
DR InterPro; IPR013519; Int_alpha_beta-p.
DR InterPro; IPR000413; Integrin_alpha.
DR InterPro; IPR013649; Integrin_alpha-2.
DR InterPro; IPR018184; Integrin_alpha_C_CS.
DR Pfam; PF01839; FG-GAP; 1.
DR Pfam; PF00357; Integrin_alpha; 1.
DR Pfam; PF08441; Integrin_alpha2; 1.
DR PRINTS; PR01185; INTEGRINA.
DR SMART; SM00191; Int_alpha; 5.
DR PROSITE; PS51470; FG_GAP; 7.
DR PROSITE; PS00242; INTEGRIN_ALPHA; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Calcium; Cell adhesion;
KW Cleavage on pair of basic residues; Complete proteome;
KW Direct protein sequencing; Disease mutation; Disulfide bond;
KW Glycoprotein; Integrin; Membrane; Metal-binding; Polymorphism;
KW Pyrrolidone carboxylic acid; Receptor; Reference proteome; Repeat;
KW Signal; Transmembrane; Transmembrane helix.
FT SIGNAL 1 31
FT CHAIN 32 1039 Integrin alpha-IIb.
FT /FTId=PRO_0000016275.
FT CHAIN 32 887 Integrin alpha-IIb heavy chain.
FT /FTId=PRO_0000016276.
FT CHAIN 891 1039 Integrin alpha-IIb light chain, form 1.
FT /FTId=PRO_0000292348.
FT CHAIN 903 1039 Integrin alpha-IIb light chain, form 2.
FT /FTId=PRO_0000016277.
FT TOPO_DOM 32 993 Extracellular (Potential).
FT TRANSMEM 994 1019 Helical; (Potential).
FT TOPO_DOM 1020 1039 Cytoplasmic (Potential).
FT REPEAT 35 96 FG-GAP 1.
FT REPEAT 110 173 FG-GAP 2.
FT REPEAT 186 238 FG-GAP 3.
FT REPEAT 251 310 FG-GAP 4.
FT REPEAT 311 371 FG-GAP 5.
FT REPEAT 373 432 FG-GAP 6.
FT REPEAT 434 496 FG-GAP 7.
FT CA_BIND 274 282 Potential.
FT CA_BIND 328 336 Potential.
FT CA_BIND 396 404 Potential.
FT CA_BIND 457 465 Potential.
FT MOTIF 1022 1026 GFFKR motif.
FT MOD_RES 891 891 Pyrrolidone carboxylic acid; in light
FT chain form 1.
FT CARBOHYD 46 46 N-linked (GlcNAc...).
FT CARBOHYD 280 280 N-linked (GlcNAc...).
FT CARBOHYD 601 601 N-linked (GlcNAc...).
FT CARBOHYD 711 711 N-linked (GlcNAc...).
FT CARBOHYD 874 874 O-linked (GalNAc...); in alloantigen HPA-
FT 3B.
FT CARBOHYD 878 878 O-linked (GalNAc...).
FT CARBOHYD 962 962 N-linked (GlcNAc...).
FT DISULFID 87 96
FT DISULFID 138 161
FT DISULFID 177 198
FT DISULFID 504 515
FT DISULFID 521 576
FT DISULFID 633 639
FT DISULFID 705 718
FT DISULFID 857 911 Interchain (between heavy and light
FT chains).
FT DISULFID 916 921
FT VAR_SEQ 910 1039 SCDSAPCTVVQCDLQEMARGQRAMVTVLAFLWLPSLYQRPL
FT DQFVLQSHAWFNVSSLPYAVPPLSLPRGEAQVWTQLLRALE
FT ERAIPIWWVLVGVLGGLLLLTILVLAMWKVGFFKRNRPPLE
FT EDDEEGE -> VSRLSGLWPGLPGTHGAEGMGGGRGVRVCC
FT GPLWATLGPWEHFK (in isoform 3).
FT /FTId=VSP_002736.
FT VAR_SEQ 948 981 Missing (in isoform 2).
FT /FTId=VSP_002737.
FT VARIANT 40 40 T -> I (in dbSNP:rs5915).
FT /FTId=VAR_014176.
FT VARIANT 86 86 L -> P (in GT; cells co-transfected with
FT mutated alpha-IIb and wild-type beta-3
FT scarcely expressed the alpha-IIb/beta-3
FT complex).
FT /FTId=VAR_030445.
FT VARIANT 139 139 A -> V (in GT).
FT /FTId=VAR_030446.
FT VARIANT 161 161 C -> W (in GT).
FT /FTId=VAR_030447.
FT VARIANT 174 174 Y -> H (in GT; abolishes the binding
FT function of alpha-IIb/beta-3 for soluble
FT ligands without disturbing alpha-IIb/
FT beta-3 expression; functional defect is
FT likely caused by its allosteric effect
FT rather than by a defect in the ligand-
FT binding site itself).
FT /FTId=VAR_030448.
FT VARIANT 176 176 P -> A (in GT; impairs surface expression
FT of alpha-IIb/beta-3 and abrogates ligand
FT binding to the activated integrin).
FT /FTId=VAR_009885.
FT VARIANT 176 176 P -> L (in GT; impairs surface expression
FT of alpha-IIb/beta-3).
FT /FTId=VAR_009886.
FT VARIANT 202 202 F -> C (in GT; associated with abrogation
FT of alpha-IIb/beta-3 complex formation).
FT /FTId=VAR_030449.
FT VARIANT 207 207 T -> I (in GT).
FT /FTId=VAR_030450.
FT VARIANT 214 214 L -> P (in GT; disrupts the structural
FT conformation and the ligand binding
FT properties of the heterodimeric complex;
FT in addition the mutation appears to
FT confer susceptibility to proteolysis).
FT /FTId=VAR_030451.
FT VARIANT 222 222 F -> L (in GT).
FT /FTId=VAR_030452.
FT VARIANT 267 267 G -> E (in GT).
FT /FTId=VAR_030453.
FT VARIANT 273 273 G -> D (in GT; alters the heterodimer
FT conformation thus impairing their
FT intracellular transport).
FT /FTId=VAR_003979.
FT VARIANT 313 313 G -> A (in dbSNP:rs1126554).
FT /FTId=VAR_054820.
FT VARIANT 320 320 F -> S (in GT; type I; impairs surface
FT expression of alpha-IIb/beta-3).
FT /FTId=VAR_009887.
FT VARIANT 329 329 V -> F (in GT; expression of mutant
FT subunit alpha-IIb/bet-3 is 28% of
FT control; mutant pro-alpha-IIb subunit is
FT retained in the endoplasmic reticulum).
FT /FTId=VAR_030454.
FT VARIANT 355 355 E -> K (in GT; type I; impairs surface
FT expression of alpha-IIb/beta-3).
FT /FTId=VAR_009888.
FT VARIANT 358 358 R -> H (in GT; type II).
FT /FTId=VAR_003980.
FT VARIANT 380 380 G -> D (in GT).
FT /FTId=VAR_030455.
FT VARIANT 405 405 I -> T (in GT; expression of mutant
FT subunit alpha-IIb/bet-3 is 11% of
FT control; mutant pro-alpha-IIb subunit is
FT retained in the endoplasmic reticulum).
FT /FTId=VAR_030456.
FT VARIANT 412 412 G -> R (in GT).
FT /FTId=VAR_030457.
FT VARIANT 449 449 G -> D (in GT; type I).
FT /FTId=VAR_003981.
FT VARIANT 456 457 Missing (in GT; alteres the conformation
FT of heterodimers such that they were
FT neither recognized by the heterodimer-
FT specific antibody A2A9 nor able to
FT undergo further intracellular processing
FT or transport to the cell surface).
FT /FTId=VAR_030458.
FT VARIANT 581 581 A -> D (in GT).
FT /FTId=VAR_030459.
FT VARIANT 596 596 I -> T (in GT; type I).
FT /FTId=VAR_030460.
FT VARIANT 649 649 V -> L (in dbSNP:rs7207402).
FT /FTId=VAR_054821.
FT VARIANT 705 705 C -> R (in GT; type II; the rate of
FT subunit maturation and the surface
FT exposure of ghlycoprotein IIb/beta-3 are
FT strongly reduced).
FT /FTId=VAR_030461.
FT VARIANT 752 752 L -> V (in GT).
FT /FTId=VAR_030462.
FT VARIANT 755 755 R -> P (in GT).
FT /FTId=VAR_030463.
FT VARIANT 778 778 Q -> P (in GT; type II).
FT /FTId=VAR_003982.
FT VARIANT 847 847 L -> P (in GT).
FT /FTId=VAR_030464.
FT VARIANT 874 874 I -> S (alloantigen HPA-3B;
FT dbSNP:rs5911).
FT /FTId=VAR_003983.
FT VARIANT 934 934 V -> F (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_069917.
FT VARIANT 943 943 P -> L (in GT; marked reduction in the
FT rate of surface expression).
FT /FTId=VAR_030465.
FT VARIANT 957 957 S -> L (in GT; the mutation prevented
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_069918.
FT VARIANT 968 968 Y -> N (in dbSNP:rs5914).
FT /FTId=VAR_014177.
FT VARIANT 982 982 V -> M (in GT; much reduced surface
FT expression of alpha-IIb/beta-3 and a
FT block in the maturation of pro-alpha-
FT IIb).
FT /FTId=VAR_030466.
FT VARIANT 989 989 A -> T (in dbSNP:rs78165611).
FT /FTId=VAR_030467.
FT VARIANT 1026 1026 R -> Q (in GT and BDPLT16; results in low
FT surface expression of the mutant
FT protein).
FT /FTId=VAR_030468.
FT VARIANT 1026 1026 R -> W (in BDPLT16; results in abnormal
FT membrane ruffling and cytoplasmic
FT protrusions as well as defective
FT proplatelet formation).
FT /FTId=VAR_069919.
FT MUTAGEN 1029 1030 PP->AA: Imparts constitutive activity
FT (ligand-binding) to alpha-IIb/beta-3.
FT CONFLICT 23 23 P -> A (in Ref. 2; AAA35926).
FT CONFLICT 120 120 A -> S (in Ref. 4; BAG37735).
FT CONFLICT 287 288 GA -> VP (in Ref. 3; AAA53150).
FT CONFLICT 346 346 E -> D (in Ref. 2; AAA35926).
FT CONFLICT 565 565 N -> D (in Ref. 2; AAA35926).
FT CONFLICT 566 566 L -> V (in Ref. 8; CAA29987).
FT CONFLICT 633 633 C -> S (in Ref. 1; AAA60114).
FT CONFLICT 729 729 Q -> E (in Ref. 8; CAA29987).
FT CONFLICT 971 971 P -> A (in Ref. 3; AAA53150).
FT CONFLICT 1029 1029 P -> H (in Ref. 2; AAA35926 and 10;
FT AAA52588).
FT CONFLICT 1030 1030 P -> T (in Ref. 10; AAA52588).
FT STRAND 36 38
FT STRAND 40 43
FT STRAND 52 58
FT STRAND 60 62
FT STRAND 64 70
FT STRAND 78 80
FT STRAND 82 88
FT STRAND 93 95
FT STRAND 107 110
FT STRAND 113 118
FT STRAND 126 131
FT STRAND 134 139
FT STRAND 143 148
FT STRAND 151 153
FT STRAND 160 164
FT TURN 166 168
FT STRAND 171 174
FT HELIX 183 188
FT TURN 189 193
FT STRAND 202 206
FT STRAND 211 216
FT HELIX 219 222
FT STRAND 225 230
FT HELIX 231 237
FT HELIX 259 261
FT STRAND 268 273
FT STRAND 279 281
FT STRAND 283 288
FT HELIX 291 294
FT STRAND 297 301
FT STRAND 307 312
FT STRAND 324 327
FT STRAND 330 333
FT STRAND 336 341
FT STRAND 345 348
FT TURN 349 351
FT STRAND 352 355
FT STRAND 358 362
FT STRAND 366 368
FT STRAND 375 379
FT STRAND 391 395
FT STRAND 400 402
FT STRAND 404 409
FT STRAND 413 417
FT STRAND 419 423
FT STRAND 427 430
FT STRAND 435 439
FT STRAND 450 456
FT STRAND 458 463
FT STRAND 465 470
FT HELIX 471 473
FT STRAND 475 479
FT STRAND 484 493
FT STRAND 507 509
FT STRAND 512 525
FT STRAND 534 541
FT TURN 542 544
FT HELIX 547 549
FT STRAND 551 554
FT TURN 555 557
FT STRAND 559 567
FT STRAND 575 583
FT HELIX 586 588
FT STRAND 596 603
FT STRAND 616 619
FT STRAND 622 627
FT TURN 634 637
FT STRAND 643 651
FT STRAND 653 655
FT STRAND 662 670
FT STRAND 678 683
FT STRAND 688 695
FT STRAND 705 708
FT STRAND 710 713
FT STRAND 715 721
FT STRAND 728 738
FT STRAND 746 755
FT STRAND 759 761
FT STRAND 767 774
FT STRAND 779 792
FT STRAND 810 819
FT STRAND 821 823
FT STRAND 825 836
FT STRAND 842 854
FT STRAND 856 861
FT STRAND 906 909
FT TURN 911 913
FT STRAND 916 926
FT STRAND 931 940
FT HELIX 942 945
FT STRAND 952 965
FT STRAND 967 969
FT STRAND 977 988
FT TURN 991 994
FT HELIX 997 1020
FT STRAND 1022 1024
FT TURN 1025 1027
FT HELIX 1028 1031
FT TURN 1035 1038
SQ SEQUENCE 1039 AA; 113377 MW; 063EE298E026F116 CRC64;
MARALCPLQA LWLLEWVLLL LGPCAAPPAW ALNLDPVQLT FYAGPNGSQF GFSLDFHKDS
HGRVAIVVGA PRTLGPSQEE TGGVFLCPWR AEGGQCPSLL FDLRDETRNV GSQTLQTFKA
RQGLGASVVS WSDVIVACAP WQHWNVLEKT EEAEKTPVGS CFLAQPESGR RAEYSPCRGN
TLSRIYVEND FSWDKRYCEA GFSSVVTQAG ELVLGAPGGY YFLGLLAQAP VADIFSSYRP
GILLWHVSSQ SLSFDSSNPE YFDGYWGYSV AVGEFDGDLN TTEYVVGAPT WSWTLGAVEI
LDSYYQRLHR LRGEQMASYF GHSVAVTDVN GDGRHDLLVG APLYMESRAD RKLAEVGRVY
LFLQPRGPHA LGAPSLLLTG TQLYGRFGSA IAPLGDLDRD GYNDIAVAAP YGGPSGRGQV
LVFLGQSEGL RSRPSQVLDS PFPTGSAFGF SLRGAVDIDD NGYPDLIVGA YGANQVAVYR
AQPVVKASVQ LLVQDSLNPA VKSCVLPQTK TPVSCFNIQM CVGATGHNIP QKLSLNAELQ
LDRQKPRQGR RVLLLGSQQA GTTLNLDLGG KHSPICHTTM AFLRDEADFR DKLSPIVLSL
NVSLPPTEAG MAPAVVLHGD THVQEQTRIV LDCGEDDVCV PQLQLTASVT GSPLLVGADN
VLELQMDAAN EGEGAYEAEL AVHLPQGAHY MRALSNVEGF ERLICNQKKE NETRVVLCEL
GNPMKKNAQI GIAMLVSVGN LEEAGESVSF QLQIRSKNSQ NPNSKIVLLD VPVRAEAQVE
LRGNSFPASL VVAAEEGERE QNSLDSWGPK VEHTYELHNN GPGTVNGLHL SIHLPGQSQP
SDLLYILDIQ PQGGLQCFPQ PPVNPLKVDW GLPIPSPSPI HPAHHKRDRR QIFLPEPEQP
SRLQDPVLVS CDSAPCTVVQ CDLQEMARGQ RAMVTVLAFL WLPSLYQRPL DQFVLQSHAW
FNVSSLPYAV PPLSLPRGEA QVWTQLLRAL EERAIPIWWV LVGVLGGLLL LTILVLAMWK
VGFFKRNRPP LEEDDEEGE
//

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
1. Alagille, D.; Josso, F.; Binet, J. L.; Blin, M. L.: La dystrophie
thrombocytaire hemorragipare: discussion nosologique. Nouv. Rev.
Franc. Hemat. 4: 755-790, 1964.

2. Awidi, A. S.: Increased incidence of Glanzmann's thrombasthenia
in Jordan as compared with Scandinavia. Scand. J. Haemat. 30: 218-222,
1983.

3. Bajt, M. L.; Ginsberg, M. H.; Frelinger, A. L., III; Berndt, M.
C.; Loftus, J. C.: A spontaneous mutation of integrin alpha(IIb)-beta(3)
(platelet glycoprotein IIb-IIIa) helps define a ligand binding site. J.
Biol. Chem. 267: 3789-3794, 1992.

4. Bellucci, S.; Devergie, A.; Gluckman, E.; Tobelem, G.; Lethielleux,
P.; Benbunan, M.; Schaison, G.; Boiron, M.: Complete correction of
Glanzmann's thrombasthenia by allogeneic bone-marrow transplantation. Brit.
J. Haemat. 59: 635-641, 1985.

5. Beutler, E.: Glanzmann's thrombasthenia and reduced glutathione. New
Eng. J. Med. 287: 1094-1095, 1972.

6. Booyse, F. M.; Kisieleski, D.; Seeler, R.; Rafelson, M., Jr.:
Possible thrombosthenin defect in Glanzmann's thrombasthenia. Blood 39:
377-381, 1972.

7. Bowie, E. J. W.; Owen, C. A., Jr.: Thrombopathy. Seminars Hemat. 5:
73-82, 1968.

8. Bowie, E. J. W.; Thompson, J. H., Jr.; Owen, C. A., Jr.: A new
abnormality of platelet function. Thromb. Diath. Haemorrh. 11: 195-203,
1964.

9. Bray, P. F.: Inherited diseases of platelet glycoproteins: considerations
for rapid molecular characterization. Thromb. Haemost. 72: 492-502,
1994.

10. Bray, P. F.; Rosa, J.-P.; Lingappa, V. R.; Kan, Y. W.; McEver,
R. P.; Shuman, M. A.: Biogenesis of the platelet receptor for fibrinogen:
evidence for separate precursors for glycoproteins IIb and IIIa. Proc.
Nat. Acad. Sci. 83: 1480-1484, 1986.

11. 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.

12. Coller, B. S.; Seligsohn, U.; Little, P. A.: Type I Glanzmann
thrombasthenia patients from the Iraqi-Jewish and Arab populations
in Israel can be differentiated by platelet glycoprotein IIIa immunoblot
analysis. Blood 69: 1696-1703, 1987.

13. Corby, D. G.; Zirbel, C. L.; Lindley, A.; Schulman, I.: Thrombasthenia. Am.
J. Dis. Child. 121: 140-144, 1971.

14. Cronberg, S.; Nilsson, I. M.; Zetterqvist, E.: Investigation
of a family with members with both severe and mild degree of thrombasthenia. Acta
Paediat. Scand. 56: 189-197, 1967.

15. Dautigny, A.; Bernier, I.; Colombani, J.; Jolles, P.: Human platelets
as a source of HL-A antigens: a study of various solubilization techniques. Biochimie 57:
1197-1201, 1975.

16. Degos, L.; Dautigny, A.; Brouet, J. C.; Colombani, M.; Ardaillou,
N.; Caen, J. P.; Colombani, J.: A molecular defect in thrombasthenic
platelets. J. Clin. Invest. 56: 236-240, 1975.

17. Ferrer, M.; Tao, J.; Iruin, G.; Sanchez-Ayuso, M.; Gonzalez-Rodriguez,
J.; Parrilla, R.; Gonzalez-Manchon, C.: Truncation of glycoprotein
(GP) IIIa (delta 616-762) prevents complex formation with GPIIb: novel
mutation in exon 11 of GPIIIa associated with thrombasthenia. Blood 92:
4712-4720, 1998.

18. Fiore, M.; Pillois, X.; Nurden, P.; Nurden, A. T.; Austerlitz,
F.: Founder effect and estimation of the age of the French Gypsy
mutation associated with Glanzmann thrombasthenia in Manouche families. Europ.
J. Hum. Genet. 19: 981-987, 2011.

19. Friedman, L. L.; Bowie, E. J. W.; Thompson, J. H., Jr.; Brown,
A. L., Jr.; Owen, C. A., Jr.: Familial Glanzmann's thrombasthenia. Mayo
Clin. Proc. 39: 908-918, 1964.

20. Giltay, J. C.; Leeksma, O. C.; Breederveld, C.; van Mourik, J.
A.: Normal synthesis and expression of endothelial IIb/IIIa in Glanzmann's
thrombasthenia. Blood 69: 809-812, 1987.

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

22. Hathaway, W. E.: Bleeding disorders due to platelet dysfunction. Am.
J. Dis. Child. 121: 127-134, 1971.

23. Herrmann, F. H.; Meyer, M.; Gogstad, G. O.; Solum, N. O.: Glycoprotein
IIb-IIIa complex in platelets of patients and heterozygotes of Glanzmann's
thrombasthenia. Thromb. Res. 32: 615-622, 1983.

24. Herrmann, F. H.; Meyer, M.; Ihle, E.: Protein and glycoprotein
abnormalities in an unusual subtype of Glanzmann's thrombasthenia. Haemostasis 12:
337-344, 1982.

25. Jallu, V.; Dusseaux, M.; Panzer, S.; Torchet, M.-F.; Hezard, N.;
Goudemand, J.; de Brevern, A. G.; Kaplan, C.: Alpha-IIb-beta-3 integrin:
new allelic variants in Glanzmann thrombasthenia, effects on ITGA2B
and ITGB3 mRNA splicing, expression, and structure-function. Hum.
Mutat. 31: 237-246, 2010.

26. Kanska, B.; Niewiarowski, S.; Ostrowski, L.; Poplawski, A.; Prokopowicz,
J.: Macrothrombocytic thrombopathia. Clinical, coagulation and hereditary
aspects. Thromb. Diath. Haemorrh. 10: 88-100, 1963.

27. Karpatkin, S.; Weiss, H. J.: Deficiency of glutathione peroxidase
associated with high levels of reduced glutathione in Glanzmann's
thrombasthenia. New Eng. J. Med. 287: 1062-1066, 1972.

28. Khanduri, U.; Pulimood, R.; Sudarsanam, A.; Carman, R. H.; Jadhav,
M.; Pereira, S.: Glanzmann's thrombasthenia: a review and report
of 42 cases from South India. Thromb. Haemost. 46: 717-721, 1981.

29. Kunicki, T. J.; Aster, R. H.: Deletion of the platelet-specific
alloantigen Pl(A1) from platelets in Glanzmann's thrombasthenia. J.
Clin. Invest. 61: 1225-1231, 1978.

30. Kunicki, T. J.; Pidard, D.; Cazenave, J.-P.; Nurden, A. T.; Caen,
J. P.: Inheritance of the human platelet alloantigen, Pl(A1), in
type I Glanzmann's thrombasthenia. J. Clin. Invest. 67: 717-724,
1981.

31. Lelong, J. C.: La thrombopathie de Glanzmann-Naegeli. Paris:
R. Foulon et Cie. (pub.) 1960.

32. Levy, J. M.; Mayer, G.; Sacrez, R.; Ruff, R.; Francfort, J. J.;
Rodier, L.: Thrombasthenie de Glanzmann-Naegeli: etude d'un groupe
ethnique a forte endogamie. Ann. Pediat. 18: 129-137, 1971.

33. Marx, R.; Jean, G.: Studien zur Pathogenese der Thrombasthenie
Glanzmann-Naegeli. Klin. Wschr. 40: 942-953, 1962.

34. McDowall, A.; Inwald, D.; Leitinger, B.; Jones, A.; Liesner, R.;
Klein, N.; Hogg, N.: A novel form of integrin dysfunction involving
beta-1, beta-2, and beta-3 integrins. J. Clin. Invest. 111: 51-60,
2003.

35. McEver, R. P.; Baenziger, J. U.; Majerus, P. W.: Isolation and
structural characterization of the polypeptide subunits of membrane
glycoprotein IIb-IIIa from human platelets. Blood 59: 80-85, 1982.

36. McEver, R. P.; Baenziger, N. L.; Majerus, P. W.: Isolation and
quantitation of the platelet membrane glycoprotein deficient in thrombasthenia
using a monoclonal hybridoma antibody. J. Clin. Invest. 66: 1311-1318,
1980.

37. Meyer, M.; Herrmann, F. H.: Diversity of glycoprotein deficiencies
in Glanzmann's thrombasthenia. Thromb. Haemost. 54: 626-629, 1985.

38. Montgomery, R. R.; Kunicki, T. J.; Taves, C.; Pidard, D.; Corcoran,
M.: Diagnosis of Bernard-Soulier syndrome and Glanzmann's thrombasthenia
with a monoclonal assay on whole blood. J. Clin. Invest. 71: 385-389,
1983.

39. Moser, K.; Lechner, K.; Vinazzer, H.: A hitherto not described
enzyme defect in thrombasthenia: glutathione reductase deficiency. Thromb.
Diath. Haemorrh. 19: 46-52, 1968.

40. Nachman, R. L.: Thrombasthenia: immunologic evidence of a platelet
protein abnormality. J. Lab. Clin. Med. 67: 411-419, 1966.

41. Newman, P. J.; Seligsohn, U.; Lyman, S.; Coller, B. S.: The molecular
genetic basis of Glanzmann thrombasthenia in the Iraqi-Jewish and
Arab populations in Israel. Proc. Nat. Acad. Sci. 88: 3160-3164,
1991.

42. Nurden, A. T.; Caen, J. P.: An abnormal platelet glycoprotein
pattern in three cases of Glanzmann's thrombasthenia. Brit. J. Haemat. 28:
253-260, 1974.

43. Nurden, A. T.; Didry, D.; Kieffer, N.; McEver, R. P.: Residual
amounts of glycoproteins IIb and IIIa may be present in the platelets
of most patients with Glanzmann's thrombasthenia. Blood 65: 1021-1024,
1985.

44. Nurden, A. T.; Rosa, J.-P.; Fournier, D.; Legrand, C.; Didry,
D.; Parquet, A.; Pidard, D.: A variant of Glanzmann's thrombasthenia
with abnormal glycoprotein IIb-IIIa complexes in the platelet membrane. J.
Clin. Invest. 79: 962-969, 1987.

45. Papayannis, A. G.; Israels, M. C. G.: Glanzmann's disease and
trait. (Letter) Lancet 296: 44 only, 1970. Note: Originally Volume
II.

46. Peretz, H.; Rosenberg, N.; Landau, M.; Usher, S.; Nelson, E. J.
R.; Mor-Cohen, R.; French, D. L.; Mitchell, B. W.; Nair, S. C.; Chandy,
M.; Coller, B. S.; Srivastava, A.; Seligsohn, U.: Molecular diversity
of Glanzmann thrombasthenia in southern India: new insights into mRNA
splicing and structure-function correlations of alpha-IIb-beta-3 integrin
(ITGA2B, ITGB3). Hum. Mutat. 27: 359-369, 2006.

47. Phillips, D. R.; Agin, R. P.: Platelet membrane defects in Glanzmann's
thrombasthenia: evidence for decreased amounts of two major glycoproteins. J.
Clin. Invest. 60: 535-545, 1977.

48. Pittman, M. A., Jr.; Graham, J. B.: Glanzmann's thrombopathy:
an autosomal recessive trait in one family. Am. J. Med. Sci. 247:
293-303, 1964.

49. Poncz, M.; Rifat, S.; Coller, B. S.; Newman, P. J.; Shattil, S.
J.; Parrella, T.; Fortina, P.; Bennett, J. S.: Glanzmann thrombasthenia
secondary to a gly273-to-asp mutation adjacent to the first calcium-binding
domain of platelet glycoprotein IIb. J. Clin. Invest. 93: 172-179,
1994.

50. Rosenberg, N.; Yatuv, R.; Orion, Y.; Zivelin, A.; Dardik, R.;
Peretz, H.; Seligsohn, U.: Glanzmann thrombasthenia caused by an
11.2-kb deletion in the glycoprotein IIIa (beta-3) is a second mutation
in Iraqi Jews that stemmed from a distinct founder. Blood 89: 3654-3662,
1997.

51. 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.

52. Russell, M. E.; Seligsohn, U.; Coller, B. S.; Ginsberg, M. H.;
Skoglund, P.; Quertermous, T.: Structural integrity of the glycoprotein
IIb and IIIa genes in Glanzmann thrombasthenia patients from Israel. Blood 72:
1833-1836, 1988.

53. Seligsohn, U.; Mibashan, R. S.; Rodeck, C. H.; Nicolaides, K.
H.; Millar, D. S.; Coller, B. S.: Prenatal diagnosis of Glanzmann's
thrombasthenia. (Letter) Lancet 326: 1419 only, 1985. Note: Originally
Volume II.

54. Stevens, R. F.; Meyer, S.: Fanconi and Glanzmann: the men and
their works. Brit. J. Haemat. 119: 901-904, 2002.

55. Tongio, M. M.; Lutz, P.; Hauptmann, G.; Rodier, L.; Levy, J.-M.;
Mayer, S.; Cazenave, J.-P.: Type I Glanzmann's thrombasthenia segregates
independently of Ss and Duffy systems and the A, B, C, factor B, C2
and C4 loci of the HLA complex. Tissue Antigens 20: 22-27, 1982.

56. Waller, H. D.; Gross, R.: Genetische Enzymdefecte als Ursache
von Thrombocytopathien. Verh. Dtsch. Ges. Inn. Med. 70: 476-494,
1964.

57. Zaizov, R.; Cohen, I.; Matoth, Y.: Thrombasthenia: a study of
two siblings. Acta Paediat. Scand. 57: 522-526, 1968.

*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

MIM 607759
*RECORD*
*FIELD* NO
607759
*FIELD* TI
*607759 INTEGRIN, ALPHA-2B; ITGA2B
;;PLATELET GLYCOPROTEIN IIb; GP2B;;
GP IIb;;
PLATELET FIBRINOGEN RECEPTOR, ALPHA SUBUNIT;;
read moreCD41B
PLATELET-SPECIFIC ANTIGEN BAK, INCLUDED
*FIELD* TX

DESCRIPTION

The ITGA2B gene encodes platelet glycoprotein IIb, the alpha subunit of
the platelet membrane adhesive protein receptor complex GPIIb/IIIa. The
beta subunit, GPIIIa, is encoded by the ITGB3 gene (173470). The
GPIIb/IIIa complex belongs to the integrin class of cell adhesion
molecule receptors that share a common heterodimeric structure with
alpha and beta subunits.

CLONING

Bray et al. (1986) studied the synthesis of GPIIb and GPIIIa in a human
erythroleukemia cell line (HEL), thus circumventing the limitations
imposed by the anucleate state of platelets and the difficulty of
harvesting megakaryocytes in adequate numbers. Their studies of mRNA
from HEL led them to the conclusion that GPIIb and GPIIIa are translated
from separate mRNAs and that the 2 subunits of GPIIb are derived from a
common single chain precursor.

Poncz et al. (1987) isolated a human GPIIb cDNA from a lambda expression
library prepared using RNA from HEL cells. The deduced 1,039-amino acid
protein contains 2 disulfide-linked subunits of 871 and 137 amino acids.
The larger subunit, referred to as the heavy or alpha chain, is
extracellular and contains 4 calcium-binding sites. The smaller subunit,
referred to as the light or beta chain, contains a hydrophobic sequence
near its C terminus that represents a potential transmembrane domain.
Northern blot analysis revealed a 4.1-kb mRNA transcript. From
megakaryocytes, Uzan et al. (1987) identified a cDNA representing 80% of
the coding region of GPIIb mRNA. Prandini et al. (1988) isolated the
GP2B gene and showed that the mRNA contains a leader sequence of 32
nucleotides.

Fitzgerald et al. (1987) compared the cDNA-derived protein sequence of
GPIIb to the alpha subunits of 2 other heterodimeric integrins, the
fibronectin receptor (135630) and the vitronectin receptor (193210). All
3 are composed of disulfide-linked large and small chains that are
posttranslationally processed from a single mRNA. The identity among the
protein sequences ranged from 36 to 44%, and the authors concluded that
the proteins evolved by a process of gene duplication. Bray et al.
(1987) concluded from Northern blot analyses that GPIIb is specific for
the platelet-megakaryocyte membrane and is distinct from the alpha
subunits of other adhesion molecule receptors.

MAPPING

Bray et al. (1987) mapped a cDNA for GPIIb to chromosome 17 by
hybridization to chromosomes separated by dual laser chromosome sorting.
By in situ hybridization with a cDNA probe, Van Cong et al. (1988)
mapped the GP2B gene to chromosome 17q21.1-q21.3.

Sosnoski et al. (1988) found close physical location of the GP2B and
GP3A genes in the segment 17q21-q23. Bray et al. (1988) found that GP2B
is located 3-prime to the GP3A gene, in the same 260-kb pulsed field gel
electrophoresis (PFGE) fragment. They noted that because of close
physical proximity of the genes with resulting linkage disequilibrium,
it may be difficult to use RFLPs in family studies to assign the defect
through either the GP2B or GP3A gene in cases of thrombasthenia. From
studies of the GPIIb gene in structurally rearranged chromosomes 17, Luo
et al. (1989) concluded that the most likely location is 17q21.32.

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 GPIIb/GPIIIa 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).

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/IIIa binding. Plate-binding analysis indicated specific
saturable binding of rsCD40L to GP IIb/IIIa. 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 GP
IIb/IIIa. Andre et al. (2002) concluded that CD40L is a GP IIb/IIIa
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 (173470) to constitutively bind soluble fibrinogen.
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 results 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.

See HOXD3 (142980) for discussion of the potential role of this homeobox
protein in the regulation of GP IIb/IIIa complex expression in
erythroleukemia cells.

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-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.

- The BAK Antigen

Von dem Borne et al. (1980) described a family in which the mother
developed platelet-specific antibodies not directed against the antigens
of the Pl(A) or Ko systems. The antibodies were only detectable in the
immunofluorescence test and the radioactive antiglobulin test on
platelets, and proved to be mainly IgG1 antibodies. The 'new' antigen,
termed BAK(a), was present in 90.76% of the Dutch population (gene
frequency, 0.696). No close linkage to other platelet, red cell,
granulocyte, or HLA groups was found. The mother was ascertained through
her first child, who died of neonatal alloimmune thrombocytopenia.
During the second pregnancy, the mother showed no rise in antibody titer
and the child was found to lack the BAK(a) antigen.

The platelet-specific antigen BAK system, an apparently diallelic system
with alleles designated a and b, is determined by an epitope on the GP2b
molecule. Letellier et al. (1988) demonstrated close linkage of the BAK
locus with the Pl(A) locus, an epitopic characteristic of the GPIIIa
molecule. They also demonstrated evidence of linkage disequilibrium.
BAK(a)/BAK(b) is also known as LEK(a)/LEK(b). Newman (1991) identified
the molecular basis for the BAK polymorphism (see 607759.0004). Djaffar
et al. (1993) further defined the molecular nature of the BAK(a)
determinant.

According to a report on the nomenclature of platelet-specific
alloantigens, BAK and LEK are referred to as HPA-4 (von dem Borne and
Decary, 1990). The allele of high frequency is called 'a,' while that of
low frequency is called 'b.'

Kataoka et al. (2004) reported a Japanese male who presented with
neonatal alloimmune thrombocytopenia (NAIT) resulting from a maternal
antibody against the BAK-b (HPA-3b) antigen on the baby's platelets. The
disorder was manifest as petechiae, brain hemorrhage, and
thrombocytopenia. Treatment with high-dose IV Ig resulted in clinical
improvement, and he was neurologically normal at 17 months of age.
Kataoka et al. (2004) noted that the antibody could only be detected
using fresh, unfixed platelets as antigen, and emphasized that Bak-b
antibodies are extremely rare.

BIOCHEMICAL FEATURES

- Crystal Structure

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.

MOLECULAR GENETICS

- Glanzmann Thrombasthenia

In 3 Arab kindreds with Glanzmann thrombasthenia (GT; 273800), Newman et
al. (1991) identified a 13-bp deletion in the ITGA2B gene (607759.0002).

Basani et al. (1996) examined the mechanism of the defect of mutations
in the calcium-binding regions of ITGA2B. The authors coexpressed in COS
cells wildtype beta-3 subunits with both wildtype and mutant alpha-IIb
subunits corresponding to deletions of each of the four calcium-binding
domains of alpha-IIb. They found that deletion of any of the
calcium-binding domains did not prevent the synthesis or assembly of
alpha-IIb, but that the mutants were not recognized by a
heterodimer-specific antibody, were not cleaved to the mature form of
the protein, and were not expressed on the cell surface. The
consequences of this mutation were the same as those found with 3 point
mutations, i.e., 607759.0007, 607759.0009, and 607759.0010. Basani et
al. (1996) concluded that the calcium-binding domains are not required
for the assembly of alpha-IIb/beta-3 heterodimers but nonetheless are
required for correct folding of the nascent protein and correct
trafficking to the cell surface.

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. Three mutations in the ITGA2B were examined for
pathogenicity and 2 were found to decrease cell surface expression of
the IIb/IIIa complex. The third mutation (Q595H; 607759.0016) was
experimentally found to cause a splicing defect and nonsense-mediated
decay of the mRNA.

- Platelet-Type Bleeding Disorder 16, Autosomal Dominant

In an Italian father and son with autosomal dominant platelet-type
bleeding disorder-16 (BDPLT16; 187800) and macrothrombocytopenia
originally reported by Hardisty et al. (1992), Peyruchaud et al. (1998)
identified a heterozygous mutation in the ITGA2B gene (R995Q;
607759.0017). In vitro expression studies suggested that the mutation
caused partial activation of the GPIIb/IIIa complex. Peyruchaud et al.
(1998) noted that a salt bridge between R995 and residue D723 in the
ITGB3 gene (173470) participates in the regulation of the activation
state of the integrin complex, and suggested that the R995Q mutation
would give rise to an integrin complex that is not locked in a high
activation state, but is more easily activatable.

In 11 patients from 4 Japanese families with autosomal dominant BDPLT16
manifest as macrothrombocytopenia, Kunishima et al. (2011) identified a
heterozygous mutation in the ITGA2B gene (R995W; 607759.0018). In vitro
studies indicated that the mutant protein caused a constitutive,
activated conformation of the integrin complex, 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 defective 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.

POPULATION GENETICS

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

*FIELD* AV
.0001
MOVED TO 173470.0014
.0002
GLANZMANN THROMBASTHENIA
ITGA2B, 13-BP DEL

In 3 Arab kindreds with Glanzmann thrombasthenia (273800), Newman et al.
(1991) identified a 13-bp deletion encompassing the splice acceptor site
of exon 4 of the GPIIb gene. The deletion results in forced alternative
splicing to a downstream AG acceptor, producing a 6-amino acid deletion
(residues 106 to 111), including one cysteine residue. As a result, the
GPIIb molecule is probably improperly folded.

.0003
GLANZMANN THROMBASTHENIA
ITGA2B, 4.5-KB DEL, EX2-9

In an American black patient with Glanzmann thrombasthenia (273800),
Burk et al. (1991) demonstrated a deletion in the GP2B gene of about 4.5
kb. The deletion began between 2 Alu repeats within intron 1 and ended
in intron 9. The GP3A gene appeared to be intact, although platelet
levels of the GPIIIa protein were secondarily low, presumably due to its
known instability in the absence of GPIIb.

.0004
BAK PLATELET-SPECIFIC ANTIGEN
ITGA2B, ILE843SER

Newman (1991) found that the molecular basis for the dimorphism
represented by the platelet-specific alloantigen BAK is an
isoleucine-to-serine substitution at amino acid 843 of the GPIIb
protein.

.0005
GLANZMANN THROMBASTHENIA
ITGA2B, ARG584TER

Kato et al. (1992) reported the case of an 8-year-old boy with Glanzmann
thrombasthenia (273800). Western blotting indicated that his platelets
contained no normal GPIIb, but showed a trace amount of an abnormal
GPIIb (approximately 6% of normal). They found that the patient was a
compound heterozygote. From his mother the patient inherited an opal
mutation at the end of exon 17 of the ITGA2B gene: a CGA-to-TGA change
converted arg584 into a stop codon with the production of only a trace
amount of GPIIb mRNA. See 607759.0006 for the mutation inherited from
the father.

.0006
GLANZMANN THROMBASTHENIA
ITGA2B, IVS25AS, C-G, -3

See 607759.0005. In a compound heterozygote with Glanzmann
thrombasthenia (273800), Kato et al. (1992) discovered that the allele
inherited from the father contained a C-G mutation at position -3 of the
splice acceptor site of exon 26 of the GPIIb gene, thus abolishing the
acceptor function and resulting in the skipping of exon 26. This
aberrant transcript encoded a single chain polypeptide characterized by
a 42-amino acid deletion which included the proteolytic cleavage site(s)
and a unique, proline-rich region at the location corresponding to the
carboxyl-terminal of the normal GPIIb alpha chain.

.0007
GLANZMANN THROMBASTHENIA
ITGA2B, GLY273ASP

In an Ashkenazi Jewish female child, the product of a consanguineous
marriage, Poncz et al. (1994) found that the basis for Glanzmann
thrombasthenia (273800) was homozygosity for a G-to-A transition at
nucleotide 818 in the ITGA2B gene, resulting in a gly273-to-asp
substitution adjacent to the first calcium-binding domain of GPIIb.
Further studies demonstrated that the mutation did not prevent the
assembly of GPIIb/IIIa heterodimers, but did alter the conformation of
these heterodimers sufficiently to impair their intracellular transport.
Clinically, the proposita presented at 2 days of age with subdural
bleeding and extensive ecchymoses. Although she had a normal platelet
count, she had prolonged cutaneous bleeding time. Ex vivo studies showed
that platelet aggregation was absent in response to ADP, collagen, and
epinephrine, but platelet agglutination was normal in response to
ristocetin.

.0008
GLANZMANN THROMBASTHENIA
ITGA2B, IVS15DS, G-A, +1

Glanzmann thrombasthenia (273800) is unusually frequent in the Gypsy
population, mainly represented in France by the Manouche tribe. Schlegel
et al. (1995) demonstrated a G-to-A substitution at nucleotide 9263 of
the ITGA2B gene, leading to a splicing defect and a premature
termination of the GPIIb chain. They described an allele-specific PCR
analysis method that could be used for carrier detection, genetic
counseling, and antenatal diagnosis. Their studies included 11
homozygous patients, 32 heterozygotes, and 9 unaffected family members.
The GT splice donor site of intron 15 was converted to AT. A new GT
site, 8 nucleotides upstream from its normal position (within exon 15),
became a cryptic GT donor site, leading to the deletion of the last 8
basepairs of exon 15 and producing a frameshift and a premature TGA stop
codon at nucleotides 1756-1758.

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.

.0009
GLANZMANN THROMBASTHENIA
ITGA2B, ARG327HIS

In a patient with Glanzmann thrombasthenia type I (273800), Wilcox et
al. (1993) identified the substitution of histidine for arginine-327.

.0010
GLANZMANN THROMBASTHENIA
ITGA2B, GLY418ASP

In a patient with Glanzmann thrombasthenia type I (273800), Wilcox et
al. (1994) identified the substitution of aspartic acid for glycine-418.
Glycine-418 is critical for proper protein folding and transport to the
plasma membrane.

.0011
GLANZMANN THROMBASTHENIA
ITGA2B, VAL425DEL AND ASP426DEL

In a patient with Glanzmann thrombasthenia (273800), born of
nonconsanguineous Caucasian parents, Basani et al. (1996) performed
SSCPA and DNA sequencing and identified a 6-bp deletion in exon 13 of
ITGA2B, resulting in a deletion of val425 and asp426. The patient was a
compound heterozygote for this mutation, inherited from her father, and
for an unidentified mutation inherited from her mother. This mutation
was located at the proximal end of the fourth of the 4 calcium-binding
domains of ITGA2B. The mutant did not impair synthesis or assembly of
the alpha-IIb/beta-3 heterodimer but altered the conformation of
alpha-IIb/beta-3 such that it was no longer recognized by the
heterodimer-specific antibody A2A9.

.0012
GLANZMANN THROMBASTHENIA
ITGA2B, GLU324LYS

Ruan et al. (1998) described a Swiss patient with type I Glanzmann
thrombasthenia (273800) whose platelets had no detectable GPIIb and a
low content of GPIIIa. They examined all exons and splice sites of both
the GPIIb and GPIIIa genes and demonstrated that the patient was a
compound heterozygote for 2 rare mutations in the GPIIb gene. (The title
of the article by Ruan et al. (1998) described the state as 'double
heterozygosity,' which refers to heterozygosity at 2 separate loci; the
summary of the article correctly referred to the condition as 'compound
heterozygosity.') One mutation was a G-to-A transition at nucleotide
1064 of the cDNA derived from the mother's allele, leading to a
glu324-to-lys amino acid substitution in GPIIb; the second mutation,
inherited from the father, was a T-to-C transition at position 1787 of
the cDNA, resulting in an ile565-to-thr substitution (607759.0013).

.0013
GLANZMANN THROMBASTHENIA
ITGA2B, ILE565THR

See 607759.0012 and Ruan et al. (1998).

.0014
GLANZMANN THROMBASTHENIA
ITGA2B, LEU214PRO

Grimaldi et al. (1998) described a 55-year-old white male diagnosed with
Glanzmann thrombasthenia (273800) who had decreased levels of mutant
GPIIb receptor expression on his platelets. This quantitative
abnormality was not as severe as in other patients. The patient carried
a T-to-C transition in exon 6, resulting in a leu214-to-pro (L214P)
substitution. When this mutation was expressed in CHO cells, there was a
disruption of the ligand-binding conformation of the receptor complex,
as shown by the inability of the GPIIb/IIIa complex-dependent monoclonal
antibodies to bind to the receptor, the inability of the mutant receptor
to bind PAC1, as well as the inability of transfected CHO cells to
adhere to immobilized fibrinogen.

.0015
GLANZMANN THROMBASTHENIA
ITGA2B, SER926LEU

In a patient with Glanzmann thrombasthenia (273800), Jallu et al. (2010)
identified a homozygous 2870C-T transition in exon 28 of the ITGA2B
gene, resulting in a ser926-to-leu (S926L) substitution in a conserved
residue in the extracellular N terminus that composes the calf-2 domain
of the mature protein. 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 (173470) protein. Jallu et al. (2010)
postulated that the mutation interferes with correct folding of the
protein.

.0016
GLANZMANN THROMBASTHENIA
ITGA2B, GLN595HIS

In a patient with Glanzmann thrombasthenia (273800), Jallu et al. (2010)
identified a homozygous 1878G-C transversion in exon 18 of the ITGA2B
gene, resulting in a gln595-to-his (Q595H) substitution. Flow cytometric
studies of the mutant protein expressed in COS-7 cells showed that the
mutation did not prevent expression of the GPIIb/IIIa complex on the
cell surface. However, the mutation was found to result in a splice site
error, skipping of exon 18, and nonsense-mediated decay of mutant mRNA.

.0017
BLEEDING DISORDER, PLATELET-TYPE, 16
ITGA2B, ARG995GLN

In an Italian father and son with autosomal dominant platelet-type
bleeding disorder-16 (BDPLT16; 187800) and macrothrombocytopenia
originally reported by Hardisty et al. (1992), Peyruchaud et al. (1998)
identified a heterozygous c.3078G-A transition in the ITGA2B gene,
resulting in an arg995-to-gln (R995Q) substitution at a highly conserved
GFFKR sequence in the cytoplasmic domain. Expression of the mutation in
CHO cells resulted in low surface expression of the mutant protein
(about 50%), suggesting that the patient had another pathogenic mutation
causing his severe reduction of ITGA2B expression (12-20% of normal).
CHO cells transfected with the R995Q mutation showed little or no
binding to PAC-1, an antibody that specifically recognizes the activated
form of the GPIIb/IIIa complex, suggesting that the mutant complex was
not in a high-affinity state. However, incubation with an activating
antibody increased PAC-1 binding compared to wildtype, suggesting that
the mutant integrin complex is more easily activatable. Peyruchaud et
al. (1998) noted that a salt bridge between R995 and residue D723 in the
ITGB3 gene (173470) participates in the regulation of the activation
state of the complex, and suggested that the R995Q mutation would give
rise to a receptor that is not locked in a high activation state, but is
more easily activatable compared to wildtype. Nurden et al. (2011) found
that the patient reported by Hardisty et al. (1992) and Peyruchaud et
al. (1998) also carried a splice site deletion in the ITGA2B gene
resulting in lack of protein expression that was inherited from his
mother, who had decreased expression of ITGA2B but no platelet
abnormalities. This second mutation explained the severe lack of
GPIIb/IIIa on the patient's platelets.

.0018
BLEEDING DISORDER, PLATELET-TYPE, 16
ITGA2B, ARG995TRP

In 11 patients from 4 unrelated Japanese families with autosomal
dominant BDPLT16 (187800) manifest as macrothrombocytopenia, Kunishima
et al. (2011) identified a heterozygous c.3077C-T transition in the
ITGA2B gene, resulting in an arg995-to-trp (R995W) substitution at a
conserved residue that forms a salt bridge with D723 in the ITGB3 gene
(173470). The disease haplotype was unique in each family, indicating
independent occurrence. 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). There
was spontaneous PAC-1 and fibrinogen binding to resting platelets, and
FAK (600758) was spontaneously phosphorylated in transfected 293T cells.
These results indicated that the mutant protein caused a constitutive,
activated conformation of the integrin complex, 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 defective 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.

*FIELD* SA
Pytela et al. (1986); Russell et al. (1988); Wilcox et al. (1995)
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*FIELD* CN
Cassandra L. Kniffin - updated: 4/25/2013
Cassandra L. Kniffin - updated: 4/23/2012
Cassandra L. Kniffin - updated: 9/22/2011
Cassandra L. Kniffin - updated: 4/8/2010
Ada Hamosh - updated: 2/1/2010
Ada Hamosh - updated: 9/30/2004

*FIELD* CD
Cassandra L. Kniffin: 5/7/2003

*FIELD* ED
carol: 05/03/2013
ckniffin: 4/25/2013
carol: 4/26/2012
ckniffin: 4/23/2012
joanna: 11/2/2011
carol: 10/24/2011
ckniffin: 9/22/2011
wwang: 4/12/2010
ckniffin: 4/8/2010
alopez: 2/2/2010
terry: 2/1/2010
carol: 5/14/2007
alopez: 11/5/2004
alopez: 10/29/2004
alopez: 10/1/2004
tkritzer: 9/30/2004
terry: 3/18/2004
tkritzer: 6/20/2003
carol: 5/14/2003
ckniffin: 5/13/2003

RBCC Red Blood Cell Collection

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