RBCC Red Blood Cell Collection

VWF (F8VWF) [Confidence: low (only semi-automatic identification from reviews)]
von Willebrand factor; vWF; von Willebrand antigen 2 (von Willebrand antigen II; Flags: Precursor)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt P04275
ID VWF_HUMAN Reviewed; 2813 AA.
AC P04275; Q99806;
DT 20-MAR-1987, integrated into UniProtKB/Swiss-Prot.
read moreDT 11-JAN-2011, sequence version 4.
DT 22-JAN-2014, entry version 191.
DE RecName: Full=von Willebrand factor;
DE Short=vWF;
DE Contains:
DE RecName: Full=von Willebrand antigen 2;
DE AltName: Full=von Willebrand antigen II;
DE Flags: Precursor;
GN Name=VWF; Synonyms=F8VWF;
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], AND VARIANTS ARG-852; ALA-1381 AND
RP HIS-1472.
RX PubMed=3489923; DOI=10.1093/nar/14.17.7125;
RA Bonthron D., Orr E.C., Mitsock L.M., Ginsburg D., Handin R.I.,
RA Orkin S.H.;
RT "Nucleotide sequence of pre-pro-von Willebrand factor cDNA.";
RL Nucleic Acids Res. 14:7125-7128(1986).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS ILE-471; ARG-852;
RP ALA-1381 AND HIS-1472.
RX PubMed=2584182;
RA Mancuso D.J., Tuley E.A., Westfield L.A., Worrall N.K.,
RA Shelton-Inloes B.B., Sorace J.M., Alevy Y.G., Sadler J.E.;
RT "Structure of the gene for human von Willebrand factor.";
RL J. Biol. Chem. 264:19514-19527(1989).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16541075; DOI=10.1038/nature04569;
RA Scherer S.E., Muzny D.M., Buhay C.J., Chen R., Cree A., Ding Y.,
RA Dugan-Rocha S., Gill R., Gunaratne P., Harris R.A., Hawes A.C.,
RA Hernandez J., Hodgson A.V., Hume J., Jackson A., Khan Z.M.,
RA Kovar-Smith C., Lewis L.R., Lozado R.J., Metzker M.L.,
RA Milosavljevic A., Miner G.R., Montgomery K.T., Morgan M.B.,
RA Nazareth L.V., Scott G., Sodergren E., Song X.-Z., Steffen D.,
RA Lovering R.C., Wheeler D.A., Worley K.C., Yuan Y., Zhang Z.,
RA Adams C.Q., Ansari-Lari M.A., Ayele M., Brown M.J., Chen G., Chen Z.,
RA Clerc-Blankenburg K.P., Davis C., Delgado O., Dinh H.H., Draper H.,
RA Gonzalez-Garay M.L., Havlak P., Jackson L.R., Jacob L.S., Kelly S.H.,
RA Li L., Li Z., Liu J., Liu W., Lu J., Maheshwari M., Nguyen B.-V.,
RA Okwuonu G.O., Pasternak S., Perez L.M., Plopper F.J.H., Santibanez J.,
RA Shen H., Tabor P.E., Verduzco D., Waldron L., Wang Q., Williams G.A.,
RA Zhang J., Zhou J., Allen C.C., Amin A.G., Anyalebechi V., Bailey M.,
RA Barbaria J.A., Bimage K.E., Bryant N.P., Burch P.E., Burkett C.E.,
RA Burrell K.L., Calderon E., Cardenas V., Carter K., Casias K.,
RA Cavazos I., Cavazos S.R., Ceasar H., Chacko J., Chan S.N., Chavez D.,
RA Christopoulos C., Chu J., Cockrell R., Cox C.D., Dang M.,
RA Dathorne S.R., David R., Davis C.M., Davy-Carroll L., Deshazo D.R.,
RA Donlin J.E., D'Souza L., Eaves K.A., Egan A., Emery-Cohen A.J.,
RA Escotto M., Flagg N., Forbes L.D., Gabisi A.M., Garza M., Hamilton C.,
RA Henderson N., Hernandez O., Hines S., Hogues M.E., Huang M.,
RA Idlebird D.G., Johnson R., Jolivet A., Jones S., Kagan R., King L.M.,
RA Leal B., Lebow H., Lee S., LeVan J.M., Lewis L.C., London P.,
RA Lorensuhewa L.M., Loulseged H., Lovett D.A., Lucier A., Lucier R.L.,
RA Ma J., Madu R.C., Mapua P., Martindale A.D., Martinez E., Massey E.,
RA Mawhiney S., Meador M.G., Mendez S., Mercado C., Mercado I.C.,
RA Merritt C.E., Miner Z.L., Minja E., Mitchell T., Mohabbat F.,
RA Mohabbat K., Montgomery B., Moore N., Morris S., Munidasa M.,
RA Ngo R.N., Nguyen N.B., Nickerson E., Nwaokelemeh O.O., Nwokenkwo S.,
RA Obregon M., Oguh M., Oragunye N., Oviedo R.J., Parish B.J.,
RA Parker D.N., Parrish J., Parks K.L., Paul H.A., Payton B.A., Perez A.,
RA Perrin W., Pickens A., Primus E.L., Pu L.-L., Puazo M., Quiles M.M.,
RA Quiroz J.B., Rabata D., Reeves K., Ruiz S.J., Shao H., Sisson I.,
RA Sonaike T., Sorelle R.P., Sutton A.E., Svatek A.F., Svetz L.A.,
RA Tamerisa K.S., Taylor T.R., Teague B., Thomas N., Thorn R.D.,
RA Trejos Z.Y., Trevino B.K., Ukegbu O.N., Urban J.B., Vasquez L.I.,
RA Vera V.A., Villasana D.M., Wang L., Ward-Moore S., Warren J.T.,
RA Wei X., White F., Williamson A.L., Wleczyk R., Wooden H.S.,
RA Wooden S.H., Yen J., Yoon L., Yoon V., Zorrilla S.E., Nelson D.,
RA Kucherlapati R., Weinstock G., Gibbs R.A.;
RT "The finished DNA sequence of human chromosome 12.";
RL Nature 440:346-351(2006).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-1400, AND VARIANTS ARG-484; ARG-852
RP AND ALA-1381.
RX PubMed=3019665;
RA Verweij C.L., Diergaarde P.J., Hart M., Pannekoek H.;
RT "Full-length von Willebrand factor (vWF) cDNA encodes a highly
RT repetitive protein considerably larger than the mature vWF subunit.";
RL EMBO J. 5:1839-1847(1986).
RN [5]
RP ERRATUM.
RA Verweij C.L., Diergaarde P.J., Hart M., Pannekoek H.;
RL EMBO J. 5:3074-3074(1986).
RN [6]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-178.
RX PubMed=2828057; DOI=10.1111/j.1432-1033.1988.tb13757.x;
RA Bonthron D., Orkin S.H.;
RT "The human von Willebrand factor gene. Structure of the 5' region.";
RL Eur. J. Biochem. 171:51-57(1988).
RN [7]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-120, AND PROTEIN SEQUENCE OF 23-56.
RC TISSUE=Umbilical vein endothelial cell;
RX PubMed=3495266; DOI=10.1016/S0006-291X(87)80016-5;
RA Shelton-Inloes B.B., Broze G.J. Jr., Miletich J.P., Sadler J.E.;
RT "Evolution of human von Willebrand factor: cDNA sequence
RT polymorphisms, repeated domains, and relationship to von Willebrand
RT antigen II.";
RL Biochem. Biophys. Res. Commun. 144:657-665(1987).
RN [8]
RP PROTEIN SEQUENCE OF 764-2813, AND VARIANTS ARG-852 AND ALA-1381.
RX PubMed=3524673; DOI=10.1021/bi00359a015;
RA Titani K., Kumar S., Takio K., Ericsson L.H., Wade R.D., Ashida K.,
RA Walsh K.A., Chopek M.W., Sadler J.E., Fujikawa K.;
RT "Amino acid sequence of human von Willebrand factor.";
RL Biochemistry 25:3171-3184(1986).
RN [9]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 744-873 AND 1289-2813, AND VARIANTS
RP ALA-789; ARG-852 AND ALA-1381.
RX PubMed=2864688; DOI=10.1073/pnas.82.19.6394;
RA Sadler J.E., Shelton-Inloes B.B., Sorace J.M., Harlan J.M., Titani K.,
RA Davie E.W.;
RT "Cloning and characterization of two cDNAs coding for human von
RT Willebrand factor.";
RL Proc. Natl. Acad. Sci. U.S.A. 82:6394-6398(1985).
RN [10]
RP PROTEIN SEQUENCE OF 764-782.
RC TISSUE=Platelet;
RX PubMed=12665801; DOI=10.1038/nbt810;
RA Gevaert K., Goethals M., Martens L., Van Damme J., Staes A.,
RA Thomas G.R., Vandekerckhove J.;
RT "Exploring proteomes and analyzing protein processing by mass
RT spectrometric identification of sorted N-terminal peptides.";
RL Nat. Biotechnol. 21:566-569(2003).
RN [11]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 781-1424, AND VARIANTS ARG-852 AND
RP ALA-1381.
RX PubMed=3488076; DOI=10.1021/bi00359a014;
RA Shelton-Inloes B.B., Titani K., Sadler J.E.;
RT "cDNA sequences for human von Willebrand factor reveal five types of
RT repeated domains and five possible protein sequence polymorphisms.";
RL Biochemistry 25:3164-3171(1986).
RN [12]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 990-1947, AND VARIANTS ALA-1381
RP AND HIS-1472.
RX PubMed=1988024; DOI=10.1021/bi00215a036;
RA Mancuso D.J., Tuley E.A., Westfield L.A., Lester-Mancuso T.L.,
RA Le Beau M.M., Sorace J.M., Sadler J.E.;
RT "Human von Willebrand factor gene and pseudogene: structural analysis
RT and differentiation by polymerase chain reaction.";
RL Biochemistry 30:253-269(1991).
RN [13]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1236-1476, AND VARIANT ALA-1381.
RX PubMed=9373253;
RA Schulte am Esch J. II, Cruz M.A., Siegel J.B., Anrather J.,
RA Robson S.C.;
RT "Activation of human platelets by the membrane-expressed A1 domain of
RT von Willebrand factor.";
RL Blood 90:4425-4437(1997).
RN [14]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 2621-2813.
RX PubMed=3874428; DOI=10.1126/science.3874428;
RA Ginsburg D., Handin R.I., Bonthron D.T., Donlon T.A., Bruns G.A.P.,
RA Latt S.A., Orkin S.H.;
RT "Human von Willebrand factor (vWF): isolation of complementary DNA
RT (cDNA) clones and chromosomal localization.";
RL Science 228:1401-1406(1985).
RN [15]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 2731-2813.
RX PubMed=3873280; DOI=10.1016/0092-8674(85)90060-1;
RA Lynch D.C., Zimmerman T.S., Collins C.J., Brown M., Morin M.J.,
RA Ling E.H., Livingston D.M.;
RT "Molecular cloning of cDNA for human von Willebrand factor:
RT authentication by a new method.";
RL Cell 41:49-56(1985).
RN [16]
RP SEQUENCE REVISION.
RA Lynch D.C.;
RL Submitted (JUL-1991) to the EMBL/GenBank/DDBJ databases.
RN [17]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 2731-2813.
RX PubMed=3875078; DOI=10.1093/nar/13.13.4699;
RA Verweij C.L., de Vries C.J.M., Distel B., van Zonneveld A.-J.,
RA Geurts van Kessel A., van Mourik J.A., Pannekoek H.;
RT "Construction of cDNA coding for human von Willebrand factor using
RT antibody probes for colony-screening and mapping of the chromosomal
RT gene.";
RL Nucleic Acids Res. 13:4699-4717(1985).
RN [18]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 2731-2813.
RX PubMed=3496594; DOI=10.1073/pnas.84.13.4393;
RA Collins C.J., Underdahl J.P., Levene R.B., Ravera C.P., Morin M.J.,
RA Dombalagian M.J., Ricca G., Livingston D.M., Lynch D.C.;
RT "Molecular cloning of the human gene for von Willebrand factor and
RT identification of the transcription initiation site.";
RL Proc. Natl. Acad. Sci. U.S.A. 84:4393-4397(1987).
RN [19]
RP SUBUNIT, AND SUBCELLULAR LOCATION.
RX PubMed=10961880;
RA Haberichter S.L., Fahs S.A., Montgomery R.R.;
RT "von Willebrand factor storage and multimerization: 2 independent
RT intracellular processes.";
RL Blood 96:1808-1815(2000).
RN [20]
RP DISULFIDE BONDS.
RX PubMed=3502076; DOI=10.1021/bi00399a013;
RA Marti T., Rosselet S.J., Titani K., Walsh K.A.;
RT "Identification of disulfide-bridged substructures within human von
RT Willebrand factor.";
RL Biochemistry 26:8099-8109(1987).
RN [21]
RP STRUCTURE OF CARBOHYDRATES.
RX PubMed=3089784; DOI=10.1111/j.1432-1033.1986.tb09750.x;
RA Samor B., Michalski J.C., Debray H., Mazurier C., Goudemand M.,
RA van Halbeek H., Vliegenthart J.F.G., Montreuil J.;
RT "Primary structure of a new tetraantennary glycan of the N-
RT acetyllactosaminic type isolated from human factor VIII/von Willebrand
RT factor.";
RL Eur. J. Biochem. 158:295-298(1986).
RN [22]
RP INTERACTION WITH F8.
RX PubMed=9218428; DOI=10.1074/jbc.272.29.18007;
RA Saenko E.L., Scandella D.;
RT "The acidic region of the factor VIII light chain and the C2 domain
RT together form the high affinity binding site for von Willebrand
RT factor.";
RL J. Biol. Chem. 272:18007-18014(1997).
RN [23]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-1515, AND MASS
RP SPECTROMETRY.
RC TISSUE=Plasma;
RX PubMed=14760718; DOI=10.1002/pmic.200300556;
RA Bunkenborg J., Pilch B.J., Podtelejnikov A.V., Wisniewski J.R.;
RT "Screening for N-glycosylated proteins by liquid chromatography mass
RT spectrometry.";
RL Proteomics 4:454-465(2004).
RN [24]
RP UBIQUITINATION [LARGE SCALE ANALYSIS] AT LYS-1720, AND MASS
RP SPECTROMETRY.
RC TISSUE=Mammary cancer;
RX PubMed=17370265; DOI=10.1002/pmic.200600410;
RA Denis N.J., Vasilescu J., Lambert J.-P., Smith J.C., Figeys D.;
RT "Tryptic digestion of ubiquitin standards reveals an improved strategy
RT for identifying ubiquitinated proteins by mass spectrometry.";
RL Proteomics 7:868-874(2007).
RN [25]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-2546, AND MASS
RP SPECTROMETRY.
RC TISSUE=Liver;
RX PubMed=19159218; DOI=10.1021/pr8008012;
RA Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H.;
RT "Glycoproteomics analysis of human liver tissue by combination of
RT multiple enzyme digestion and hydrazide chemistry.";
RL J. Proteome Res. 8:651-661(2009).
RN [26]
RP GLYCOSYLATION AT ASN-1515.
RX PubMed=19139490; DOI=10.1074/mcp.M800504-MCP200;
RA Jia W., Lu Z., Fu Y., Wang H.P., Wang L.H., Chi H., Yuan Z.F.,
RA Zheng Z.B., Song L.N., Han H.H., Liang Y.M., Wang J.L., Cai Y.,
RA Zhang Y.K., Deng Y.L., Ying W.T., He S.M., Qian X.H.;
RT "A strategy for precise and large scale identification of core
RT fucosylated glycoproteins.";
RL Mol. Cell. Proteomics 8:913-923(2009).
RN [27]
RP X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 1261-1468.
RX PubMed=9553097; DOI=10.1074/jbc.273.17.10396;
RA Emsley J., Cruz M., Handin R., Liddington R.;
RT "Crystal structure of the von Willebrand factor A1 domain and
RT implications for the binding of platelet glycoprotein Ib.";
RL J. Biol. Chem. 273:10396-10401(1998).
RN [28]
RP X-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS) OF 1685-1873.
RX PubMed=9331419; DOI=10.1016/S0969-2126(97)00266-9;
RA Huizinga E.G., Martijn van der Plas R., Kroon J., Sixma J.J., Gros P.;
RT "Crystal structure of the A3 domain of human von Willebrand factor:
RT implications for collagen binding.";
RL Structure 5:1147-1156(1997).
RN [29]
RP X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF 1686-1872.
RX PubMed=9312128; DOI=10.1074/jbc.272.40.25162;
RA Bienkowska J., Cruz M., Atiemo A., Handin R., Liddington R.;
RT "The von Willebrand factor A3 domain does not contain a metal ion-
RT dependent adhesion site motif.";
RL J. Biol. Chem. 272:25162-25167(1997).
RN [30]
RP REVIEW.
RX PubMed=12871266; DOI=10.1046/j.1538-7836.2003.00260.x;
RA Ruggeri Z.M.;
RT "von Willebrand factor, platelets and endothelial cell interactions.";
RL J. Thromb. Haemost. 1:1335-1342(2003).
RN [31]
RP VARIANTS VWD2 TRP-1597 AND ASP-1607.
RX PubMed=2786201; DOI=10.1073/pnas.86.10.3723;
RA Ginsburg D., Konkle B.A., Gill J.C., Montgomery R.R.,
RA Bockenstedt P.L., Johnson T.A., Yang A.Y.;
RT "Molecular basis of human von Willebrand disease: analysis of platelet
RT von Willebrand factor mRNA.";
RL Proc. Natl. Acad. Sci. U.S.A. 86:3723-3727(1989).
RN [32]
RP VARIANT VWD2 THR-1628.
RX PubMed=1673047;
RA Iannuzzi M.C., Hidaka N., Boehnke M., Bruck M.E., Hanna W.T.,
RA Collins F.S., Ginsburg D.;
RT "Analysis of the relationship of von Willebrand disease (vWD) and
RT hereditary hemorrhagic telangiectasia and identification of a
RT potential type IIA vWD mutation (IIe865 to Thr).";
RL Am. J. Hum. Genet. 48:757-763(1991).
RN [33]
RP VARIANTS VWD2 TRP-816 AND GLN-854.
RX PubMed=1832934; DOI=10.1111/j.1365-2141.1991.tb04480.x;
RA Gaucher C., Mercier B., Jorieux S., Oufkir D., Mazurier C.;
RT "Identification of two point mutations in the von Willebrand factor
RT gene of three families with the 'Normandy' variant of von Willebrand
RT disease.";
RL Br. J. Haematol. 78:506-514(1991).
RN [34]
RP VARIANT VWD2 CYS-1308.
RX PubMed=1761120;
RA Donner M., Andersson A.-M., Kristoffersson A.-C., Nilsson I.M.,
RA Dahlback B., Holmberg L.;
RT "An Arg545-->Cys545 substitution mutation of the von Willebrand factor
RT in type IIB von Willebrand's disease.";
RL Eur. J. Haematol. 47:342-345(1991).
RN [35]
RP VARIANTS VWD2 TRP-1306; CYS-1308 AND PRO-1613.
RX PubMed=2010538; DOI=10.1172/JCI115122;
RA Randi A.M., Rabinowitz I., Mancuso D.J., Mannucci P.M., Sadler J.E.;
RT "Molecular basis of von Willebrand disease type IIB. Candidate
RT mutations cluster in one disulfide loop between proposed platelet
RT glycoprotein Ib binding sequences.";
RL J. Clin. Invest. 87:1220-1226(1991).
RN [36]
RP VARIANTS VWD2 TRP-1306; CYS-1308; MET-1316 AND GLN-1341, AND VARIANT
RP HIS-1399.
RX PubMed=1672694; DOI=10.1172/JCI115123;
RA Cooney K.A., Nichols W.C., Bruck M.E., Bahou W.F., Shapiro A.D.,
RA Bowie E.J.W., Gralnick H.R., Ginsburg D.;
RT "The molecular defect in type IIB von Willebrand disease.
RT Identification of four potential missense mutations within the
RT putative GpIb binding domain.";
RL J. Clin. Invest. 87:1227-1233(1991).
RN [37]
RP VARIANT VWD2 CYS-1313.
RX PubMed=2011604; DOI=10.1073/pnas.88.7.2946;
RA Ware J., Dent J.A., Azuma H., Sugimoto M., Kyrle P.A., Yoshioka A.,
RA Ruggeri Z.M.;
RT "Identification of a point mutation in type IIB von Willebrand disease
RT illustrating the regulation of von Willebrand factor affinity for the
RT platelet membrane glycoprotein Ib-IX receptor.";
RL Proc. Natl. Acad. Sci. U.S.A. 88:2946-2950(1991).
RN [38]
RP VARIANT VWD2 MET-791.
RX PubMed=1906179; DOI=10.1073/pnas.88.14.6377;
RA Tuley E.A., Gaucher C., Jorieux S., Worrall N.K., Sadler J.E.,
RA Mazurier C.;
RT "Expression of von Willebrand factor 'Normandy': an autosomal mutation
RT that mimics hemophilia A.";
RL Proc. Natl. Acad. Sci. U.S.A. 88:6377-6381(1991).
RN [39]
RP VARIANT VWD2 MET-1316.
RX PubMed=1729889;
RA Murray E.W., Giles A.R., Lillicrap D.;
RT "Germ-line mosaicism for a valine-to-methionine substitution at
RT residue 553 in the glycoprotein Ib-binding domain of von Willebrand
RT factor, causing type IIB von Willebrand disease.";
RL Am. J. Hum. Genet. 50:199-207(1992).
RN [40]
RP VARIANTS VWD2 TRP-1306; MET-1316; THR-1628 AND SER-1648.
RX PubMed=1420817;
RA Pietu G., Ribba A.S., de Paillette L., Cherel G., Lavergne J.-M.,
RA Bahnak B.R., Meyer D.;
RT "Molecular study of von Willebrand disease: identification of
RT potential mutations in patients with type IIA and type IIB.";
RL Blood Coagul. Fibrinolysis 3:415-421(1992).
RN [41]
RP VARIANTS VWD2 TRP-1306; CYS-1308; LEU-1314 AND LEU-1318.
RX PubMed=1419803; DOI=10.1111/j.1365-2141.1992.tb04594.x;
RA Donner M., Kristoffersson A.-C., Lenk H., Scheibel E., Dahlback B.,
RA Nilsson I.M., Holmberg L.;
RT "Type IIB von Willebrand's disease: gene mutations and clinical
RT presentation in nine families from Denmark, Germany and Sweden.";
RL Br. J. Haematol. 82:58-65(1992).
RN [42]
RP VARIANT VWD2 ARG-1272.
RX PubMed=1419804; DOI=10.1111/j.1365-2141.1992.tb04595.x;
RA Lavergne J.-M., de Paillette L., Bahnak B.R., Ribba A.-S.,
RA Fressinaud E., Meyer D., Pietu G.;
RT "Defects in type IIA von Willebrand disease: a cysteine 509 to
RT arginine substitution in the mature von Willebrand factor disrupts a
RT disulphide loop involved in the interaction with platelet glycoprotein
RT Ib-IX.";
RL Br. J. Haematol. 82:66-72(1992).
RN [43]
RP VARIANT VWD2 LYS-1638.
RX PubMed=1429668;
RA Ribba A.S., Voorberg J., Meyer D., Pannekoek H., Pietu G.;
RT "Characterization of recombinant von Willebrand factor corresponding
RT to mutations in type IIA and type IIB von Willebrand disease.";
RL J. Biol. Chem. 267:23209-23215(1992).
RN [44]
RP VARIANT VWD2 SER-1324.
RX PubMed=1409710; DOI=10.1073/pnas.89.20.9846;
RA Rabinowitz I., Tuley E.A., Mancuso D.J., Randi A.M., Firkin B.G.,
RA Howard M.A., Sadler J.E.;
RT "von Willebrand disease type B: a missense mutation selectively
RT abolishes ristocetin-induced von Willebrand factor binding to platelet
RT glycoprotein Ib.";
RL Proc. Natl. Acad. Sci. U.S.A. 89:9846-9849(1992).
RN [45]
RP VARIANTS VWD2 GLN-1597; ARG-1609 AND GLU-1665.
RX PubMed=8338947;
RA Inbal A., Englender T., Kornbrot N., Randi A.M., Castaman G.,
RA Mannucci P.M., Sadler J.E.;
RT "Identification of three candidate mutations causing type IIA von
RT Willebrand disease using a rapid, nonradioactive, allele-specific
RT hybridization method.";
RL Blood 82:830-836(1993).
RN [46]
RP VARIANT VWD2 CYS-1514.
RX PubMed=8435341; DOI=10.1111/j.1365-2141.1993.tb04637.x;
RA Gaucher C., Hanss M., Dechavanne M., Mazurier C.;
RT "Substitution of cysteine for phenylalanine 751 in mature von
RT Willebrand factor is a novel candidate mutation in a family with type
RT IIA von Willebrand disease.";
RL Br. J. Haematol. 83:94-99(1993).
RN [47]
RP VARIANTS VWD2 GLY-1597 AND ARG-1609, AND VARIANT CYS-1584.
RX PubMed=8348943;
RA Donner M., Kristoffersson A.C., Berntorp E., Scheibel E., Thorsen S.,
RA Dahlback B., Nilsson I.M., Holmberg L.;
RT "Two new candidate mutations in type IIA von Willebrand's disease
RT (Arg834-->Gly, Gly846-->Arg) and one polymorphism (Tyr821-->Cys) in
RT the A2 region of the von Willebrand factor.";
RL Eur. J. Haematol. 51:38-44(1993).
RN [48]
RP VARIANT VWD2 ASP-1268.
RX PubMed=8376405;
RA Rabinowitz I., Randi A.M., Shindler K.S., Tuley E.A., Rustagi P.K.,
RA Sadler J.E.;
RT "Type IIB mutation His-505-->Asp implicates a new segment in the
RT control of von Willebrand factor binding to platelet glycoprotein
RT Ib.";
RL J. Biol. Chem. 268:20497-20501(1993).
RN [49]
RP VARIANT VWD2 LEU-1266.
RX PubMed=8486782; DOI=10.1172/JCI116443;
RA Holmberg L., Dent J.A., Schneppenheim R., Budde U., Ware J.,
RA Ruggeri Z.M.;
RT "von Willebrand factor mutation enhancing interaction with platelets
RT in patients with normal multimeric structure.";
RL J. Clin. Invest. 91:2169-2177(1993).
RN [50]
RP VARIANT VWD2 VAL-1460.
RX PubMed=8123843;
RA Hilbert L., Gaucher C., de Romeuf C., Horellou M.H., Vink T.,
RA Mazurier C.;
RT "Leu 697-->Val mutation in mature von Willebrand factor is responsible
RT for type IIB von Willebrand disease.";
RL Blood 83:1542-1550(1994).
RN [51]
RP VARIANTS VWD2 PRO-1540 AND THR-1628.
RX PubMed=8123844;
RA Lyons S.E., Cooney K.A., Bockenstedt P., Ginsburg D.;
RT "Characterization of Leu777Pro and Ile865Thr type IIA von Willebrand
RT disease mutations.";
RL Blood 83:1551-1557(1994).
RN [52]
RP VARIANT VWD3 TYR-2739.
RX PubMed=8088787; DOI=10.1006/geno.1994.1241;
RA Zhang Z.P., Blombaeck M., Egberg N., Falk G., Anvret M.;
RT "Characterization of the von Willebrand factor gene (VWF) in von
RT Willebrand disease type III patients from 24 families of Swedish and
RT Finnish origin.";
RL Genomics 21:188-193(1994).
RN [53]
RP VARIANT VWD3 CYS-377.
RX PubMed=7989040; DOI=10.1007/BF00206958;
RA Schneppenheim R., Krey S., Bergmann F., Bock D., Budde U., Lange M.,
RA Linde R., Mittler U., Meili E., Mertes G., Olek K., Plendl H.,
RA Simeoni E.;
RT "Genetic heterogeneity of severe von Willebrand disease type III in
RT the German population.";
RL Hum. Genet. 94:640-652(1994).
RN [54]
RP VARIANT VWD2 SER-528.
RX PubMed=8011991;
RA Uno H., Nishida N., Ishizaki J., Suzuki M., Nishikubo T., Miyata S.,
RA Takahashi Y., Yoshioka A., Tsuda K.;
RT "Investigation of type IIC von Willebrand disease.";
RL Int. J. Hematol. 59:219-225(1994).
RN [55]
RP VARIANTS VWD2 CYS-1374 AND HIS-1374.
RX PubMed=7620154;
RA Hilbert L., Gaucher C., Mazurier C.;
RT "Identification of two mutations (Arg611Cys and Arg611His) in the A1
RT loop of von Willebrand factor (vWF) responsible for type 2 von
RT Willebrand disease with decreased platelet-dependent function of
RT vWF.";
RL Blood 86:1010-1018(1995).
RN [56]
RP VARIANT VWD2 HIS-1374.
RX PubMed=7734373; DOI=10.1111/j.1365-2141.1995.tb08383.x;
RA Castaman G., Eikenboom C.J.C., Rodeghiero F., Briet K., Reitsma P.H.;
RT "A novel candidate mutation (Arg611-->His) in type I 'platelet
RT discordant' von Willebrand's disease with desmopressin-induced
RT thrombocytopenia.";
RL Br. J. Haematol. 89:656-658(1995).
RN [57]
RP VARIANT VWD2 VAL-1461.
RX PubMed=8547152; DOI=10.1111/j.1365-2141.1995.tb05423.x;
RA Hilbert L., Gaucher C., Mazurier C.;
RT "Effects of different amino-acid substitutions in the leucine 694-
RT proline 708 segment of recombinant von Willebrand factor.";
RL Br. J. Haematol. 91:983-990(1995).
RN [58]
RP VARIANT VWD2 ARG-550.
RX PubMed=7789955; DOI=10.1007/BF00209487;
RA Schneppenheim R., Thomas K.B., Krey S., Budde U., Jessat U.,
RA Sutor A.H., Zeiger B.;
RT "Identification of a candidate missense mutation in a family with von
RT Willebrand disease type IIC.";
RL Hum. Genet. 95:681-686(1995).
RN [59]
RP VARIANT VWD2 ARG-2773.
RX PubMed=8622978; DOI=10.1073/pnas.93.8.3581;
RA Schneppenheim R., Brassard J., Krey S., Budde U., Kunicki T.J.,
RA Holmberg L., Ware J., Ruggeri Z.M.;
RT "Defective dimerization of von Willebrand factor subunits due to a
RT Cys-> Arg mutation in type IID von Willebrand disease.";
RL Proc. Natl. Acad. Sci. U.S.A. 93:3581-3586(1996).
RN [60]
RP VARIANT VWD1 TRP-273, AND VARIANT VWD3 TRP-273.
RX PubMed=10887119;
RA Allen S., Abuzenadah A.M., Hinks J., Blagg J.L., Gursel T.,
RA Ingerslev J., Goodeve A.C., Peake I.R., Daly M.E.;
RT "A novel von Willebrand disease-causing mutation (Arg273Trp) in the
RT von Willebrand factor propeptide that results in defective
RT multimerization and secretion.";
RL Blood 96:560-568(2000).
RN [61]
RP VARIANT VWD1 ARG-1149, AND MUTAGENESIS OF CYS-1149 AND CYS-1169.
RX PubMed=11698279; DOI=10.1182/blood.V98.10.2973;
RA Bodo I., Katsumi A., Tuley E.A., Eikenboom J.C., Dong Z., Sadler J.E.;
RT "Type 1 von Willebrand disease mutation Cys1149Arg causes
RT intracellular retention and degradation of heterodimers: a possible
RT general mechanism for dominant mutations of oligomeric proteins.";
RL Blood 98:2973-2979(2001).
RN [62]
RP VARIANT VWD2 ARG-1060.
RX PubMed=12406074; DOI=10.1046/j.1365-2141.2002.03819.x;
RA Mazurier C., Parquet-Gernez A., Gaucher C., Lavergne J.-M.,
RA Goudemand J.;
RT "Factor VIII deficiency not induced by FVIII gene mutation in a female
RT first cousin of two brothers with haemophilia A.";
RL Br. J. Haematol. 119:390-392(2002).
RN [63]
RP VARIANT CYS-1584.
RX PubMed=15755288; DOI=10.1111/j.1365-2141.2005.05375.x;
RA Bowen D.J., Collins P.W., Lester W., Cumming A.M., Keeney S.,
RA Grundy P., Enayat S.M., Bolton-Maggs P.H., Keeling D.M., Khair K.,
RA Tait R.C., Wilde J.T., Pasi K.J., Hill F.G.;
RT "The prevalence of the cysteine1584 variant of von Willebrand factor
RT is increased in type 1 von Willebrand disease: co-segregation with
RT increased susceptibility to ADAMTS13 proteolysis but not clinical
RT phenotype.";
RL Br. J. Haematol. 128:830-836(2005).
RN [64]
RP VARIANT [LARGE SCALE ANALYSIS] CYS-1570.
RX PubMed=16959974; DOI=10.1126/science.1133427;
RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S.,
RA Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J.,
RA Dawson D., Willson J.K.V., Gazdar A.F., Hartigan J., Wu L., Liu C.,
RA Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N.,
RA Vogelstein B., Kinzler K.W., Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal
RT cancers.";
RL Science 314:268-274(2006).
RN [65]
RP VARIANT VWD2 PHE-1272.
RX PubMed=21592258; DOI=10.1111/j.1365-2516.2011.02569.x;
RA Woods A.I., Sanchez-Luceros A., Kempfer A.C., Powazniak Y.,
RA Calderazzo Pereyra J.C., Blanco A.N., Meschengieser S.S.,
RA Lazzari M.A.;
RT "C1272F: a novel type 2A von Willebrand's disease mutation in A1
RT domain; its clinical significance.";
RL Haemophilia 18:112-116(2012).
CC -!- FUNCTION: Important in the maintenance of hemostasis, it promotes
CC adhesion of platelets to the sites of vascular injury by forming a
CC molecular bridge between sub-endothelial collagen matrix and
CC platelet-surface receptor complex GPIb-IX-V. Also acts as a
CC chaperone for coagulation factor VIII, delivering it to the site
CC of injury, stabilizing its heterodimeric structure and protecting
CC it from premature clearance from plasma.
CC -!- SUBUNIT: Multimeric. Interacts with F8.
CC -!- INTERACTION:
CC Self; NbExp=15; IntAct=EBI-981819, EBI-981819;
CC Q76LX8:ADAMTS13; NbExp=5; IntAct=EBI-981819, EBI-981764;
CC P07359:GP1BA; NbExp=2; IntAct=EBI-981819, EBI-297082;
CC Q96CV9:OPTN; NbExp=2; IntAct=EBI-981819, EBI-748974;
CC -!- SUBCELLULAR LOCATION: Secreted. Secreted, extracellular space,
CC extracellular matrix. Note=Localized to storage granules.
CC -!- TISSUE SPECIFICITY: Plasma.
CC -!- DOMAIN: The von Willebrand antigen 2 is required for
CC multimerization of vWF and for its targeting to storage granules.
CC -!- PTM: All cysteine residues are involved in intrachain or
CC interchain disulfide bonds.
CC -!- PTM: N- and O-glycosylated.
CC -!- DISEASE: von Willebrand disease 1 (VWD1) [MIM:193400]: A common
CC hemorrhagic disorder due to defects in von Willebrand factor
CC protein and resulting in impaired platelet aggregation. Von
CC Willebrand disease type 1 is characterized by partial quantitative
CC deficiency of circulating von Willebrand factor, that is otherwise
CC structurally and functionally normal. Clinical manifestations are
CC mucocutaneous bleeding, such as epistaxis and menorrhagia, and
CC prolonged bleeding after surgery or trauma. Note=The disease is
CC caused by mutations affecting the gene represented in this entry.
CC -!- DISEASE: von Willebrand disease 2 (VWD2) [MIM:613554]: A
CC hemorrhagic disorder due to defects in von Willebrand factor
CC protein and resulting in altered platelet aggregation. Von
CC Willebrand disease type 2 is characterized by qualitative
CC deficiency and functional anomalies of von Willebrand factor. It
CC is divided in different subtypes including 2A, 2B, 2M and 2N
CC (Normandy variant). The mutant VWF protein in types 2A, 2B and 2M
CC are defective in their platelet-dependent function, whereas the
CC mutant protein in type 2N is defective in its ability to bind
CC factor VIII. Clinical manifestations are mucocutaneous bleeding,
CC such as epistaxis and menorrhagia, and prolonged bleeding after
CC surgery or trauma. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- DISEASE: von Willebrand disease 3 (VWD3) [MIM:277480]: A severe
CC hemorrhagic disorder due to a total or near total absence of von
CC Willebrand factor in the plasma and cellular compartments, also
CC leading to a profound deficiency of plasmatic factor VIII.
CC Bleeding usually starts in infancy and can include epistaxis,
CC recurrent mucocutaneous bleeding, excessive bleeding after minor
CC trauma, and hemarthroses. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Contains 1 CTCK (C-terminal cystine knot-like) domain.
CC -!- SIMILARITY: Contains 4 TIL (trypsin inhibitory-like) domains.
CC -!- SIMILARITY: Contains 3 VWFA domains.
CC -!- SIMILARITY: Contains 3 VWFC domains.
CC -!- SIMILARITY: Contains 4 VWFD domains.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAB59512.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Sequence of unknown origin in the N-terminal part;
CC -!- WEB RESOURCE: Name=vWF; Note=von Willebrand factor (vWF) mutation
CC db;
CC URL="http://www.vwf.group.shef.ac.uk/";
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/VWF";
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Von Willebrand factor entry;
CC URL="http://en.wikipedia.org/wiki/Von_Willebrand_factor";
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; X04385; CAA27972.1; -; mRNA.
DR EMBL; M25865; AAB59458.1; -; Genomic_DNA.
DR EMBL; M25828; AAB59458.1; JOINED; Genomic_DNA.
DR EMBL; M25829; AAB59458.1; JOINED; Genomic_DNA.
DR EMBL; M25830; AAB59458.1; JOINED; Genomic_DNA.
DR EMBL; M25831; AAB59458.1; JOINED; Genomic_DNA.
DR EMBL; M25832; AAB59458.1; JOINED; Genomic_DNA.
DR EMBL; M25833; AAB59458.1; JOINED; Genomic_DNA.
DR EMBL; M25834; AAB59458.1; JOINED; Genomic_DNA.
DR EMBL; M25835; AAB59458.1; JOINED; Genomic_DNA.
DR EMBL; M25836; AAB59458.1; JOINED; Genomic_DNA.
DR EMBL; M25837; AAB59458.1; JOINED; Genomic_DNA.
DR EMBL; M25838; AAB59458.1; JOINED; Genomic_DNA.
DR EMBL; M25839; AAB59458.1; JOINED; Genomic_DNA.
DR EMBL; M25840; AAB59458.1; JOINED; Genomic_DNA.
DR EMBL; M25841; AAB59458.1; JOINED; Genomic_DNA.
DR EMBL; M25842; AAB59458.1; JOINED; Genomic_DNA.
DR EMBL; M25843; AAB59458.1; JOINED; Genomic_DNA.
DR EMBL; M25844; AAB59458.1; JOINED; Genomic_DNA.
DR EMBL; M25845; AAB59458.1; JOINED; Genomic_DNA.
DR EMBL; M25846; AAB59458.1; JOINED; Genomic_DNA.
DR EMBL; M25847; AAB59458.1; JOINED; Genomic_DNA.
DR EMBL; M25848; AAB59458.1; JOINED; Genomic_DNA.
DR EMBL; M25849; AAB59458.1; JOINED; Genomic_DNA.
DR EMBL; M25850; AAB59458.1; JOINED; Genomic_DNA.
DR EMBL; M25851; AAB59458.1; JOINED; Genomic_DNA.
DR EMBL; M25852; AAB59458.1; JOINED; Genomic_DNA.
DR EMBL; M25853; AAB59458.1; JOINED; Genomic_DNA.
DR EMBL; M25854; AAB59458.1; JOINED; Genomic_DNA.
DR EMBL; M25855; AAB59458.1; JOINED; Genomic_DNA.
DR EMBL; M25856; AAB59458.1; JOINED; Genomic_DNA.
DR EMBL; M25857; AAB59458.1; JOINED; Genomic_DNA.
DR EMBL; M25858; AAB59458.1; JOINED; Genomic_DNA.
DR EMBL; M25859; AAB59458.1; JOINED; Genomic_DNA.
DR EMBL; M25860; AAB59458.1; JOINED; Genomic_DNA.
DR EMBL; M25861; AAB59458.1; JOINED; Genomic_DNA.
DR EMBL; M25862; AAB59458.1; JOINED; Genomic_DNA.
DR EMBL; M25863; AAB59458.1; JOINED; Genomic_DNA.
DR EMBL; M25864; AAB59458.1; JOINED; Genomic_DNA.
DR EMBL; AC005845; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC005846; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC005904; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; X04146; CAA27765.1; -; mRNA.
DR EMBL; X06828; CAA29985.1; -; Genomic_DNA.
DR EMBL; X06829; CAA29985.1; JOINED; Genomic_DNA.
DR EMBL; M17588; AAA65940.1; -; mRNA.
DR EMBL; M10321; AAB59512.1; ALT_SEQ; mRNA.
DR EMBL; M60675; AAA61295.1; -; Genomic_DNA.
DR EMBL; U81237; AAB39987.1; -; mRNA.
DR EMBL; K03028; AAA61293.1; -; mRNA.
DR EMBL; X02672; CAA26503.1; -; mRNA.
DR EMBL; M16946; AAA61294.1; -; Genomic_DNA.
DR EMBL; M16945; AAA61294.1; JOINED; Genomic_DNA.
DR PIR; A34480; VWHU.
DR RefSeq; NP_000543.2; NM_000552.3.
DR UniGene; Hs.440848; -.
DR PDB; 1AO3; X-ray; 2.20 A; A/B=1686-1872.
DR PDB; 1ATZ; X-ray; 1.80 A; A/B=1685-1873.
DR PDB; 1AUQ; X-ray; 2.30 A; A=1261-1468.
DR PDB; 1FE8; X-ray; 2.03 A; A/B/C=1683-1874.
DR PDB; 1FNS; X-ray; 2.00 A; A=1271-1465.
DR PDB; 1IJB; X-ray; 1.80 A; A=1263-1464.
DR PDB; 1IJK; X-ray; 2.60 A; A=1263-1464.
DR PDB; 1M10; X-ray; 3.10 A; A=1261-1468.
DR PDB; 1OAK; X-ray; 2.20 A; A=1271-1465.
DR PDB; 1SQ0; X-ray; 2.60 A; A=1260-1471.
DR PDB; 1U0N; X-ray; 2.95 A; A=1261-1468.
DR PDB; 1UEX; X-ray; 2.85 A; C=1260-1468.
DR PDB; 2ADF; X-ray; 1.90 A; A=1683-1874.
DR PDB; 3GXB; X-ray; 1.90 A; A/B=1495-1671.
DR PDB; 3HXO; X-ray; 2.40 A; A=1260-1468.
DR PDB; 3HXQ; X-ray; 2.69 A; A=1260-1468.
DR PDB; 3PPV; X-ray; 1.90 A; A=1488-1675.
DR PDB; 3PPW; X-ray; 1.90 A; A=1488-1675.
DR PDB; 3PPX; X-ray; 1.91 A; A=1488-1675.
DR PDB; 3PPY; X-ray; 2.00 A; A=1488-1675.
DR PDB; 3ZQK; X-ray; 1.70 A; A/B/C=1478-1674.
DR PDB; 4DMU; X-ray; 2.80 A; B/D/F/H/J/L=1683-1874.
DR PDBsum; 1AO3; -.
DR PDBsum; 1ATZ; -.
DR PDBsum; 1AUQ; -.
DR PDBsum; 1FE8; -.
DR PDBsum; 1FNS; -.
DR PDBsum; 1IJB; -.
DR PDBsum; 1IJK; -.
DR PDBsum; 1M10; -.
DR PDBsum; 1OAK; -.
DR PDBsum; 1SQ0; -.
DR PDBsum; 1U0N; -.
DR PDBsum; 1UEX; -.
DR PDBsum; 2ADF; -.
DR PDBsum; 3GXB; -.
DR PDBsum; 3HXO; -.
DR PDBsum; 3HXQ; -.
DR PDBsum; 3PPV; -.
DR PDBsum; 3PPW; -.
DR PDBsum; 3PPX; -.
DR PDBsum; 3PPY; -.
DR PDBsum; 3ZQK; -.
DR PDBsum; 4DMU; -.
DR ProteinModelPortal; P04275; -.
DR SMR; P04275; 1261-1468, 1495-1671, 1685-1873.
DR DIP; DIP-29667N; -.
DR IntAct; P04275; 47.
DR MINT; MINT-244925; -.
DR STRING; 9606.ENSP00000261405; -.
DR ChEMBL; CHEMBL2021748; -.
DR DrugBank; DB00025; Antihemophilic Factor.
DR MEROPS; I08.950; -.
DR PhosphoSite; P04275; -.
DR UniCarbKB; P04275; -.
DR DMDM; 269849730; -.
DR PaxDb; P04275; -.
DR PRIDE; P04275; -.
DR Ensembl; ENST00000261405; ENSP00000261405; ENSG00000110799.
DR GeneID; 7450; -.
DR KEGG; hsa:7450; -.
DR UCSC; uc001qnn.1; human.
DR CTD; 7450; -.
DR GeneCards; GC12M006058; -.
DR H-InvDB; HIX0010356; -.
DR H-InvDB; HIX0171640; -.
DR HGNC; HGNC:12726; VWF.
DR HPA; CAB001694; -.
DR HPA; HPA001815; -.
DR HPA; HPA002082; -.
DR MIM; 193400; phenotype.
DR MIM; 277480; phenotype.
DR MIM; 613160; gene.
DR MIM; 613554; phenotype.
DR neXtProt; NX_P04275; -.
DR Orphanet; 166078; Von Willebrand disease type 1.
DR Orphanet; 166084; Von Willebrand disease type 2A.
DR Orphanet; 166087; Von Willebrand disease type 2B.
DR Orphanet; 166090; Von Willebrand disease type 2M.
DR Orphanet; 166093; Von Willebrand disease type 2N.
DR Orphanet; 166096; Von Willebrand disease type 3.
DR PharmGKB; PA37337; -.
DR eggNOG; NOG12793; -.
DR HOGENOM; HOG000169747; -.
DR HOVERGEN; HBG004380; -.
DR InParanoid; P04275; -.
DR KO; K03900; -.
DR OMA; ECCGRCL; -.
DR OrthoDB; EOG73V6J9; -.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_118779; Extracellular matrix organization.
DR Reactome; REACT_604; Hemostasis.
DR ChiTaRS; VWF; human.
DR EvolutionaryTrace; P04275; -.
DR GeneWiki; Von_Willebrand_factor; -.
DR GenomeRNAi; 7450; -.
DR NextBio; 29172; -.
DR PRO; PR:P04275; -.
DR ArrayExpress; P04275; -.
DR Bgee; P04275; -.
DR CleanEx; HS_VWF; -.
DR Genevestigator; P04275; -.
DR GO; GO:0005783; C:endoplasmic reticulum; IDA:UniProtKB.
DR GO; GO:0009897; C:external side of plasma membrane; IEA:Ensembl.
DR GO; GO:0031012; C:extracellular matrix; IDA:UniProtKB.
DR GO; GO:0005576; C:extracellular region; IDA:UniProtKB.
DR GO; GO:0031093; C:platelet alpha granule lumen; TAS:Reactome.
DR GO; GO:0005578; C:proteinaceous extracellular matrix; IEA:UniProtKB-SubCell.
DR GO; GO:0033093; C:Weibel-Palade body; IDA:UniProtKB.
DR GO; GO:0051087; F:chaperone binding; IDA:UniProtKB.
DR GO; GO:0005518; F:collagen binding; IDA:UniProtKB.
DR GO; GO:0001948; F:glycoprotein binding; IDA:UniProtKB.
DR GO; GO:0019865; F:immunoglobulin binding; IDA:UniProtKB.
DR GO; GO:0002020; F:protease binding; IDA:MGI.
DR GO; GO:0042803; F:protein homodimerization activity; IDA:UniProtKB.
DR GO; GO:0007597; P:blood coagulation, intrinsic pathway; TAS:Reactome.
DR GO; GO:0031589; P:cell-substrate adhesion; IDA:UniProtKB.
DR GO; GO:0001889; P:liver development; IEA:Ensembl.
DR GO; GO:0001890; P:placenta development; IEA:Ensembl.
DR GO; GO:0030168; P:platelet activation; IDA:UniProtKB.
DR GO; GO:0002576; P:platelet degranulation; TAS:Reactome.
DR GO; GO:0051260; P:protein homooligomerization; IDA:UniProtKB.
DR Gene3D; 3.40.50.410; -; 3.
DR InterPro; IPR006207; Cys_knot_C.
DR InterPro; IPR002919; TIL_dom.
DR InterPro; IPR014853; Unchr_dom_Cys-rich.
DR InterPro; IPR012011; VWF.
DR InterPro; IPR002035; VWF_A.
DR InterPro; IPR001007; VWF_C.
DR InterPro; IPR001846; VWF_type-D.
DR Pfam; PF08742; C8; 4.
DR Pfam; PF01826; TIL; 5.
DR Pfam; PF00092; VWA; 3.
DR Pfam; PF00093; VWC; 2.
DR Pfam; PF00094; VWD; 4.
DR PIRSF; PIRSF002495; VWF; 1.
DR SMART; SM00832; C8; 4.
DR SMART; SM00041; CT; 1.
DR SMART; SM00327; VWA; 3.
DR SMART; SM00214; VWC; 5.
DR SMART; SM00216; VWD; 4.
DR SUPFAM; SSF57567; SSF57567; 5.
DR PROSITE; PS01185; CTCK_1; 1.
DR PROSITE; PS01225; CTCK_2; 1.
DR PROSITE; PS50234; VWFA; 3.
DR PROSITE; PS01208; VWFC_1; 3.
DR PROSITE; PS50184; VWFC_2; 3.
DR PROSITE; PS51233; VWFD; 4.
PE 1: Evidence at protein level;
KW 3D-structure; Blood coagulation; Cell adhesion;
KW Cleavage on pair of basic residues; Complete proteome;
KW Direct protein sequencing; Disease mutation; Disulfide bond;
KW Extracellular matrix; Glycoprotein; Hemostasis; Isopeptide bond;
KW Polymorphism; Reference proteome; Repeat; Secreted; Signal;
KW Ubl conjugation; von Willebrand disease.
FT SIGNAL 1 22
FT CHAIN 23 763 von Willebrand antigen 2.
FT /FTId=PRO_0000022682.
FT CHAIN 764 2813 von Willebrand factor.
FT /FTId=PRO_0000022683.
FT DOMAIN 34 240 VWFD 1.
FT DOMAIN 295 348 TIL 1.
FT DOMAIN 387 598 VWFD 2.
FT DOMAIN 652 707 TIL 2.
FT DOMAIN 776 827 TIL 3.
FT DOMAIN 866 1074 VWFD 3.
FT DOMAIN 1146 1196 TIL 4.
FT DOMAIN 1277 1453 VWFA 1; binding site for platelet
FT glycoprotein Ib.
FT DOMAIN 1498 1665 VWFA 2.
FT DOMAIN 1691 1871 VWFA 3; main binding site for collagens
FT type I and III.
FT DOMAIN 1949 2153 VWFD 4.
FT DOMAIN 2255 2328 VWFC 1.
FT DOMAIN 2429 2495 VWFC 2.
FT DOMAIN 2580 2645 VWFC 3.
FT DOMAIN 2724 2812 CTCK.
FT REGION 764 787 Amino-terminal.
FT REGION 788 833 E1.
FT REGION 826 853 CX.
FT REGION 2216 2261 E2.
FT MOTIF 2507 2509 Cell attachment site.
FT CARBOHYD 99 99 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 156 156 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 211 211 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 666 666 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 857 857 N-linked (GlcNAc...).
FT CARBOHYD 1147 1147 N-linked (GlcNAc...); atypical.
FT CARBOHYD 1231 1231 N-linked (GlcNAc...).
FT CARBOHYD 1248 1248 O-linked (GalNAc...) (Probable).
FT CARBOHYD 1255 1255 O-linked (GalNAc...) (Probable).
FT CARBOHYD 1256 1256 O-linked (GalNAc...) (Probable).
FT CARBOHYD 1263 1263 O-linked (GalNAc...) (Probable).
FT CARBOHYD 1468 1468 O-linked (GalNAc...) (Probable).
FT CARBOHYD 1477 1477 O-linked (GalNAc...) (Probable).
FT CARBOHYD 1486 1486 O-linked (GalNAc...) (Probable).
FT CARBOHYD 1487 1487 O-linked (GalNAc...) (Probable).
FT CARBOHYD 1515 1515 N-linked (GlcNAc...) (complex).
FT CARBOHYD 1574 1574 N-linked (GlcNAc...).
FT CARBOHYD 1679 1679 O-linked (GalNAc...) (Probable).
FT CARBOHYD 2223 2223 N-linked (GlcNAc...).
FT CARBOHYD 2290 2290 N-linked (GlcNAc...).
FT CARBOHYD 2298 2298 O-linked (GalNAc...) (Probable).
FT CARBOHYD 2357 2357 N-linked (GlcNAc...).
FT CARBOHYD 2400 2400 N-linked (GlcNAc...).
FT CARBOHYD 2546 2546 N-linked (GlcNAc...).
FT CARBOHYD 2585 2585 N-linked (GlcNAc...).
FT CARBOHYD 2790 2790 N-linked (GlcNAc...).
FT DISULFID 767 808
FT DISULFID 776 804
FT DISULFID 810 821
FT DISULFID 867 996
FT DISULFID 889 1031
FT DISULFID 898 993
FT DISULFID 914 921
FT DISULFID 1060 1084
FT DISULFID 1071 1111
FT DISULFID 1089 1091
FT DISULFID 1126 1130
FT DISULFID 1149 1169
FT DISULFID 1153 1165
FT DISULFID 1196 1199
FT DISULFID 1234 1237
FT DISULFID 1272 1458
FT DISULFID 1669 1670
FT DISULFID 1686 1872
FT DISULFID 1879 1904
FT DISULFID 1899 1940 Or C-1899 with C-1942.
FT DISULFID 1927 2088
FT DISULFID 1950 2085
FT DISULFID 1972 2123
FT DISULFID 1993 2001
FT DISULFID 2724 2774 By similarity.
FT DISULFID 2739 2788 By similarity.
FT DISULFID 2750 2804 By similarity.
FT DISULFID 2754 2806 By similarity.
FT DISULFID ? 2811 By similarity.
FT CROSSLNK 1720 1720 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in ubiquitin).
FT VARIANT 273 273 R -> W (in VWD1 and VWD3; defect in
FT secretion and formation of multimers;
FT dbSNP:rs61753997).
FT /FTId=VAR_010242.
FT VARIANT 318 318 N -> K (in dbSNP:rs1800387).
FT /FTId=VAR_057023.
FT VARIANT 377 377 W -> C (in VWD3).
FT /FTId=VAR_005782.
FT VARIANT 471 471 V -> I (in dbSNP:rs1800377).
FT /FTId=VAR_060591.
FT VARIANT 484 484 H -> R (in dbSNP:rs1800378).
FT /FTId=VAR_024553.
FT VARIANT 528 528 N -> S (in VWD2).
FT /FTId=VAR_005783.
FT VARIANT 550 550 G -> R (in VWD2).
FT /FTId=VAR_005784.
FT VARIANT 740 740 M -> I (in dbSNP:rs16932374).
FT /FTId=VAR_057024.
FT VARIANT 788 788 C -> Y (in VWD2).
FT /FTId=VAR_009141.
FT VARIANT 789 789 T -> A (in dbSNP:rs1063856).
FT /FTId=VAR_005785.
FT VARIANT 791 791 T -> M (in VWD2; Normandy type).
FT /FTId=VAR_005786.
FT VARIANT 816 816 R -> W (in VWD2; Normandy type).
FT /FTId=VAR_005787.
FT VARIANT 852 852 Q -> R (in dbSNP:rs216321).
FT /FTId=VAR_005788.
FT VARIANT 854 854 R -> Q (in VWD2; Normandy type;
FT dbSNP:rs41276738).
FT /FTId=VAR_005789.
FT VARIANT 857 857 N -> D.
FT /FTId=VAR_005790.
FT VARIANT 885 885 F -> S (in dbSNP:rs11064002).
FT /FTId=VAR_057025.
FT VARIANT 1060 1060 C -> R (in VWD2).
FT /FTId=VAR_028446.
FT VARIANT 1149 1149 C -> R (in VWD1; reduced secretion of
FT homodimers and heterodimers with wild
FT type VWD and increased degradation by the
FT proteasome).
FT /FTId=VAR_064925.
FT VARIANT 1266 1266 P -> L (in VWD2).
FT /FTId=VAR_005791.
FT VARIANT 1268 1268 H -> D (in VWD2).
FT /FTId=VAR_005792.
FT VARIANT 1272 1272 C -> F (in VWD2; subtype 2A).
FT /FTId=VAR_067340.
FT VARIANT 1272 1272 C -> R (in VWD2).
FT /FTId=VAR_005793.
FT VARIANT 1306 1306 R -> W (in VWD2).
FT /FTId=VAR_005794.
FT VARIANT 1308 1308 R -> C (in VWD2).
FT /FTId=VAR_005795.
FT VARIANT 1313 1313 W -> C (in VWD2).
FT /FTId=VAR_005796.
FT VARIANT 1314 1314 V -> L (in VWD2).
FT /FTId=VAR_005797.
FT VARIANT 1316 1316 V -> M (in VWD2).
FT /FTId=VAR_005798.
FT VARIANT 1318 1318 V -> L (in VWD2).
FT /FTId=VAR_005799.
FT VARIANT 1324 1324 G -> S (in VWD2).
FT /FTId=VAR_005800.
FT VARIANT 1341 1341 R -> Q (in VWD2).
FT /FTId=VAR_005801.
FT VARIANT 1374 1374 R -> C (in VWD2).
FT /FTId=VAR_005802.
FT VARIANT 1374 1374 R -> H (in VWD2).
FT /FTId=VAR_005803.
FT VARIANT 1381 1381 T -> A (in dbSNP:rs216311).
FT /FTId=VAR_005804.
FT VARIANT 1399 1399 R -> H (in dbSNP:rs216312).
FT /FTId=VAR_005805.
FT VARIANT 1460 1460 L -> V (in VWD2).
FT /FTId=VAR_005806.
FT VARIANT 1461 1461 A -> V (in VWD2).
FT /FTId=VAR_005807.
FT VARIANT 1472 1472 D -> H (in dbSNP:rs1800383).
FT /FTId=VAR_029656.
FT VARIANT 1514 1514 F -> C (in VWD2).
FT /FTId=VAR_005808.
FT VARIANT 1540 1540 L -> P (in VWD2).
FT /FTId=VAR_005809.
FT VARIANT 1565 1565 V -> L (in dbSNP:rs1800385).
FT /FTId=VAR_014630.
FT VARIANT 1570 1570 Y -> C (in a breast cancer sample;
FT somatic mutation).
FT /FTId=VAR_036276.
FT VARIANT 1584 1584 Y -> C (exhibits increased in
FT susceptibility to proteolysis by
FT ADAMTS13; dbSNP:rs1800386).
FT /FTId=VAR_005810.
FT VARIANT 1597 1597 R -> G (in VWD2).
FT /FTId=VAR_005811.
FT VARIANT 1597 1597 R -> Q (in VWD2).
FT /FTId=VAR_005812.
FT VARIANT 1597 1597 R -> W (in VWD2).
FT /FTId=VAR_005813.
FT VARIANT 1607 1607 V -> D (in VWD2).
FT /FTId=VAR_005814.
FT VARIANT 1609 1609 G -> R (in VWD2).
FT /FTId=VAR_005815.
FT VARIANT 1613 1613 S -> P (in VWD2).
FT /FTId=VAR_005816.
FT VARIANT 1628 1628 I -> T (in VWD2).
FT /FTId=VAR_005817.
FT VARIANT 1638 1638 E -> K (in VWD2).
FT /FTId=VAR_005818.
FT VARIANT 1648 1648 P -> S (in VWD2).
FT /FTId=VAR_005819.
FT VARIANT 1665 1665 V -> E (in VWD2).
FT /FTId=VAR_005820.
FT VARIANT 2063 2063 P -> S (in VWD3; dbSNP:rs61750615).
FT /FTId=VAR_009142.
FT VARIANT 2178 2178 A -> S (in dbSNP:rs34230288).
FT /FTId=VAR_057026.
FT VARIANT 2185 2185 R -> Q (in dbSNP:rs2229446).
FT /FTId=VAR_057027.
FT VARIANT 2362 2362 C -> F (in VWD3).
FT /FTId=VAR_009143.
FT VARIANT 2546 2546 N -> Y (in VWD3).
FT /FTId=VAR_009144.
FT VARIANT 2705 2705 G -> R (in dbSNP:rs7962217).
FT /FTId=VAR_057028.
FT VARIANT 2739 2739 C -> Y (in VWD3).
FT /FTId=VAR_005821.
FT VARIANT 2773 2773 C -> R (in VWD2).
FT /FTId=VAR_005822.
FT MUTAGEN 1149 1149 C->R: Reduced secretion and increased
FT intracellular retention. Similar
FT phenotype; when associated with S-1169.
FT MUTAGEN 1169 1169 C->S: Reduced secretion and increased
FT intracellular retention. Similar
FT phenotype; when associated with R-1149.
FT CONFLICT 770 770 P -> H (in Ref. 9; AAB59512).
FT CONFLICT 804 804 C -> S (in Ref. 8; AA sequence and 9;
FT AAB59512).
FT CONFLICT 1914 1914 S -> T (in Ref. 1; CAA27972).
FT CONFLICT 2168 2168 C -> S (in Ref. 8; AA sequence).
FT STRAND 1267 1269
FT STRAND 1276 1283
FT HELIX 1290 1305
FT TURN 1307 1310
FT STRAND 1313 1329
FT HELIX 1337 1345
FT HELIX 1357 1367
FT STRAND 1369 1371
FT STRAND 1377 1385
FT HELIX 1391 1393
FT HELIX 1394 1396
FT HELIX 1397 1406
FT STRAND 1409 1417
FT HELIX 1422 1431
FT STRAND 1432 1434
FT STRAND 1438 1442
FT HELIX 1443 1445
FT HELIX 1446 1460
FT STRAND 1498 1504
FT TURN 1507 1509
FT HELIX 1511 1527
FT STRAND 1534 1550
FT HELIX 1558 1567
FT HELIX 1578 1587
FT TURN 1588 1590
FT HELIX 1592 1594
FT HELIX 1595 1599
FT STRAND 1602 1608
FT STRAND 1623 1631
FT HELIX 1636 1643
FT STRAND 1649 1652
FT TURN 1654 1656
FT HELIX 1657 1670
FT STRAND 1690 1697
FT STRAND 1699 1702
FT HELIX 1704 1720
FT STRAND 1727 1743
FT STRAND 1745 1747
FT HELIX 1751 1759
FT HELIX 1770 1782
FT HELIX 1784 1786
FT STRAND 1792 1800
FT HELIX 1809 1817
FT STRAND 1820 1831
FT HELIX 1833 1839
FT HELIX 1841 1847
FT STRAND 1849 1853
FT HELIX 1856 1862
FT STRAND 1863 1865
FT HELIX 1866 1870
SQ SEQUENCE 2813 AA; 309265 MW; D5C1C78360917C29 CRC64;
MIPARFAGVL LALALILPGT LCAEGTRGRS STARCSLFGS DFVNTFDGSM YSFAGYCSYL
LAGGCQKRSF SIIGDFQNGK RVSLSVYLGE FFDIHLFVNG TVTQGDQRVS MPYASKGLYL
ETEAGYYKLS GEAYGFVARI DGSGNFQVLL SDRYFNKTCG LCGNFNIFAE DDFMTQEGTL
TSDPYDFANS WALSSGEQWC ERASPPSSSC NISSGEMQKG LWEQCQLLKS TSVFARCHPL
VDPEPFVALC EKTLCECAGG LECACPALLE YARTCAQEGM VLYGWTDHSA CSPVCPAGME
YRQCVSPCAR TCQSLHINEM CQERCVDGCS CPEGQLLDEG LCVESTECPC VHSGKRYPPG
TSLSRDCNTC ICRNSQWICS NEECPGECLV TGQSHFKSFD NRYFTFSGIC QYLLARDCQD
HSFSIVIETV QCADDRDAVC TRSVTVRLPG LHNSLVKLKH GAGVAMDGQD VQLPLLKGDL
RIQHTVTASV RLSYGEDLQM DWDGRGRLLV KLSPVYAGKT CGLCGNYNGN QGDDFLTPSG
LAEPRVEDFG NAWKLHGDCQ DLQKQHSDPC ALNPRMTRFS EEACAVLTSP TFEACHRAVS
PLPYLRNCRY DVCSCSDGRE CLCGALASYA AACAGRGVRV AWREPGRCEL NCPKGQVYLQ
CGTPCNLTCR SLSYPDEECN EACLEGCFCP PGLYMDERGD CVPKAQCPCY YDGEIFQPED
IFSDHHTMCY CEDGFMHCTM SGVPGSLLPD AVLSSPLSHR SKRSLSCRPP MVKLVCPADN
LRAEGLECTK TCQNYDLECM SMGCVSGCLC PPGMVRHENR CVALERCPCF HQGKEYAPGE
TVKIGCNTCV CQDRKWNCTD HVCDATCSTI GMAHYLTFDG LKYLFPGECQ YVLVQDYCGS
NPGTFRILVG NKGCSHPSVK CKKRVTILVE GGEIELFDGE VNVKRPMKDE THFEVVESGR
YIILLLGKAL SVVWDRHLSI SVVLKQTYQE KVCGLCGNFD GIQNNDLTSS NLQVEEDPVD
FGNSWKVSSQ CADTRKVPLD SSPATCHNNI MKQTMVDSSC RILTSDVFQD CNKLVDPEPY
LDVCIYDTCS CESIGDCACF CDTIAAYAHV CAQHGKVVTW RTATLCPQSC EERNLRENGY
ECEWRYNSCA PACQVTCQHP EPLACPVQCV EGCHAHCPPG KILDELLQTC VDPEDCPVCE
VAGRRFASGK KVTLNPSDPE HCQICHCDVV NLTCEACQEP GGLVVPPTDA PVSPTTLYVE
DISEPPLHDF YCSRLLDLVF LLDGSSRLSE AEFEVLKAFV VDMMERLRIS QKWVRVAVVE
YHDGSHAYIG LKDRKRPSEL RRIASQVKYA GSQVASTSEV LKYTLFQIFS KIDRPEASRI
TLLLMASQEP QRMSRNFVRY VQGLKKKKVI VIPVGIGPHA NLKQIRLIEK QAPENKAFVL
SSVDELEQQR DEIVSYLCDL APEAPPPTLP PDMAQVTVGP GLLGVSTLGP KRNSMVLDVA
FVLEGSDKIG EADFNRSKEF MEEVIQRMDV GQDSIHVTVL QYSYMVTVEY PFSEAQSKGD
ILQRVREIRY QGGNRTNTGL ALRYLSDHSF LVSQGDREQA PNLVYMVTGN PASDEIKRLP
GDIQVVPIGV GPNANVQELE RIGWPNAPIL IQDFETLPRE APDLVLQRCC SGEGLQIPTL
SPAPDCSQPL DVILLLDGSS SFPASYFDEM KSFAKAFISK ANIGPRLTQV SVLQYGSITT
IDVPWNVVPE KAHLLSLVDV MQREGGPSQI GDALGFAVRY LTSEMHGARP GASKAVVILV
TDVSVDSVDA AADAARSNRV TVFPIGIGDR YDAAQLRILA GPAGDSNVVK LQRIEDLPTM
VTLGNSFLHK LCSGFVRICM DEDGNEKRPG DVWTLPDQCH TVTCQPDGQT LLKSHRVNCD
RGLRPSCPNS QSPVKVEETC GCRWTCPCVC TGSSTRHIVT FDGQNFKLTG SCSYVLFQNK
EQDLEVILHN GACSPGARQG CMKSIEVKHS ALSVELHSDM EVTVNGRLVS VPYVGGNMEV
NVYGAIMHEV RFNHLGHIFT FTPQNNEFQL QLSPKTFASK TYGLCGICDE NGANDFMLRD
GTVTTDWKTL VQEWTVQRPG QTCQPILEEQ CLVPDSSHCQ VLLLPLFAEC HKVLAPATFY
AICQQDSCHQ EQVCEVIASY AHLCRTNGVC VDWRTPDFCA MSCPPSLVYN HCEHGCPRHC
DGNVSSCGDH PSEGCFCPPD KVMLEGSCVP EEACTQCIGE DGVQHQFLEA WVPDHQPCQI
CTCLSGRKVN CTTQPCPTAK APTCGLCEVA RLRQNADQCC PEYECVCDPV SCDLPPVPHC
ERGLQPTLTN PGECRPNFTC ACRKEECKRV SPPSCPPHRL PTLRKTQCCD EYECACNCVN
STVSCPLGYL ASTATNDCGC TTTTCLPDKV CVHRSTIYPV GQFWEEGCDV CTCTDMEDAV
MGLRVAQCSQ KPCEDSCRSG FTYVLHEGEC CGRCLPSACE VVTGSPRGDS QSSWKSVGSQ
WASPENPCLI NECVRVKEEV FIQQRNVSCP QLEVPVCPSG FQLSCKTSAC CPSCRCERME
ACMLNGTVIG PGKTVMIDVC TTCRCMVQVG VISGFKLECR KTTCNPCPLG YKEENNTGEC
CGRCLPTACT IQLRGGQIMT LKRDETLQDG CDTHFCKVNE RGEYFWEKRV TGCPPFDEHK
CLAEGGKIMK IPGTCCDTCE EPECNDITAR LQYVKVGSCK SEVEVDIHYC QGKCASKAMY
SIDINDVQDQ CSCCSPTRTE PMQVALHCTN GSVVYHEVLN AMECKCSPRK CSK
//

MIM 193400
*RECORD*
*FIELD* NO
193400
*FIELD* TI
#193400 VON WILLEBRAND DISEASE, TYPE 1; VWD1
;;VON WILLEBRAND DISEASE, TYPE I;;
VWD, TYPE 1
read more*FIELD* TX
A number sign (#) is used with this entry because von Willebrand disease
(VWD) type 1 is caused by heterozygous mutation in the gene encoding von
Willebrand factor (VWF; 613160), which maps to chromosome 12p13. VWD
type 2 (VWD2; 613554) and VWD type 3 (VWD3; 277480) are also caused by
mutation in the VWF gene.

DESCRIPTION

Von Willebrand disease is the most common inherited bleeding disorder.
It is characterized clinically by mucocutaneous bleeding, such as
epistaxis and menorrhagia, and prolonged bleeding after surgery or
trauma. The disorder results from a defect in platelet aggregation due
to defects in the von Willebrand factor protein. Von Willebrand factor
is a large, multimeric protein that plays a role in platelet adhesion
and also serves as a carrier for the thrombotic protein factor VIII (F8;
300841). F8 is mutated in hemophilia A (review by Goodeve, 2010).

- Classification of von Willebrand Disease

The classification of von Willebrand disease has a long and complex
history. The current classification is based on that described by Sadler
(1994) and updated by Sadler et al. (2006), which delineates 3 main
subtypes according to the mutant protein phenotype. An earlier
classification developed by a working party of the European Thrombosis
Research Organization was provided by Zimmerman and Ruggeri (1983).

Von Willebrand Disease Type 1

VWD type 1 is a quantitative partial deficiency of circulating VWF. In
this type of VWD, there is a normal ratio of functional VWF activity
(VWF:RCo, ristocetin cofactor activity) relative to VWF antigen level
(VWF:Ag) (Sadler et al., 2006, Goodeve, 2010). Mannucci (2004) stated
that type 1 VWD accounts for 60 to 80% of all VWD cases and is
characterized by mild to moderate quantitative deficiencies of VWF and
factor VIII, which are coordinately reduced to 5 to 30% of normal plasma
levels (pathogenic levels of 5 to 30 IU/dL). In an updated consensus
statement, Sadler et al. (2006) noted that (1) some cases of VWF type 1
may have subtle abnormal VWF multimer patterns, but still retain normal
functional activity, and (2) that loci other than VWF may be responsible
for some cases of VWD.

In reviews, James and Lillicrap (2008) and Lillicrap (2009) stated that
the knowledge of the pathogenesis and molecular basis of type 1 VWD is
still in its infancy and still evolving. Population studies have
indicated that type 1 VWD is a complex genetic trait associated with a
variety of genetic and environmental factors, and that additional loci
in addition to VWF are likely involved. There is still uncertainty about
the pathogenicity of many identified putative VWF variants, and the
incomplete penetrance and variable expressivity of type 1 disease
contributes to complexity in diagnosis and understanding of disease
pathogenesis.

Von Willebrand Disease Type 2

VWD type 2 (613554), which accounts for 10 to 30% of cases, is
characterized by qualitative abnormalities of VWF; it is further divided
into subtypes 2A, 2B, 2M, and 2N. The mutant VWF protein in types 2A,
2B, and 2M are defective in their platelet-dependent function, whereas
the mutant protein in type 2N is defective in its ability to bind F8
(Mannucci, 2004; Sadler et al., 2006; Goodeve, 2010).

Von Willebrand Disease Type 3

VWD type 3 (277480), which accounts for 1 to 5% of cases, is
characterized by a severe quantitative defect of VWF in plasma (less
than 1% of normal plasma levels), with low but usually detectable levels
of factor VIII (1 to 10% of normal plasma levels). In the rare type 3
disease (1 in 1 million people), symptoms are more frequent and severe
(Mannucci, 2004, Sadler et al., 2006).

CLINICAL FEATURES

Type 1 VWD is the most frequent type of von Willebrand disease. However,
laboratory aspects of diagnosis rely on phenotypic assays of VWF which
have an uncertain relationship with VWF function in vivo and with
clinical bleeding. Type 1 VWD is characterized by mild to moderate
reductions of plasma VWF levels, which can vary with time, and plasma
levels of VWF vary widely in the normal population, ranging from less
than 50 U/dl to about 200 U/dl. The molecular diagnosis of type 1 is
poorly understood. All of these factors make the definitive diagnosis of
type 1 VWD particularly difficult (O'Brien et al., 2003; Cumming et al.,
2006).

O'Brien et al. (2003) reported 12 probands, 10 Canadian and 2 from the
U.K., with a clinical diagnosis of type 1 VWD. All had a bleeding
history with epistaxis, menorrhagia, easy bruising, and excessive
bleeding from wounds, especially after surgery and dental procedures.
Laboratory studies showed that all had VWF multimers of various sizes,
but at reduced intensity, consistent with a quantitative defect in type
1 VWD. Testing for VWF:Ag (VWF protein antigen levels) and VWF:RCo (VWF
platelet-induced aggregation function with ristocetin) showed decreased
levels of both compared to normal, and FVIII:C (factor 8 pro-coagulant
activity) was normal in all except 1 patient. Notably, all except 1 had
type O of the ABO blood group. All patients were found to have the same
heterozygous mutation in the VWF gene (Y1584C; 613160.0029).

Cumming et al. (2006) examined 40 U.K. families with a clinical
diagnosis of type 1 VWD. After review, 6 were found to have type 2 VWD
and 2 additional families did not have VWD. Genetic analysis identified
6 pathogenic VWF mutations in 9 (28%) of the 32 remaining families with
type 1 VWD. Three index cases (9%) had more than 1 candidate mutation.
Fifteen (47%) families had no identified mutation. Cumming et al. (2006)
identified the Y1584C change (613160.0029) in 8 (25%) families, but the
variant segregated with the disease in only 3 families, did not
segregate in 3 families, and yielded equivocal results in 2 families,
suggesting that it is a common polymorphism that increases
susceptibility to the disease, but does not cause the disease by itself.
The authors concluded that mutation screening of the VWF gene has
limited general utility in genetic diagnostic and family studies in type
1 VWD due to incomplete penetrance and variable expressivity.

Goodeve et al. (2007) identified VWF mutations in 105 (70%) of 150 index
patients from 9 European countries with a clinical diagnosis of type 1
VWD. A total of 123 candidate VWF mutations were identified, including
53 novel mutations: 88 patients had 1 mutation, 16 had 2, and 1 had 3.
However, multimer analysis showed that a substantial part of the cohort
(38%, 57 of 150) had an abnormal multimer pattern that did not fit into
the accepted criteria for type 1 VWD. In addition, 18 patients had
decreased binding of F8 to VWF, including 3 with markedly reduced
binding consistent with type 2N VWD. Fifty-one probands with normal
multimers had a VWF mutation, and 42 with normal multimers had no
identifiable VWF mutations, indicating genetic heterogeneity. Incomplete
segregation was observed in many of the families with mutations.

James et al. (2007) examined 123 Canadian families with a clinical
diagnosis of type 1 VWD. All patients had excessive mucocutaneous
bleeding, including menorrhagia, easy bruising, epistaxis, postdental
procedure bleeding, and postoperative bleeding. The mean VWF:Ag level
for the index cases was 0.36 IU/mL, the mean VWF:RCo level was 0.34
IU/mL, and the mean FVIII level was 0.54 IU/mL. The VWF multimer pattern
was normal. Most of the index cases (77, or 62%) were blood group O (see
110300). Putative VWF mutations were found in 78 patients (63%), leaving
37% with no identified changes. The changes comprised 50 different
variants: 31 (62%) missense mutations, 8 (16%) changes involving the VWF
transcriptional regulatory region, 5 (10%) small deletions/insertions, 5
(10%) splice site mutations, and 1 nonsense mutation. Twenty-one of the
index cases had more than 1 putative VWF mutation, although many of
these genetic changes may have been polymorphisms. James et al. (2007)
noted that sequence variations within the VWF gene were clearly not the
sole genetic determinants of the type 1 VWD phenotype in some cases. In
addition, the relative contribution of VWF sequence variation appeared
to be most important in more severely affected individuals, and the
contribution of factors such as ABO blood group became more significant
in milder cases. The findings indicated that more severe cases of type 1
VWD tend to have mutations within the VWF gene that are highly
heritable. In contrast, milder cases, where heritability is variable,
have more complex genetic determinants, and are more likely to have
contributions from other genetic factors, such as ABO blood group, as
well as possibly environmental factors.

- Relationship to Blood Group O

Gill et al. (1987) found a significant association between ABO blood
group O (see 110300) and decreased levels of VWF antigen (VWF:Ag) among
1,117 volunteer blood donors analyzed by quantitative
immunoelectrophoresis. Individuals with blood group O had the lowest
mean VWF:Ag levels (74.8 U/dL), followed by group A (105.9 U/dL), group
B (116.9 U/dL), and group AB (123.3 U/dL). In addition, multiple
regression analysis revealed that age significantly correlated with
VWF:Ag levels in each blood group. Among 114 patients with type 1 VWD,
blood group O was found in 88 (77%), group A in 21 (18%), group B in 5
(4%), and group AB in none (0%), whereas the frequency of these blood
groups in the normal population was significantly different (45%, 45%,
7% and 3%, respectively). In contrast, patients with VWD type 2 or type
3 had ABO blood group frequencies that were not different from the
expected distribution. Gill et al. (1987) concluded that there may be a
subset of symptomatic type 1 VWD patients with decreased concentrations
of structurally normal VWF due to the presence of blood group O.
Similarly, some individuals with blood group AB and a genetic defect in
VWF may not be diagnosed as affected because VWF levels are elevated due
to their blood type.

Plasma VWF levels may be modified by genetic and environmental factors
such as thyroid hormones, estrogens, or stress. The best-characterized
genetic modifier is the ABO blood group, which accounts for
approximately 30% of the genetic effect (Nichols and Ginsburg, 1997).
See also NituWhalley et al. (2000) concerning the influence of the ABO
blood group in type 1 VWD. In the study of Casana et al. (2001), the
number of patients with blood group O was regarded as significant in the
milder deficiency group with variable expression of the gene, i.e.,
blood group may be irrelevant in families with complete penetrance, but
might be a factor in cases with mild phenotypes and incomplete
penetrance. Mutations affecting genetic modifiers might also cause type
1 VWD, even in the absence of a mutation at the VWF gene, which might be
the case for the families in which no linkage was obtained by Casana et
al. (2001).

The effect of blood group O on VWD appears to be through reduced
survival, or increased clearance, of VWF, which may be related to
different glycosyltransferase alleles that determine the ABO blood
group. ABO antigens are added to the N-linked oligosaccharide chains
present in mature VWF, and this glycosylation may protect VWF from
clearance. However, the glycosyltransferase is nonfunctional in blood
group O due to a null allele. Individuals with blood group O would thus
have a lack of glycosylation of VWF, which would result in a loss of
protective carbohydrate structure and increased clearance of VWF (review
by Goodeve, 2010).

- Acquired Von Willebrand Disease

A phenocopy of von Willebrand disease in a patient with the autoimmune
disorder systemic lupus erythematosus (SLE; 152700) was reported by
Simone et al. (1968). Acquired von Willebrand disease may have an
autoimmune basis, the target of immunologic damage being endothelial
cells that synthesize von Willebrand factor (Wautier et al., 1976).

OTHER FEATURES

Early reports described disorders associated with von Willebrand
disease. Quick (1967) reported a mother and daughter with telangiectasia
and von Willebrand disease. Association with angiodysplasia of
intestinal vessels, in some cases demonstrable by arteriography and
visible at surgery, has been described (Ramsey et al., 1976).

Kernoff et al. (1981) found extensive atherosclerosis in an elderly man
with von Willebrand disease, suggesting that the defect in platelet
adhesion does not interfere with the atherosclerotic process.

PATHOGENESIS

Several observations (Cornu et al., 1963; Biggs and Matthews, 1963) are
pertinent to the nature of the factor VIII defect in von Willebrand
disease: (1) Blood from a patient with hemophilia A (306700), due to a
defect in the F8 gene, will correct the clotting defect in von
Willebrand disease. (2) The converse is not true: blood from a patient
with von Willebrand disease will not correct the clotting defect in
hemophilia A. (3) The bleeding tendency in von Willebrand disease is
corrected promptly by normal blood. (4) After administration of
hemophilia A blood to von Willebrand patients there is a delay of
several hours before the level of F8 reaches normal. These observations
indicated a relationship between VWF and F8.

In 3 patients with von Willebrand disease, Gralnick and Coller (1976)
found that the factor VIII-von Willebrand factor protein was present in
normal amounts and had normal procoagulant and antigen activities. The
protein was, however, deficient in both carbohydrate and von Willebrand
factor activity. The carbohydrate portion of this glycoprotein seemed to
be essential to its interaction with platelets or blood vessel wall or
both.

Nachman et al. (1980) studied the factor VIII antigen molecule in
classic type 1 and variant type 2A. The 2-dimensional peptide maps were
'remarkably similar' both to each other and to normal factor VIII. Thus,
the differences observed in von Willebrand disease were probably not due
to qualitatively abnormal molecules but rather to 'quantitative shifts
in the metabolism of normal factor VIII antigen molecules.' Type 1 is
usually associated with a concordant decrease in VIII:C, VIII:A, and
VIII:VWF, whereas type 2A shows a disproportionate decrease in VIII:VWF.

CLINICAL MANAGEMENT

Patients with type 1 VWD have a high probability of responding to the
vasopressin analog desmopressin acetate (1-desamino-8-D-arginine
vasopressin; dDAVP), which raises the level of factor VIII/von
Willebrand factor in plasma. The likelihood of responding correlates
with the initial VWF:Ag level, such that patients with very low VWF
usually do not respond well (Sadler et al., 2006).

MAPPING

Some small families with VWD type 1 have been observed to cosegregate
with polymorphic markers at the VWF locus (Cumming et al., 1992; Inbal
et al., 1992), whereas lack of association between the type 1 phenotype
and intragenic markers of the VWF gene on chromosome 12p13 have been
reported in families from a population study (Castaman et al., 1999).

In a study in Spain, Casana et al. (2001) performed linkage analysis of
12 families with definite or possible type 1 VWD. One family with
classic type 1 had a high lod score (maximum lod = 5.28 at theta =
0.00). Four families with fully penetrant disease had a total lod score
of 10.68. In 2 families, linkage was rejected, and 3 families did not
show conclusive evidence of linkage.

Linkage disequilibrium mapping may be useful in genomic regions of less
than 1 cM where the number of informative meioses needed to detect
recombinant individuals within pedigrees is exceptionally high. Its
utility for refining target areas for candidate disease genes before
initiating chromosomal walks and cloning experiments is based on an
understanding of the relationship between linkage disequilibrium and
physical distance. To address this matter, Watkins et al. (1994)
characterized linkage disequilibrium in a 144-kb region of the VWF gene
in 60 CEPH and 12 von Willebrand families. The analysis revealed a
general trend in which linkage disequilibrium dissipates more rapidly
with physical distance in telomeric regions than in centromeric regions.
This trend was consistent with higher recombination rates near
telomeres.

MOLECULAR GENETICS

Sadler and Ginsburg (1993) reported on a database of polymorphisms in
the VWF gene and pseudogene; Ginsburg and Sadler (1993) reported on a
database of point mutations, insertions, and deletions.

Eikenboom et al. (1996) described a family in the Netherlands in which 3
affected members with type 1 von Willebrand disease and VWF levels 10 to
15% of normal were heterozygous for a mutation in the VWF gene (C1149R;
613160.0028). The mutation resulted in a decrease in the secretion of
coexpressed normal VWF, and the mutation was proposed to cause
intracellular retention of pro-VWF heterodimers.

- 'Vicenza' Variant of Von Willebrand Factor

In affected members of 7 Italian families and in 1 German patient with
von Willebrand disease 'Vicenza,' Schneppenheim et al. (2000) identified
a heterozygous R1205H mutation in the VWF gene (613160.0027). Haplotype
identity, with minor deviations in 1 Italian family, suggested a common
but not very recent genetic origin of R1205H. Von Willebrand disease
'Vicenza' was originally described in patients living in the region of
Vicenza in Italy (Mannucci et al., 1988). A number of additional
families were identified in Germany by Zieger et al. (1997). The
phenotype was characterized by these groups as showing autosomal
dominant inheritance and low levels of VWF antigen in the presence of
high molecular weight and ultra high molecular weight multimers,
so-called 'supranormal' multimers, similar to those seen in normal
plasma after infusion of desmopressin. Randi et al. (1993) had
demonstrated genetic linkage between the VWF gene and the 'Vicenza
variant' of VWD type 1, suggesting that the disorder is due to a
mutation in the VWF gene that results in an abnormal VWF molecule that
is processed to a lesser extent than a normal VWF.

Casonato et al. (2002) identified 4 additional families with the R1205H
variant. Individuals with this variant showed a mild bleeding tendency
and significant decrease in plasma VWF antigen and ristocetin cofactor
activity, but normal platelet VWF levels. Larger than normal VWF
multimers were also observed. However, VWF multimers disappeared rapidly
from the circulation after desmopressin, indicating reduced survival of
the mutant protein. Since ristocetin-induced platelet aggregation was
normal, Casonato et al. (2002) attributed the phenotype to reduced
survival of normally synthesized VWF, which is consistent with type 1
VWF.

Cumming et al. (2006) identified the Vicenza variant in 4 (12.5%) of 32
UK patients with type 1 VWD. The R1205H mutation was highly penetrant
and consistently associated with moderate to severe type 1 disease. VWF
multimer studies did not show the presence of ultralarge multimers in
any affected individuals; the authors thus classified the Vicenza
variant to be a type 1 quantitative defect, rather than a type 2M
qualitative defect as had been suggested by Castaman et al. (2002).
Three of the 4 families reported by Cumming et al. (2006) shared the
same haplotype, suggesting a common origin of the mutation.

- Susceptibility Alleles

In 10 Canadian families and 2 families from the U. K. with type 1 VWD,
O'Brien et al. (2003) identified a heterozygous Y1584C (613160.0029)
substitution in the VWF gene.

Bowen and Collins (2004) described a patient with type 1 von Willebrand
disease in whom the von Willebrand factor showed increased
susceptibility to proteolysis by ADAMTS13 (604134). Investigation of
additional family members indicated that increased susceptibility was
heritable, but it did not track uniquely with type 1 VWD. Sequence
analysis showed that increased susceptibility to proteolysis tracked
with the Y1584C substitution. A prospective study of 200 individuals
yielded 2 Y1584C heterozygotes; for both, plasma VWF showed increased
susceptibility to proteolysis.

Cumming et al. (2006) identified heterozygosity for the Y1584C variant
in 8 (25%) of 32 U.K. families and in 19 (17%) of 119 related
individuals with type 1 VWD. Eighteen (95%) of the 19 individuals were
blood group O. Heterozygosity for Y1584C segregated with VWD is 3
families, did not segregate with VWD in 4 families, and showed equivocal
results in 2 families. Cumming et al. (2006) concluded that Y1594C is a
polymorphism that is frequently associated with type 1 VWD, but shows
incomplete penetrance and does not consistently segregate with the
disease. The association with blood group type O may be related to the
fact that both blood group O and Y1584C are associated with increased
proteolysis of VWF by ADAMTS13 (604134).

INHERITANCE

Mannucci (2004) stated that type 1 VWD is typically transmitted as an
autosomal dominant trait.

Cumming et al. (2006) concluded that type 1 VWD is best considered a
complex multifactorial disorder, with interrelating genetic and
environmental components. In a study of 32 UK families with type 1 VWD,
Cumming et al. (2006) found that putative mutations did not always
segregate with the disease, indicating incomplete penetrance, and that
47% of index cases did not have VWF mutations. In addition, linkage
analysis of affected families does not always show linkage to the VWF
locus, suggesting that additional loci may be involved.

POPULATION GENETICS

Miller et al. (1986) ascertained and studied 5 families with both VWD
and hemophilia A. This suggested to them that VWD is a rather frequent
disorder. They proposed 1.4% as the frequency of VWD heterozygotes.

A frequency of 2.5 to 5.0% was estimated for VWD heterozygotes in Sweden
(Bowie, 1984).

Sutherland et al. (2009) identified a recurrent 8.6-kb deletion of exons
4 and 5 of the VWF gene (613160.0038) in Caucasian British patients with
VWD type 1 and VWD type 3. The deletion was not found in VWD patients of
Asian origin, and haplotype analysis confirmed a founder effect in the
white British population. The mutation was unusual in that the truncated
VWF protein produced had a dominant-negative effect on expression of the
second allele.

HISTORY

Von Willebrand (1926, 1931) discovered a hemorrhagic condition in
persons living on the Aland Islands in the Sea of Bothnia between Sweden
and Finland and called it 'pseudohemophilia.' (See 300600 for another
Aland Island disease.) The main difference from classic hemophilia was
prolonged bleeding time. Major clinical problems were gastrointestinal,
urinary, and uterine bleeding; hemarthroses were rare, but present. Von
Willebrand and Jurgens (1933), using the capillary thrombometer,
suggested the designation 'constitutional thrombopathy.' Nyman et al.
(1981) followed up on the kindred originally reported by von Willebrand
(1926). The relatively severe phenotype suggesting that some members of
the family, which showed evidence of consanguinity, may have had VWD
type 3 (277480), which is transmitted as an autosomal recessive
disorder. Zhang et al. (1993) stated that the original family reported
by von Willebrand (1926) carried a common 1-bp deletion in the VWF gene
(613160.0021).

Alexander and Goldstein (1953) discovered low antihemophilic globulin
(AHG, or factor VIII; 300841) in this disorder. Thereafter the condition
became known as 'vascular hemophilia.' In the next 10 years, the main
developments were the demonstrations that (1) the platelet is
intrinsically normal but has reduced adhesiveness because of factor VIII
deficiency, and (2) plasma from persons with classic hemophilia will
correct both the vascular defect and the factor VIII deficiency.

Goldin et al. (1980) reported a hint of linkage with glutamate-pyruvate
transaminase (GPT1; 138200), but Verp et al. (1982) found no evidence of
linkage to GPT1.

Pickering et al. (1981) found mitral valve prolapse in 9 of 15 patients
(60%) with von Willebrand disease and 4 of 30 sex- and age-matched
healthy controls (13.3%). They suggested that von Willebrand disease is
'a mesenchymal dysplasia that resembles the heritable disorders of
connective tissue.'

ANIMAL MODEL

Von Willebrand disease has been identified in a number of mammalian
species. The disease is autosomal recessive in the pig (Fass et al.,
1979). Bahou et al. (1988) studied a family of pigs with the porcine
form of VWD. Using a RFLP lying within the porcine VWF gene, they showed
tight linkage with the disease (lod score of 5.3 with no crossovers).

Bowie et al. (1986) reported that bone marrow transplantation in a pig
with severe VWD caused only partial correction of the bleeding problem.
They concluded that the 'plasmatic compartment is only minimally
replenished by the VWF from platelets and megakaryocytes.' Both
endothelial cells and megakaryocytes synthesize VWF.

Sweeney et al. (1990) described a mouse model for human type I VWD. The
affected mice showed prolonged bleeding time, normal VWF multimer
distribution, autosomal dominant inheritance, and proportionately
decreased plasma VWF antigen, ristocetin cofactor, and factor VIII
activities. Genetic linkage analysis indicated that murine VWD is caused
by a defect at a novel genetic locus, distinct from the murine VWF gene.
Mohlke et al. (1996) extended these studies by localizing the major gene
modifying VWF cells in the inbred mouse strain originally studied by
Sweeney et al. (1990). A novel locus accounting for 63% of the total
variants in VWF level was mapped to distal mouse chromosome 11, which is
distinct from the murine Vwf locus on chromosome 6. They designated this
locus Mvwf for 'modifier of VWF.' A single dominant gene accounting for
the low VWF phenotype of the original strain studied (RIIIS/J) was
demonstrated in crosses with several other strains. The pattern of
inheritance suggested a gain-of-function mutation in a unique component
of VWF biosynthesis or processing. Mohlke et al. (1996) commented that
characterization of the human homolog of Mvwf may have relevance for a
subset of type 1 VWD cases and may define an important genetic factor
modifying penetrance and expression of mutations at the VWF locus.
Mohlke et al. (1999) found that Mvwf, the gene responsible for modifying
plasma levels of Vwf in a strain of mice, was Galgt2 (B4GALNT2; 111730).
They showed that the mutation causing deficiency of Vwf changed
expression of the gene from gut specific to the vascular endothelium.
Ginsburg (1999) expressed the opinion that the same alteration is highly
unlikely in humans. However, the Mvwf modifier gene effect may be a
useful paradigm for understanding genetic modification of plasma VWF
levels.

Denis et al. (1998) generated a mouse model for von Willebrand disease
by using gene targeting. VWF-deficient mice appeared normal at birth;
they were viable and fertile. Neither von Willebrand factor nor
VWF-propolypeptide (von Willebrand antigen II) was detectable in plasma,
platelets, or endothelial cells of the homozygous mutant mice. The
mutant mice exhibited defects in hemostasis with a highly prolonged
bleeding time and spontaneous bleeding events in approximately 10% of
neonates. As in the human disease, the factor VIII level in these mice
was reduced strongly as a result of the lack of protection provided by
von Willebrand factor. Defective thrombosis in mutant mice was also
evident in an in vivo model of vascular injury. In this model, the
exteriorized mesentery was superfused with ferric chloride and the
accumulation of fluorescently labeled platelets was observed by
intravascular microscopy. Denis et al. (1998) concluded that these mice
very closely mimic severe human von Willebrand disease.

*FIELD* SA
Andrews et al. (1989); Barrow et al. (1965); Bennett et al. (1972);
Bernardi et al. (1990); Blomback et al. (1963); Booyse et al. (1977);
Cramer et al. (1976); Dodds (1970); Firkin et al. (1973); Fuster
and Bowie (1978); Gaucher et al. (1991); Gralnick and Coller (1976);
Gralnick et al. (1975); Gralnick et al. (1977); Gralnick et al. (1985);
Gralnick et al. (1985); Green and Chediak (1977); Green and Potter
(1976); Hagedorn (1971); Hall et al. (1987); Howard et al. (1982);
Iannuzzi et al. (1991); Lavabre-Bertrand et al. (1994); Lester et
al. (2006); Lian (1976); Lian and Deykin (1976); Lombardi et al.
(1981); Mannucci et al. (1985); McGrath et al. (1979); Meyer et al.
(1978); Miller et al. (1979); Miller et al. (1979); Nachman (1977);
Nevanlinna et al. (1962); Nichols et al. (1994); Peake et al. (1974);
Raccuglia and Neel (1960); Richardson and Robinson (1985); Ruggeri
(1997); Shoa'i et al. (1977); Strauss and Bloom (1965); Wahlberg et
al. (1983); Warkentin et al. (1992); Weiss (1968); Zimmerman and
Ruggeri (1987)
*FIELD* RF
1. Alexander, B.; Goldstein, R.: Dual hemostatic defect in pseudohemophilia.
(Abstract) J. Clin. Invest. 32: 551, 1953.

2. Andrews, R. K.; Booth, W. J.; Gorman, J. J.; Castaldi, P. A.; Berndt,
M. C.: Purification of botrocetin from Bothrops jararaca venom: analysis
of the botrocetin-mediated interaction between von Willebrand factor
and the human platelet membrane glycoprotein Ib-IX complex. Biochemistry 28:
8317-8326, 1989.

3. Bahou, W. F.; Bowie, E. J. W.; Fass, D. N.; Ginsburg, D.: Molecular
genetic analysis of porcine von Willebrand disease: tight linkage
to the von Willebrand factor locus. Blood 72: 308-313, 1988.

4. Barrow, E. M.; Heindel, C. C.; Roberts, H. R.; Graham, J. B.:
Heterozygosity and homozygosity in von Willebrand's disease. Proc.
Soc. Exp. Biol. Med. 118: 684-687, 1965.

5. Bennett, B.; Ratnoff, O. D.; Levin, J.: Immunological studies
in von Willebrand's disease: evidence that the antihemophilic factor
(AHF) produced after transfusions lacks an antigen associated with
normal AHF and the inactive material produced by patients with classic
hemophilia. J. Clin. Invest. 51: 2597-2601, 1972.

6. Bernardi, F.; Marchetti, G.; Guerra, S.; Casonato, A.; Gemmati,
D.; Patracchini, P.; Ballerini, G.; Conconi, F.: A de novo and heterozygous
gene deletion causing a variant of von Willebrand disease. Blood 75:
677-683, 1990.

7. Biggs, R.; Matthews, J. M.: The treatment of haemorrhage in von
Willebrand's disease and the blood level of factor VIII (AHG). Brit.
J. Haemat. 9: 203-214, 1963.

8. Blomback, M.; Jorpes, J. E.; Nilsson, I. M.: Von Willebrand's
disease. Am. J. Med. 34: 236-241, 1963.

9. Booyse, F. M.; Quarfaat, A. J.; Bell, S.; Fass, D. N.; Lewis, J.
C.; Mann, K. G.; Bowie, E. J.: Cultured aortic endothelial cells
from pigs with von Willebrand disease: in vitro model for studying
the molecular defect(s) of the disease. Proc. Nat. Acad. Sci. 74:
5702-5706, 1977.

10. Bowen, D. J.; Collins, P. W.: An amino acid polymorphism in von
Willebrand factor correlates with increased susceptibility to proteolysis
by ADAMTS13. Blood 103: 941-947, 2004.

11. Bowie, E. J. W.: Von Willebrand's disease: state of the art. Scand.
J. Haemat. 33 (suppl. 40): 431-440, 1984.

12. Bowie, E. J. W.; Solberg, L. A., Jr.; Fass, D. N.; Johnson, C.
M.; Knutson, G. J.; Stewart, M. L.; Zoecklein, L. J.: Transplantation
of normal bone marrow into a pig with severe von Willebrand's disease. J.
Clin. Invest. 78: 26-30, 1986.

13. Casana, P.; Martinez, F.; Haya, S.; Espinos, C.; Aznar, J. A.
: Significant linkage and non-linkage of type 1 von Willebrand disease
to the von Willebrand factor gene. Brit. J. Haemat. 115: 692-700,
2001.

14. Casonato, A.; Pontara, E.; Sartorello, F.; Cattini, M. G.; Sartori,
M. T.; Padrini, R.; Girolami, A.: Reduced von Willebrand factor survival
in type Vicenza von Willebrand disease. Blood 99: 180-184, 2002.

15. Castaman, G.; Eikenboom, J. C. J.; Bertina, R. M.; Rodeghiero,
F.: Inconsistency of association between type 1 von Willebrand disease
phenotype and genotype in families identified in an epidemiological
investigation. Thromb. Haemost. 82: 1065-1070, 1999.

16. Castaman, G.; Rodeghiero, F.; Mannucci, P. M.: The elusive pathogenesis
of von Willebrand disease Vicenza. (Letter) Blood 99: 4243-4244,
2002.

17. Cornu, P.; Larrieu, M. J.; Caen, J. P.; Bernard, J.: Transfusion
studies in von Willebrand's disease: effect on bleeding time and factor
VIII. Brit. J. Haemat. 9: 189-202, 1963.

18. Cramer, A. D.; Melaragno, A. J.; Phifer, S. J.; Hougie, C.: Von
Willebrand disease San Diego, a new variant. Lancet 308: 12-14,
1976. Note: Originally Volume II.

19. Cumming, A.; Grundy, P.; Keeney, S.; Lester, W.; Enayat, S.; Guilliatt,
A.; Bowen, D.; Pasi, J.; Keeling, D.; Hill, F.; Bolton-Maggs, P. H.
B.; Hay, C.; Collins, P.: An investigation of the von Willebrand
factor genotype in UK patients diagnosed to have type 1 von Willebrand
disease. Thromb. Haemost. 96: 630-641, 2006.

20. Cumming, A. M.; Armstrong, J. G.; Pendry, K.; Burn, A. M.; Wensley,
R. T.: Polymerase chain reaction amplification of two polymorphic
simple repeat sequences within the von Willebrand factor gene: application
to family studies in von Willebrand disease. Hum. Genet. 89: 194-198,
1992.

21. Denis, C.; Methia, N.; Frenette, P. S.; Rayburn, H.; Ullman-Cullere,
M.; Hynes, R. O.; Wagner, D. D.: A mouse model of severe von Willebrand
disease: defects in hemostasis and thrombosis. Proc. Nat. Acad. Sci. 95:
9524-9529, 1998.

22. Dodds, W. J.: Canine von Willebrand's disease. J. Lab. Clin.
Med. 76: 713-721, 1970.

23. Eikenboom, J. C. J.; Matsushita, T.; Reitsma, P. H.; Tuley, E.
A.; Castaman, G.; Briet, E.; Sadler, J. E.: Dominant type 1 von Willebrand
disease caused by mutated cysteine residues in the D3 domain of von
Willebrand factor. Blood 88: 2433-2441, 1996.

24. Fass, D. N.; Bowie, E. J. W.; Owen, C. A., Jr.; Zollman, P. E.
: Inheritance of porcine von Willebrand's disease: study of a kindred
of over 700 pigs. Blood 53: 712-719, 1979.

25. Firkin, B. G.; Firkin, F.; Stott, L.: Von Willebrand's disease
type B: a newly defined bleeding diathesis. Aust. New Zeal. J. Med. 3:
225-229, 1973.

26. Fuster, V.; Bowie, E. J. W.: The von Willebrand pig as a model
for atherosclerosis research. Thromb. Haemost. 39: 322-327, 1978.

27. Gaucher, C.; Mercier, B.; Jorieux, S.; Oufkir, D.; Mazurier, C.
: Identification of two point mutations in the von Willebrand factor
gene of three families with the 'Normandy' variant of von Willebrand
disease. Brit. J. Haemat. 78: 506-514, 1991.

28. Gill, J. C.; Endres-Brooks, J.; Bauer, P. J.; Marks, W. J., Jr.;
Montgomery, R. R.: The effect of ABO blood group on the diagnosis
of von Willebrand disease. Blood 69: 1691-1695, 1987.

29. Ginsburg, D.: Molecular genetics of von Willebrand disease. Thromb.
Haemat. 82: 585-591, 1999.

30. Ginsburg, D.; Sadler, J. E.: Von Willebrand disease: a database
of point mutations, insertions, and deletions. Thromb. Haemost. 69:
177-184, 1993.

31. Goldin, L. R.; Elston, R. C.; Graham, J. B.; Miller, C. H.: Genetic
analysis of von Willebrand's disease in two large pedigrees: a multivariate
approach. Am. J. Med. Genet. 7: 279-293, 1980.

32. Goodeve, A.; Eikenboom, J.; Castaman, G.; Rodeghiero, F.; Federici,
A. B.; Batlle, J.; Meyer, D.; Mazurier, C.; Goudemand, J.; Schneppenheim,
R.; Budde, U.; Ingerslev, J.; and 12 others: Phenotype and genotype
of a cohort of families historically diagnosed with type 1 von Willebrand
disease in the European study, Molecular and Clinical Markers for
the Diagnosis and Management of Type 1 von Willebrand Disease (MCMDM-1VWD). Blood 109:
112-121, 2007. Note: Erratum: Blood 111: 3299-3300, 2008.

33. Goodeve, A. C.: The genetic basis of von Willebrand disease. Blood
Rev. 24: 123-134, 2010.

34. Gralnick, H. R.; Coller, B. S.: Molecular defects in haemophilia
A and von Willebrand's disease. Lancet 307: 837-838, 1976. Note:
Originally Volume I.

35. Gralnick, H. R.; Coller, B. S.: Carbohydrate-deficiency of the
factor VIII von Willebrand factor protein in von Willebrand's disease
variants. Science 192: 56-59, 1976.

36. Gralnick, H. R.; Coller, B. S.; Sultan, Y.: Studies of the human
factor VIII-von Willebrand factor protein. III. Qualitative defects
in von Willebrand's disease. J. Clin. Invest. 56: 814-827, 1975.

37. Gralnick, H. R.; Sultan, Y.; Coller, B. S.: Von Willebrand's
disease: combined qualitative and quantitative abnormalities. New
Eng. J. Med. 296: 1024-1030, 1977.

38. Gralnick, H. R.; Williams, S. B.; McKeown, L. P.; Maisonneuve,
P.; Jenneau, C.; Sultan, Y.; Rick, M. E.: In vitro correction of
the abnormal multimeric structure of von Willebrand's disease. Proc.
Nat. Acad. Sci. 82: 5968-5972, 1985.

39. Gralnick, H. R.; Williams, S. B.; McKeown, L. P.; Rick, M. E.;
Maisonneuve, P.; Jenneau, C.; Sultan, Y.: Von Willebrand's disease
with spontaneous platelet aggregation induced by an abnormal plasma
von Willebrand factor. J. Clin. Invest. 76: 1522-1529, 1985.

40. Green, D.; Chediak, J. R.: Von Willebrand's disease: current
concepts. Am. J. Med. 62: 315-318, 1977.

41. Green, D.; Potter, E. V.: Failure of AHF concentrate to control
bleeding in von Willebrand's disease. Am. J. Med. 60: 357-360, 1976.

42. Hagedorn, B.: Von Willebrand's disease. JAMA 216: 991-995,
1971.

43. Hall, J. D.; Willis, D. W.; Evatt, B. L.; Jackson, D. W.: Using
a monoclonal antibody to identify patients with type I and type II
von Willebrand's disease. Thromb. Haemost. 57: 332-336, 1987.

44. Howard, M. A.; Salem, H. H.; Thomas, K. B.; Hau, L.; Perkin, J.;
Coghlan, M.; Firkin, B. G.: Variant von Willebrand's disease type
B--revisited. Blood 60: 1420-1428, 1982.

45. Iannuzzi, M. C.; Hidaka, N.; Boehnke, M.; Bruck, M. E.; Hanna,
W. T.; Collins, F. S.; Ginsburg, D.: Analysis of the relationship
of von Willebrand disease (vWD) and hereditary hemorrhagic telangiectasia
and identification of a potential type IIA vWD mutation (ile865-to-thr). Am.
J. Hum. Genet. 48: 757-763, 1991.

46. Inbal, A.; Kornbrot, N.; Zivelin, A.; Shaklai, M.; Seligsohn,
U.: The inheritance of type I and type III von Willebrand's disease
in Israel: linkage analysis, carrier detection and prenatal diagnosis
using three intragenic restriction fragment length polymorphisms. Blood
Coagulation Fibrinolysis 3: 167-177, 1992.

47. James, P.; Lillicrap, D.: The role of molecular genetics in diagnosing
von Willebrand disease. Semin. Thromb. Hemost. 34: 502-508, 2008.

48. James, P. D.; Notley, C.; Hegadorn, C.; Leggo, J.; Tuttle, A.;
Tinlin, S.; Brown, C.; Andrews, C.; Labelle, A.; Chirinian, Y.; O'Brien,
L.; Othman, M.; Rivard, G.; Rapson, D.; Hough, C.; Lillicrap, D.:
The mutational spectrum of type 1 von Willebrand disease: results
from a Canadian cohort study. Blood 109: 145-154, 2007.

49. Kernoff, L. M.; Rose, A. G.; Hughes, J.; Jacobs, P.: Autopsy
findings in an elderly man suffering from severe von Willebrand's
disease. Thromb. Haemost. 46: 714-716, 1981.

50. Lavabre-Bertrand, T.; Navarro, M.; Blanc, P.; Larrey, D.; Michel,
H.; Rouanet, C.: Von Willebrand's disease, digestive angiodysplasia,
and estrogen-progesterone treatment. (Letter) Am. J. Hemat. 46:
254-255, 1994.

51. Lester, W. A.; Guilliatt, A. M.; Surdhar, G. K.; Enayat, S. M.;
Wilde, J. T.; Willoughby, S.; Grundy, P.; Cumming, A. M.; Collins,
P. W.; Hill, F. G. H.: Inherited and de novo von Willebrand disease
'Vicenza' in UK families with the R1205H mutation: diagnostic pitfalls
and new insights. Brit. J. Haemat. 135: 91-96, 2006.

52. Lian, E. C.-Y.: Von Willebrand's disease--a common bleeding disorder. Adv.
Intern. Med. 22: 207-228, 1976.

53. Lian, E. C.-Y.; Deykin, D.: Diagnosis of von Willebrand's disease:
a comparative study of diagnostic tests on nine families with von
Willebrand's disease and its differential diagnosis from hemophilia
and thrombocytopathy. Am. J. Med. 60: 344-356, 1976.

54. Lillicrap, D.: Genotype/phenotype association in von Willebrand
disease: is the glass half full or empty? J. Thromb. Haemost. 7
(suppl. 1): 65-70, 2009.

55. Lombardi, R.; Mannucci, P. M.; Seghatchian, M. J.; Garcia, V.
V.; Coppola, R.: Alterations of factor VIII von Willebrand factor
in clinical conditions associated with an increase in its plasma concentration. Brit.
J. Haemat. 49: 61-68, 1981.

56. Mannucci, P. M.: Treatment of von Willebrand's disease. New
Eng. J. Med. 351: 683-694, 2004.

57. Mannucci, P. M.; Lombardi, R.; Bader, R.; Vianello, L.; Federici,
A. B.; Solinas, S.; Mazzucconi, M. G.; Mariani, G.: Heterogeneity
of type I von Willebrand disease: evidence for a subgroup with an
abnormal von Willebrand factor. Blood 66: 796-802, 1985.

58. Mannucci, P. M.; Lombardi, R.; Castaman, G.; Dent, J. A.; Lattuada,
A.; Rodeghiero, F.; Zimmerman, T. S.: Von Willebrand disease 'Vicenza'
with larger-than-normal (supranormal) von Willebrand factor multimers. Blood 71:
65-70, 1988.

59. McGrath, K. M.; Johnson, C. A.; Stuart, J. J.: Acquired von Willebrand
disease associated with an inhibitor to factor VIII antigen and gastrointestinal
telangiectasia. Am. J. Med. 67: 693-696, 1979.

60. Meyer, D.; McKee, P. A.; Hoyer, L. W.; Zimmerman, T. S.; Gralnick,
H. R.: Molecular biology of factor VIII--von Willebrand factor. Thromb.
Haemost. 40: 245-251, 1978.

61. Miller, C. H.; Graham, J. B.; Goldin, L. R.; Elston, R. C.: Genetics
of classic von Willebrand's disease. II. Optimal assignment of the
heterozygous genotype (diagnosis) by discriminant analysis. Blood 54:
137-145, 1979.

62. Miller, C. H.; Graham, J. B.; Goldin, L. R.; Elston, R. C.: Genetics
of classic von Willebrand's disease. I. Phenotypic variation within
families. Blood 54: 117-136, 1979.

63. Miller, C. H.; Hilgartner, M. W.; Harris, M. B.; Bussel, J. B.;
Aledort, L. M.: Concurrence of von Willebrand's disease and hemophilia
A: implications for carrier detection and prevalence. Am. J. Med.
Genet. 24: 83-94, 1986.

64. Mohlke, K. L.; Nichols, W. C.; Westrick, R. J.; Novak, E. K.;
Cooney, K. A.; Swank, R. T.; Ginsburg, D.: A novel modifier gene
for plasma von Willebrand factor level maps to distal mouse chromosome
11. Proc. Nat. Acad. Sci. 93: 15352-15357, 1996.

65. Mohlke, K. L.; Purkayastha, A. A.; Westrick, R. J.; Smith, P.
L.; Petryniak, B.; Lowe, J. B.; Ginsburg, D.: Mvwf, a dominant modifier
of murine von Willebrand factor, results from altered lineage-specific
expression of a glycosyltransferase. Cell 96: 111-120, 1999.

66. Nachman, R. L.: Von Willebrand's disease and the molecular pathology
of hemostasis. (Editorial) New Eng. J. Med. 296: 1059-1060, 1977.

67. Nachman, R. L.; Jaffe, E. A.; Miller, C.; Brown, W. T.: Structural
analysis of factor VIII antigen in von Willebrand disease. Proc.
Nat. Acad. Sci. 77: 6832-6836, 1980.

68. Nevanlinna, H. R.; Ikkala, E.; Vuopio, P.: Von Willebrand's disease. Acta
Haemat. 27: 65-77, 1962.

69. Nichols, W. C.; Cooney, K. A.; Mohlke, K. L.; Ballew, J. D.; Yang,
A.; Bruck, M. E.; Reddington, M.; Novak, E. K.; Swank, R. T.; Ginsburg,
D.: Von Willebrand Disease in the RIIIS/J mouse is caused by a defect
outside the von Willebrand factor gene . Blood 83: 3225-3231, 1994.
Note: Erratum: Blood 86: 2461 only, 1995.

70. Nichols, W. C.; Ginsburg, D.: Von Willebrand disease. Medicine 76:
1-20, 1997.

71. Nitu-Whalley, I. C.; Lee, C. A.; Griffioen, A.; Jenkins, P. V.;
Pasi, K. J.: Type 1 von Willebrand disease: a clinical retrospective
study of the diagnosis, the influence of the ABO blood group and the
role of the bleeding history. Brit. J. Haemat. 108: 259-264, 2000.

72. Nyman, D.; Eriksson, A. W.; Blomback, M.; Frants, R. R.; Wahlberg,
P.: Recent investigations of the first bleeder family in Aland (Finland)
described by von Willebrand. Thromb. Haemost. 45: 73-76, 1981.

73. O'Brien, L. A.; James, P. D.; Othman, M.; Berber, E.; Cameron,
C.; Notley, C. R. P.; Hegadorn, C. A.; Sutherland, J. J.; Hough, C.;
Rivard, G. E.; O'Shaunessey, D.; Association of Hemophilia Clinic
Directors of Canada; Lillicrap, D.: Founder von Willebrand factor
haplotype associated with type I von Willebrand disease. Blood 102:
549-557, 2003.

74. Peake, I. R.; Bloom, A. L.; Giddings, J. C.: Inherited variants
of factor-VII related protein in von Willebrand's disease. New Eng.
J. Med. 291: 113-117, 1974.

75. Pickering, N. J.; Brody, J. I.; Barrett, M. J.: Von Willebrand
syndromes and mitral-valve prolapse: linked mesenchymal dysplasias. New
Eng. J. Med. 305: 131-134, 1981.

76. Quick, A. J.: Telangiectasia: its relationship to the Minot-von
Willebrand syndrome. Am. J. Med. Sci. 254: 585-601, 1967.

77. Raccuglia, G.; Neel, J. V.: Congenital vascular defect associated
with platelet abnormality and antihemophilic factor deficiency. Blood 15:
807-829, 1960.

78. Ramsey, P. M.; Buist, T. A. S.; MacLeod, D. A. D.; Heading, R.
C.: Persistent gastrointestinal bleeding due to angiodysplasia of
the gut in von Willebrand's disease. Lancet 308: 275-278, 1976.
Note: Originally Volume II.

79. Randi, A. M.; Sacchi, E.; Castaman, G. C.; Rodeghiero, F.; Mannucci,
P. M.: The genetic defect of type I von Willebrand disease 'Vicenza'
is linked to the von Willebrand factor gene. Thromb. Haemost. 69:
173-176, 1993.

80. Richardson, D. W.; Robinson, A. G.: Desmopressin. Ann. Intern.
Med. 103: 228-239, 1985.

81. Ruggeri, Z. M.: von Willebrand factor. J. Clin. Invest. 99:
559-564, 1997. Note: Erratum: J. Clin. Invest. 100: 237 only, 1997.

82. Sadler, J. E.: A revised classification of von Willebrand disease:
for the Subcommittee on von Willebrand Factor of the Scientific and
Standardization Committee of the International Society on Thrombosis
and Haemostasis. Thromb. Haemost. 71: 520-525, 1994.

83. Sadler, J. E.; Budde, U.; Eikenboom, J. C. J.; Favaloro, E. J.;
Hill, F. G. H.; Holmberg, L.; Ingerslev, J.; Lee, C. A.; Lillicrap,
D.; Mannucci, P. M.; Mazurier, C.; Meyer, D.; and 9 others: Update
on the pathophysiology and classification of von Willebrand disease:
a report of the Subcommittee on von Willebrand Factor. J. Thromb.
Haemost. 4: 2103-2114, 2006.

84. Sadler, J. E.; Ginsburg, D.: A database of polymorphisms in the
von Willebrand factor gene and pseudogene. Thromb. Haemost. 69:
185-191, 1993.

85. Schneppenheim, R.; Federici, A. B.; Budde, U.; Castaman, G.; Drewke,
E.; Krey, S.; Mannucci, P. M.; Riesen, G.; Rodeghiero, F.; Zieger,
B.; Zimmermann, R.: Von Willebrand disease type 2M 'Vicenza' in Italian
and German patients: identification of the first candidate mutation
(G3864A; R1205H) in 8 families. Thromb. Haemost. 82: 136-140, 2000.

86. Shoa'i, I.; Lavergne, J. M.; Aradaillou, N.; Obert, B.; Ala, F.;
Meyer, D.: Heterogeneity of von Willebrand's disease: study of 40
Iranian cases. Brit. J. Haemat. 37: 67-83, 1977.

87. Simone, J. V.; Cornet, J. A.; Abildgaard, C. F.: Acquired von
Willebrand's syndrome in systemic lupus erythematosus. Blood 31:
806-812, 1968.

88. Strauss, H. S.; Bloom, G. E.: Von Willebrand's disease: use of
a platelet-adhesiveness test in diagnosis and family investigation. New
Eng. J. Med. 273: 171-181, 1965.

89. Sutherland, M. S.; Cumming, A. M.; Bowman, M.; Bolton-Maggs, P.
H. B.; Bowen, D. J.; Collins, P. W.; Hay, C. R. M.; Will, A. M.; Keeney,
S.: A novel deletion mutation is recurrent in von Willebrand disease
types 1 and 3. Blood 114: 1091-1098, 2009.

90. Sweeney, J. D.; Novak, E. K.; Reddington, M.; Takeuchi, K. H.;
Swank, R. T.: The RIIIS/J inbred mouse strain as a model for von
Willebrand disease. Blood 76: 2258-2265, 1990.

91. Verp, M. S.; Green, D.; Conneally, M.; Radvany, R. M.; Martin,
A. O.; Simpson, J. L.: Linkage and von Willebrand disease. (Abstract) Am.
J. Hum. Genet. 34: 113A, 1982.

92. von Willebrand, E. A.: Ueber hereditaere Pseudohaemophilie. Acta
Med. Scand. 76: 521-550, 1931.

93. von Willebrand, E. A.: Hereditar pseudohemofili. Finska Lakar.
Hand. 68: 87-112, 1926.

94. von Willebrand, E. A.; Jurgens, R.: Ueber eine neue Bluterkrankheit:
die konstitutionelle Thrombopathie. Klin. Wschr. 12: 414-417, 1933.

95. Wahlberg, T. B.; Blomback, M.; Ruggeri, Z. M.: Differences between
heterozygous dominant and recessive von Willebrand's disease type
I expressed by bleeding symptoms and combinations of factor VIII variables. Thromb.
Haemost. 50: 864-868, 1983.

96. Warkentin, T. E.; Moore, J. C.; Morgan, D. G.: Aortic stenosis
and bleeding gastrointestinal angiodysplasia: is acquired von Willebrand's
disease the link? Lancet 340: 35-37, 1992.

97. Watkins, W. S.; Zenger, R.; O'Brien, E.; Nyman, D.; Eriksson,
A. W.; Renlund, M.; Jorde, L. B.: Linkage disequilibrium patterns
vary with chromosomal location: a case study from the von Willebrand
factor region. Am. J. Hum. Genet. 55: 348-355, 1994.

98. Wautier, J.-L.; Caen, J. P.; Rymer, R.: Angiodysplasia in acquired
Von Willebrand disease. (Letter) Lancet 308: 973 only, 1976. Note:
Originally Volume II.

99. Weiss, H. J.: Von Willebrand's disease--diagnostic criteria. Blood 32:
668-679, 1968.

100. Zhang, Z. P.; Blomback, M.; Nyman, D.; Anvret, M.: Mutations
of von Willebrand factor gene in families with von Willebrand disease
in the Aland Islands. Proc. Nat. Acad. Sci. 90: 7937-7940, 1993.

101. Zieger, B.; Budde, U.; Jessat, U.; Zimmermann, R.; Simon, M.;
Katzel, R.; Sutor, A. H.: New families with von Willebrand disease
type 2M (Vicenza). Thromb. Res. 87: 57-64, 1997.

102. Zimmerman, T. S.; Ruggeri, Z. M.: Von Willebrand's disease. Clin.
Haemat. 12: 175-200, 1983.

103. Zimmerman, T. S.; Ruggeri, Z. M.: Von Willebrand disease. Hum.
Path. 18: 140-152, 1987.

*FIELD* CS
INHERITANCE:
Autosomal dominant

HEAD AND NECK:
[Nose];
Epistaxis

GENITOURINARY:
[Internal genitalia, female];
Menorrhagia

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

HEMATOLOGY:
Prolonged bleeding time due to quantitative decrease of VWF protein;
Defect in platelet aggregation;
Mucocutaneous bleeding;
Menorrhagia

LABORATORY ABNORMALITIES:
Decreased levels of plasma VWF antigen;
Decreased levels of plasma factor VIII

MISCELLANEOUS:
Highly variable phenotype;
Variably expressivity;
Incomplete penetrance;
Most common inherited bleeding disorder

MOLECULAR BASIS:
Caused by mutation in the von Willebrand factor gene (VWF, 613160.0028)

*FIELD* CN
Cassandra L. Kniffin - revised: 12/27/2010

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

*FIELD* ED
joanna: 05/18/2011
joanna: 5/18/2011
ckniffin: 12/27/2010

*FIELD* CN
update !$: 3/28/2013
Cassandra L. Kniffin - updated: 12/27/2010
Cassandra L. Kniffin - reorganized: 10/4/2010
Cassandra L. Kniffin - updated: 9/29/2010
Patricia A. Hartz - updated: 7/11/2008
Matthew B. Gross - updated: 4/30/2007
Victor A. McKusick - updated: 4/25/2007
Patricia A. Hartz - updated: 3/28/2006
Marla J. F. O'Neill - updated: 11/3/2005
Victor A. McKusick - updated: 9/30/2004
Victor A. McKusick - updated: 4/22/2004
Victor A. McKusick - updated: 10/20/2003
Ada Hamosh - updated: 9/18/2002
Victor A. McKusick - updated: 2/26/2002
Victor A. McKusick - updated: 2/14/2002
Victor A. McKusick - updated: 5/1/2000
Victor A. McKusick - updated: 11/6/1998
Victor A. McKusick - updated: 7/10/1998
Victor A. McKusick - updated: 4/10/1997
Victor A. McKusick - updated: 2/21/1997

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

*FIELD* ED
terry: 04/04/2013
terry: 3/28/2013
carol: 3/28/2013
carol: 4/7/2011
wwang: 2/7/2011
wwang: 1/5/2011
ckniffin: 12/27/2010
ckniffin: 10/11/2010
terry: 10/8/2010
carol: 10/4/2010
ckniffin: 9/29/2010
terry: 5/28/2010
terry: 6/3/2009
terry: 2/10/2009
carol: 11/5/2008
wwang: 7/14/2008
terry: 7/11/2008
mgross: 4/30/2007
alopez: 4/26/2007
terry: 4/25/2007
mgross: 8/10/2006
wwang: 4/4/2006
terry: 3/28/2006
terry: 12/21/2005
wwang: 11/3/2005
tkritzer: 12/29/2004
tkritzer: 10/4/2004
terry: 9/30/2004
tkritzer: 4/23/2004
terry: 4/22/2004
carol: 3/17/2004
cwells: 10/20/2003
carol: 6/24/2003
tkritzer: 1/2/2003
alopez: 9/20/2002
tkritzer: 9/18/2002
terry: 3/11/2002
mgross: 3/6/2002
terry: 2/26/2002
carol: 2/20/2002
cwells: 2/19/2002
terry: 2/14/2002
mcapotos: 5/26/2000
mcapotos: 5/23/2000
terry: 5/1/2000
terry: 6/11/1999
carol: 1/5/1999
psherman: 12/23/1998
dkim: 12/15/1998
carol: 11/16/1998
terry: 11/6/1998
dkim: 9/11/1998
dkim: 7/24/1998
dkim: 7/17/1998
carol: 7/10/1998
terry: 7/10/1998
mark: 4/10/1997
terry: 4/3/1997
jamie: 3/12/1997
jenny: 2/21/1997
terry: 2/5/1997
jamie: 11/6/1996
terry: 10/28/1996
terry: 10/22/1996
mark: 5/9/1996
terry: 5/7/1996
terry: 4/30/1996
mark: 7/9/1995
terry: 8/26/1994
jason: 7/18/1994
davew: 6/1/1994
pfoster: 4/25/1994
warfield: 4/21/1994

MIM 277480
*RECORD*
*FIELD* NO
277480
*FIELD* TI
#277480 VON WILLEBRAND DISEASE, TYPE 3; VWD3
;;VON WILLEBRAND DISEASE, TYPE III;;
VWD, TYPE 3
read more*FIELD* TX
A number sign (#) is used with this entry because von Willebrand disease
(VWD) type 3 is caused by homozygous or compound heterozygous mutation
in the gene encoding von Willebrand factor (VWF; 613160), which maps to
chromosome 12p13.

DESCRIPTION

Von Willebrand disease is a bleeding disorder resulting from a defect in
platelet aggregation due to defects in the von Willebrand factor
protein. Type 3 von Willebrand disease, which is inherited as an
autosomal recessive disorder, is associated with a severe quantitative
defect or virtual absence of VWF in plasma, a prolonged bleeding time,
and more severe bleeding tendencies compared to the other types of VWD.
Type 3 accounts for about 1% of patients with VWD. Bleeding usually
starts in infancy and can include epistaxis, recurrent mucocutaneous
bleeding, bleeding after surgery, and hemarthroses. Since VWF also
serves as a carrier protein for coagulation factor VIII (F8; 300841),
affected individuals also have very low levels of plasma F8, resembling
hemophilia A (306700) (summary by Zhang et al., 1992, 1993; reviews by
Sadler et al., 2006 and Lillicrap, 2009).

For a general description and a classification of the types of von
Willebrand disease, see VWD type 1 (193400).

CLINICAL FEATURES

Von Willebrand (1926, 1931) discovered a hemorrhagic condition in
persons living on the Aland Islands in the Sea of Bothnia between Sweden
and Finland and called it 'pseudohemophilia.' (See 300600 for another
Aland Island disease.) The main difference from classic hemophilia was
prolonged bleeding time. Major clinical problems were gastrointestinal,
urinary, and uterine bleeding; hemarthroses were rare, but present.
Nyman et al. (1981) followed up on the kindred originally reported by
von Willebrand (1926). Zhang et al. (1993) described patients descended
from the original family reported by von Willebrand (1926). Only
heterozygotes were found surviving. The proposita was a 5-year-old girl,
who later bled to death during her fourth menstrual period. She had a
normal coagulation time, but the bleeding time was prolonged, despite a
normal platelet count. All but 1 of her 11 sibs had bleeding symptoms,
as did both of her parents, who were third cousins, and many members of
her family on both sides. Four of the proband's sisters had died of
uncontrolled bleeding in early childhood; 3 died from gastrointestinal
bleeding and 1 from bleeding after she bit her tongue in a fall. The
predominant symptoms were bleeding from mucous membranes, such as from
the nose, the gingivae after tooth extractions, the uterus, and the
gastrointestinal tract. In contrast to hemophilia, hemarthroses seemed
to be rare. All 5 of the girls who died from uncontrolled bleeding were
probably homozygotes.

Zimmerman et al. (1979) studied the factor VIII abnormalities in
patients with severe recessive von Willebrand disease from 8 families.
In 5 families, the parents were first or second cousins. Heterozygous
parents had normal to moderately decreased factor VIII-related antigen.
A qualitative abnormality of the trace quantities of factor VIII-related
antigen was demonstrated in 5 of 6 patients, with absence or relative
decrease of the larger, less anodal forms. In addition, 5 different
patterns were observed, each suggesting a different molecular
abnormality. The findings indicated that severe von Willebrand disease
is allelic to the dominant forms of the disorders, with different
mutations responsible for the defect.

Berliner et al. (1986) observed a relatively high incidence of severe
autosomal recessive VWD type 3 in Israel, especially among Arabs. In 15
obligate carriers of type 3 disease, mean levels of factor VIII clotting
activity, of von Willebrand factor, and of ristocetin cofactor were
significantly higher than the corresponding mean values in 31
symptomatic and 12 asymptomatic VWD type 1 patients, and in turn lower
than the values observed in 30 healthy subjects. Ristocetin cofactor was
the best criterion for discrimination of type 3 carriers, normals, and
type 1 patients.

OTHER FEATURES

Sramek et al. (2004) studied atherosclerotic lesions in the carotid and
femoral arteries of 47 individuals with type 3 VWD and 84 healthy
controls and found no difference in intima-media thickness, proportion
with atherosclerotic plaques, or thickness of plaques. There was no
effect of VWF treatment on intima-media or plaque thickness in VWD
patients. Sramek et al. (2004) concluded that VWF does not play a
substantial role in human atherogenesis.

INHERITANCE

Von Willebrand disease is inherited as an autosomal recessive trait
(Lillicrap, 2009).

Autosomal recessive inheritance of VWD was described by several authors,
including Veltkamp and van Tilburg (1974), Holmberg (1974), Sultan et
al. (1975), Ruggeri et al. (1976), and Ingram (1978). Sultan et al.
(1975) noted that the phenotype can be as severe as that observed in
hemophilia. Many of the patients were born of consanguineous parents. In
some instances, heterozygous parents showed minor laboratory
abnormalities in the absence of clinical features of the disorder.

CLINICAL MANAGEMENT

In a review of VWD, James and Lillicrap (2008) noted that VWD type 3 is
associated with the development of anti-VWF alloantibodies after
exposure to therapeutic VWF concentrates, representing an important
issue in the clinical management of this subtype.

POPULATION GENETICS

Lillicrap (2009) stated that VWD type 3 varies in incidence from
frequencies of 1 per 500,000 to 1 per million in many Western countries,
to figures as high as 6 per million in countries where consanguineous
marriages are more frequent.

Sutherland et al. (2009) identified a recurrent 8.6-kb deletion of exons
4 and 5 of the VWF gene (613160.0038) in Caucasian British patients with
VWD type 3 and VWD type 1 (193400). The deletion was not found in VWD
patients of Asian origin, and haplotype analysis confirmed a founder
effect in the white British population.

MOLECULAR GENETICS

Ngo et al. (1988) studied the genomic DNA from 10 affected persons from
6 families with severe von Willebrand disease, characterized by
undetectable or trace quantities of VWF in plasma and tissue stores.
Four patients from 1 family showed complete homozygous deletion of the
VWF gene. Gene dosage analysis was consistent with heterozygous deletion
in both of the asymptomatic parents and in 4 asymptomatic sibs. A second
family had complete heterozygous deletion of the VWF gene in the proband
and in 1 asymptomatic parent, suggesting that a different type of
genetic abnormality was inherited from the other parent, consistent with
compound heterozygosity. Alloantibodies to VWF after treatment developed
only in the kindred with homozygous deletions.

In a patient with severe type 3 von Willebrand disease, Peake et al.
(1990) found a homozygous 2.3-kb deletion in the VWF gene which included
exon 42; a novel 182-bp insertion was found between the breakpoints. The
patient had an alloantibody inhibitor to VWF. The insertion was detected
by PCR amplification both in the patient's DNA and in his carrier
relatives.

In patients with VWD type 3, Zhang et al. (1992, 1992, 1992) identified
homozygous or compound heterozygous mutations in the VWF gene (see,
e.g., 613160.0015-613160.0017). Some heterozygous family members had a
less severe phenotype, consistent with VWD type 1.

Zhang et al. (1993) found that the original family with VWD reported by
von Willebrand (1926) carried a common 1-bp deletion in the VWF gene
(613160.0021).

Eikenboom et al. (1998) reviewed families with recessive VWD type 3 from
northern Italy. Several mutations located throughout the gene were
identified, indicating diverse molecular defects (see, e.g., C2362F,
613160.0034).

GENOTYPE/PHENOTYPE CORRELATIONS

Shelton-Inloes et al. (1987) found a correlation between the development
of alloantibodies to VWF and the nature of the genetic lesion in VWD.
Alloantibodies to VWF have been described only in the severe type 3
disease. Shelton-Inloes et al. (1987) studied 19 patients with severe
recessive VWD type 3 by Southern blotting with probes encompassing the
full 9 kb of the VWF cDNA. Two presumably unrelated patients with type 3
who had large deletions within the VWF gene were the only ones among
those studied who developed inhibitory alloantibodies to VWF.

*FIELD* SA
Veltkamp and Van Tilburg (1973); Wise et al. (1993)
*FIELD* RF
1. Berliner, S. A.; Seligsohn, U.; Zivelin, A.; Zwang, E.; Sofferman,
G.: A relatively high frequency of severe (type III) von Willebrand's
disease in Israel. Brit. J. Haemat. 62: 535-543, 1986.

2. Eikenboom, J. C. J.; Castaman, G.; Vos, H. L.; Bertina, R. M.;
Rodeghiero, F.: Characterization of the genetic defects in recessive
type 1 and type 3 von Willebrand disease patients of Italian origin. Thromb.
Haemost. 79: 709-717, 1998.

3. Holmberg, L.: Von Willebrand's disease with normal factor VIII
activity in a homozygote. Haemostasis 3: 237-246, 1974.

4. Ingram, G. I. C.: Classification of von Willebrand's disease. Lancet 312:
1364-1365, 1978. Note: Originally Volume II.

5. James, P.; Lillicrap, D.: The role of molecular genetics in diagnosing
von Willebrand disease. Semin. Thromb. Hemost. 34: 502-508, 2008.

6. Lillicrap, D.: Genotype/phenotype association in von Willebrand
disease: is the glass half full or empty? J. Thromb. Haemost. 7
(suppl. 1): 65-70, 2009.

7. Ngo, K. Y.; Glotz, V. T.; Koziol, J. A.; Lynch, D. C.; Gitschier,
J.; Ranieri, P.; Ciavarella, N.; Ruggeri, Z. M.; Zimmerman, T. S.
: Homozygous and heterozygous deletions of the von Willebrand factor
gene in patients and carriers of severe von Willebrand disease. Proc.
Nat. Acad. Sci. 85: 2753-2757, 1988.

8. Nyman, D.; Eriksson, A. W.; Blomback, M.; Frants, R. R.; Wahlberg,
P.: Recent investigations of the first bleeder family in Aland (Finland)
described by von Willebrand. Thromb. Haemost. 45: 73-76, 1981.

9. Peake, I. R.; Liddell, M. B.; Moodie, P.; Standen, G.; Mancuso,
D. J.; Tuley, E. A.; Westfield, L. A.; Sorace, J. M.; Sadler, J. E.;
Verweij, C. L.; Bloom, A. L.: Severe type III von Willebrand's disease
caused by deletion of exon 42 of the von Willebrand factor gene: family
studies that identify carriers of the condition and a compound heterozygous
individual. Blood 75: 654-661, 1990.

10. Ruggeri, Z. M.; Mannucci, P. M.; Jeffcoate, S. L.; Ingram, G.
I. C.: Immunoradiometric assay of factor VIII related antigen, with
observations in 32 patients with von Willebrand's disease. Brit.
J. Haemat. 33: 221-223, 1976.

11. Sadler, J. E.; Budde, U.; Eikenboom, J. C. J.; Favaloro, E. J.;
Hill, F. G. H.; Holmberg, L.; Ingerslev, J.; Lee, C. A.; Lillicrap,
D.; Mannucci, P. M.; Mazurier, C.; Meyer, D.; and 9 others: Update
on the pathophysiology and classification of von Willebrand disease:
a report of the Subcommittee on von Willebrand Factor. J. Thromb.
Haemost. 4: 2103-2114, 2006.

12. Shelton-Inloes, B. B.; Chehab, F. F.; Mannucci, P. M.; Federici,
A. B.; Sadler, J. E.: Gene deletions correlate with the development
of alloantibodies in von Willebrand disease. J. Clin. Invest. 79:
1459-1465, 1987.

13. Sramek, A.; Bucciarelli, P.; Federici, A. B.; Mannucci, P. M.;
De Rosa, V.; Castaman, G.; Morfini, M.; Mazzucconi, M. G.; Rocino,
A.; Schiavoni, M.; Scaraggi, F. A.; Reiber, J. H. C.; Rosendaal, F.
R.: Patients with type 3 severe von Willebrand disease are not protected
against atherosclerosis: results from a multicenter study in 47 patients. Circulation 109:
740-744, 2004.

14. Sultan, Y.; Simeon, J.; Caen, J. P.: Detection of heterozygotes
in both parents of homozygous patients with von Willebrand's disease. J.
Clin. Path. 28: 309-316, 1975.

15. Sutherland, M. S.; Cumming, A. M.; Bowman, M.; Bolton-Maggs, P.
H. B.; Bowen, D. J.; Collins, P. W.; Hay, C. R. M.; Will, A. M.; Keeney,
S.: A novel deletion mutation is recurrent in von Willebrand disease
types 1 and 3. Blood 114: 1091-1098, 2009.

16. Veltkamp, J. J.; van Tilburg, N. H.: Autosomal haemophilia: a
variant of von Willebrand's disease. Brit. J. Haemat. 26: 141-152,
1974.

17. Veltkamp, J. J.; Van Tilburg, N. H.: Detection of heterozygotes
for recessive von Willebrand's disease by the assay of antihemophilic-factor-like
antigen. New Eng. J. Med. 289: 882-885, 1973.

18. von Willebrand, E. A.: Ueber hereditaere Pseudohaemophilie. Acta
Med. Scand. 76: 521-550, 1931.

19. von Willebrand, E. A.: Hereditar pseudohemofili. Finska Lakar.
Hand. 68: 87-112, 1926.

20. Wise, R. J.; Ewenstein, B. M.; Gorlin, J.; Narins, S. C.; Jesson,
M.; Handin, R. I.: Autosomal recessive transmission of hemophilia
A due to a von Willebrand factor mutation. Hum. Genet. 91: 367-372,
1993.

21. Zhang, Z. P.; Blomback, M.; Nyman, D.; Anvret, M.: Mutations
of von Willebrand factor gene in families with von Willebrand disease
in the Aland Islands. Proc. Nat. Acad. Sci. 90: 7937-7940, 1993.

22. Zhang, Z. P.; Falk, G.; Blomback, M.; Egberg, N.; Anvret, M.:
A single cytosine deletion in exon 18 of the von Willebrand factor
gene is the most common mutation in Swedish vWD type III patients. Hum.
Molec. Genet. 1: 767-768, 1992.

23. Zhang, Z. P.; Falk, G.; Blomback, M.; Egberg, N.; Anvret, M.:
Identification of a new nonsense mutation in the von Willebrand factor
gene in patients with von Willebrand disease type III. Hum. Molec.
Genet. 1: 61-62, 1992.

24. Zhang, Z. P.; Lindstedt, M.; Falk, G.; Blomback, M.; Egberg, N.;
Anvret, M.: Nonsense mutations of the von Willebrand factor gene
in patients with von Willebrand disease type III and type I. Am.
J. Hum. Genet. 51: 850-858, 1992.

25. Zimmerman, T. S.; Abildgaard, C. F.; Meyer, D.: The factor VIII
abnormality in severe von Willebrand's disease. New Eng. J. Med. 301:
1307-1310, 1979.

*FIELD* CS
INHERITANCE:
Autosomal recessive

HEAD AND NECK:
[Nose];
Epistaxis

SKELETAL:
Hemarthrosis may occur

SKIN, NAILS, HAIR:
[Skin];
Easy bruising

HEMATOLOGY:
Prolonged bleeding time;
Mucocutaneous bleeding;
Prolonged bleeding after surgery or trauma;
Menorrhagia

LABORATORY ABNORMALITIES:
Severely decreased antigen levels of VWF and factor VIII

MISCELLANEOUS:
Most severe type of von Willebrand disease

MOLECULAR BASIS:
Caused by mutation in the von Willebrand factor gene (VWF, 613160.0015)

*FIELD* CN
Cassandra L. Kniffin - revised: 12/27/2010

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

*FIELD* ED
joanna: 10/03/2013
joanna: 7/17/2012
ckniffin: 12/27/2010

*FIELD* CN
Cassandra L. Kniffin - updated: 12/27/2010
Cassandra L. Kniffin - reorganized: 10/4/2010
Cassandra L. Kniffin - updated: 9/29/2010
Victor A. McKusick - updated: 7/10/1998

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

*FIELD* ED
terry: 07/31/2012
carol: 4/7/2011
wwang: 1/5/2011
ckniffin: 12/27/2010
terry: 10/8/2010
carol: 10/4/2010
ckniffin: 9/29/2010
terry: 3/25/2009
terry: 2/12/2009
carol: 7/15/1998
terry: 7/10/1998
warfield: 4/4/1994
mimadm: 3/12/1994
carol: 9/8/1992
supermim: 3/17/1992
carol: 3/2/1992
supermim: 3/20/1990

MIM 613160
*RECORD*
*FIELD* NO
613160
*FIELD* TI
*613160 VON WILLEBRAND FACTOR; VWF
;;FACTOR VIII-VON WILLEBRAND FACTOR; F8VWF
*FIELD* TX
read more
DESCRIPTION

The VWF gene encodes von Willebrand factor (VWF), a large multimeric
glycoprotein that plays a central role in the blood coagulation system,
serving both as a major mediator of platelet-vessel wall interaction and
platelet adhesion, and as a carrier for coagulation factor VIII (F8;
300841). Diminished or abnormal VWF activity results in von Willebrand
disease (VWD; see 193400), a common and complex hereditary bleeding
disorder (Ginsburg et al., 1985).

The receptor for von Willebrand factor is a large complex comprising 4
proteins: glycoprotein Ib (GP1BA; 606672 and GP1BB; 138720), platelet
glycoprotein IX (GP9; 173515) and platelet glycoprotein V (GP5; 173511).

CLONING

Ginsburg et al. (1985) isolated overlapping cDNA clones corresponding to
the human VWF gene. The 8.2-kb transcript accounted for approximately
0.3% of endothelial cell mRNA, but was undetectable in several other
tissues examined.

Sadler et al. (1985) isolated cDNA clones from cultured human umbilical
vein endothelial cells. Two inserts, which together coded for about 80%
of the protein, were identified. One corresponded to residues 1 to 110
of the circulating mature protein and the second coded for 1,525
residues at the C terminus; there was about a 350-residue gap between
the 2 clones. At least 3 separate polypeptide segments showed evidence
of internal duplication, suggesting a complex evolutionary history. The
full-length mature protein contains 2,050 amino acids (Titani et al.,
1986).

Bonthron et al. (1986) presented the nucleotide sequence of pre-pro-von
Willebrand factor cDNA.

Lynch et al. (1985) also cloned the VWF gene, and Lynch et al. (1986)
stated that 4 separate groups had reported isolation of VWF-specific
clones from human endothelial cell cDNA libraries.

VWF is synthesized in endothelial cells and megakaryocytes as a
2,813-residue pre-protein. It dimerizes, undergoes extensive
posttranslational modification, and is packaged as a mature protein into
endothelial cell Weibel-Palade bodies and platelet alpha granules.
Endothelial cells secrete VWF constitutively, whereas platelets release
VWF when stimulated. Circulating VWF multimers are composed of up to 40
subunits and range in size from 500 to 10,000 kD (review by Goodeve,
2010). VWF is synthesized in megakaryocytes and endothelial cells with a
22-amino acid signal peptide, 741-amino acid propeptide and 2,050-amino
acid mature VWF (review by Goodeve, 2010).

GENE STRUCTURE

Mancuso et al. (1989) concluded that the VWF gene is approximately 178
kb long and contains 52 exons. The exons vary from 40 to 1379 bp, and
the introns from 97 bp to approximately 19.9 kb. The signal peptide and
propeptide (von Willebrand antigen II) are encoded by 17 exons in
approximately 80 kb of DNA, while the mature subunit of von Willebrand
factor and the 3-prime noncoding region are encoded by 35 exons in the
remainder of the gene. A number of repetitive sequences were identified,
including 14 Alu repeats and a polymorphic TCTA simple repeat of about
670 bp in intron 40. Regions of the gene that encode homologous domains
have similar structures, supporting a model for their origin by gene
segment duplication.

From a study of a series of overlapping cosmid genomic clones of VWF,
Collins et al. (1987) identified the transcription initiation site, a
portion of the promoter region, and the translation termination codon.
Their evidence supported the existence of a single VWF gene in the
haploid genome.

MAPPING

Verweij et al. (1985) cloned the gene for VWF and assigned it to
chromosome 12 using cDNA probes with panels of human-rodent hybrid
cells.

By somatic cell hybridization and in situ hybridization using a cDNA
clone of the gene, Ginsburg et al. (1985) assigned the VWF gene to
12pter-p12.

Shelton-Inloes et al. (1987) confirmed the localization of the gene to
chromosome 12 and identified a homologous sequence on chromosome 22. The
VWF gene is the most distally mapped gene on 12p13.3 (NIH/CEPH
Collaborative Mapping Group, 1992).

Barrow et al. (1993) showed that the loci for neurotrophin-3 (NTF3;
162660) and von Willebrand factor map to 12p13 in the human and are
closely linked on mouse chromosome 6.

- Pseudogene

Mancuso et al. (1991) reported that the partially unprocessed pseudogene
on chromosome 22q11-q13 is 21 to 29 kb long and corresponds to exons 23
to 34 of the VWF gene. They found splice site and nonsense mutations,
suggesting that the pseudogene cannot yield functional transcripts. By
in situ hybridization experiments on metaphase spreads from a
Philadelphia-chromosome-positive chronic myelogenous leukemia (151410)
patient, Patracchini et al. (1992) found that the pseudogene is located
centromeric to the breakpoint cluster region.

GENE FUNCTION

Ruggeri (1997) reviewed VWF within a series on cell adhesion in vascular
biology and took the opportunity to review the understanding of platelet
function in hemostasis and thrombosis.

Sporn et al. (1987) found that the VWF released from endothelial cell
Weibel-Palade bodies bound particularly avidly to the extracellular
matrix. Wagner et al. (1991) showed that the VWF propolypeptide is
necessary for the formation of the Weibel-Palade storage granules.
Following secretagogue stimulation, Weibel-Palade bodies undergo
exocytosis and release long VWF filaments, averaging 100 micrometers,
that capture platelets along their length. Subsequent activation and
aggregation of platelets cause the formation of a hemostatic plug
(Michaux et al., 2006). Michaux et al. (2006) determined that the
propeptide of VWF, which is released into the bloodstream at exocytosis,
was involved in a pH-dependent interaction with the first 3 domains of
mature VWF protein and this interaction was required for compact storage
of VWF filaments. They showed that multimerization and tubular storage
were a prerequisite for rapid unfurling of long VWF filaments in
stimulated human umbilical vein endothelial cells in culture and in
laser-injured cremaster venules in mice. If tubules were disassembled
prior to exocytosis, short or tangled filaments were released and
platelet recruitment was reduced. Michaux et al. (2006) concluded that
compaction of VWF into tubules determines the rod-like shape of
Weibel-Palade bodies and is critical to the protein's hemostatic
function.

ADAMTS13 (604134) specifically cleaves a peptidyl bond between tyr1605
and met1606 in the A2 domain of VWF and thus acts to regulate VWF size.
Kokame et al. (2004) identified a 73-amino acid peptide, which they
designated VWF73, as the minimal VWF substrate cleavable by ADAMTS13.
VWF73 contains asp1596 to arg1668 of VWF.

Wu et al. (2006) cleaved VWF73 into shorter peptides and found that a
24-amino acid peptide encompassing pro1645 to lys1668 was the shortest
peptide that could bind ADAMTS13 and competitively inhibit its cleavage
of a VWF-derived substrate. This peptide and longer peptides containing
this core sequence also inhibited cleavage of multimeric VWF by
ADAMTS13. These results suggested the presence of a complementary
extended binding site, or exosite, on ADAMTS13. Asp1653-to-ala and
asp1663-to-ala mutations in the VWF-derived substrate significantly
reduced the rate of cleavage of the substrate peptide by ADAMTS13,
whereas a glu1655-to-ala mutation significantly enhanced the rate of
cleavage. Wu et al. (2006) concluded that ionic interactions between the
exosite on ADAMTS13 and a region of VWF spanning pro1645 to lys1668 play
a significant role in substrate recognition.

Cao et al. (2008) showed that, under shear stress and at physiologic pH
and ionic strength, coagulation factor VIII (F8; 300841) accelerated, by
a factor of about 10, the rate of ADAMTS13-mediated cleavage of the
tyr1605/met1606 bond in VWF. Multimer analysis revealed that factor VIII
preferentially accelerated the cleavage of high molecular weight (HMW)
multimers. The ability of factor VIII to enhance VWF cleavage by
ADAMTS13 was rapidly lost after pretreatment of factor VIII with
thrombin (F2; 176930). Cao et al. (2008) concluded that factor VIII
regulates proteolytic processing of VWF by ADAMTS13 under shear stress,
which depends on the high-affinity interaction between factor VIII and
VWF.

BIOCHEMICAL FEATURES

- Crystal Structure

Huizinga et al. (2002) presented the crystal structure of the platelet
receptor glycoprotein 1B-alpha (GP1BA; 606672) amino-terminal domain and
its complex with the VWF domain A1. In the complex, GP1BA wraps around
one side of A1, providing 2 contact areas bridged by an area of solvated
charge interaction. The structures explain the effects of
gain-of-function mutations related to bleeding disorders and provide a
model for shear-induced activation.

MOLECULAR GENETICS

Sadler and Ginsburg (1993) reported on a database of polymorphisms in
the VWF gene and pseudogene; Ginsburg and Sadler (1993) reported on a
database of point mutations, insertions, and deletions.

- Von Willebrand Disease Type 1

Eikenboom et al. (1996) described a family in the Netherlands in which 3
affected members with type 1 von Willebrand disease (193400) and VWF
levels 10 to 15% of normal were heterozygous for a mutation in the VWF
gene (C1149R; 613160.0028) The mutation resulted in a decrease in the
secretion of coexpressed normal VWF, and the mutation was proposed to
cause intracellular retention of pro-VWF heterodimers.

In affected members of 7 Italian families and in 1 German patient with
von Willebrand disease 'Vicenza,' Schneppenheim et al. (2000) identified
a heterozygous R1205H mutation in the VWF gene (613160.00027). Haplotype
identity, with minor deviations in 1 Italian family, suggested a common
but not very recent genetic origin of R1205H. The phenotype was
characterized by these groups as showing autosomal dominant inheritance
and low levels of VWF antigen in the presence of high molecular weight
and ultra high molecular weight multimers, so-called 'supranormal'
multimers, similar to those seen in normal plasma after infusion of
desmopressin.

- Von Willebrand Disease Type 2

In a patient with type 2 von Willebrand disease (613554), Bernardi et
al. (1990) identified a heterozygous de novo deletion of a portion of
the VWF gene containing at least codons 1147 through 1854. The VWF
antigen (VWF:Ag) levels were one-fourth of normal, and ristocetin
cofactor (VWF:RCo) activity was severely impaired. VWF morphology showed
a reduction of high molecular weight multimers in plasma and platelets,
consistent with type 2A VWD.

Iannuzzi et al. (1991) identified a heterozygous mutation in the VWF
gene (613160.0001) in a patient with von Willebrand disease type 2A,
which is characterized by a qualitative defect in VWF, resulting in the
absence of large and intermediate VWF multimers, which may be caused by
increased VWF proteolysis.

In 2 families with VWD, 1 with type 2B and another with type 1,
Eikenboom et al. (1994) identified multiple consecutive nucleotide
changes in the 5-prime end of exon 28 that resulted in sequences
identical to the VWF pseudogene, although they were demonstrated to be
in the active gene. Eikenboom et al. (1994) hypothesized that each of
these multiple substitutions arose from a recombination event between
the gene and pseudogene, rather than from single mutation events. The
findings thus represented interchromosomal gene conversion involving
chromosomes 12 and 22.

In affected members of 2 unrelated families with VWD type 2CB (see
613554), Riddell et al. (2009) identified 2 different heterozygous
mutations in the collagen-binding A3 domain of the VWF gene (W1745C;
613160.0040 and S1783A; 613160.0042, respectively). The patients had
clinically significant bleeding episodes. Laboratory studies showed
normal values of VWF:RCo to VWF:Ag (RCo:Ag), normal VWF multimer
analysis, and normal ristocetin-induced platelet aggregation, but
markedly reduced ratios of VWF collagen-binding activity to VWF antigen
(CB:Ag) against type III collagen and type I collagen. Treatment with
DDAVP resulted in a good functional response with a rise in VWF:CB
resulting from an overall increase in the amount of circulating VWF,
even though the qualitative defect in collagen binding remained. These
findings and in vitro expression studies indicated that these mutant
proteins caused a specific defect in collagen binding, which Riddell et
al. (2009) suggested represented a novel classification subtype termed
'VWF 2CB.'

A decreased VWF:RCo/VWF:Ag ratio implies a VWD type 2M defect that is
characterized by decreased VWF-platelet interactions in the presence of
normal multimer structure. Based on laboratory findings, Flood et al.
(2010) observed an overrepresentation of VWD type 2M in African American
individuals (80%) compared to Caucasians (30%), among all those
categorized as having VWD type 2. In addition, most of the African
American individuals had minimal bleeding symptoms despite a
significantly reduced VWF:RCo/VWF:Ag ratio. Genetic analysis of 59
African American and 113 Caucasian controls identified a nonsynonymous
SNP (asp1472-to-his; D1472H; dbSNP rs1800383) in exon 28 in the A1
domain of the VWF gene that could fully explain the lower VWF:RCo/VWF:Ag
ratios in African Americans (0.81) compared to Caucasians (0.94).
Whereas 63% of the African Americans were positive for D1472H, only 17%
of Caucasians had this SNP. Further analysis showed that the VWF 1472H
allele fully accounted for the variation in VWF:RCo/VWF:Ag independent
of race. In vitro studies showed that the D1472H substitution had no
effect on VWF binding to platelet GP1BA in assays that did not use
ristocetin, and did not alter VWF binding to collagen. Therefore, the
VWF D1472H polymorphism causes substantial variation in VWF:RCo without
altering the hemostatic function of VWF in vivo. Flood et al. (2010)
concluded that polymorphisms in this region may affect the measurement
of VWF activity by the ristocetin assay and may not reflect a functional
defect or true hemorrhagic risk.

Schneppenheim et al. (2010) reported a high frequency (29%) of VWD type
2A subtype IIE among patients with type 2A studied in their laboratory.
Subtype IIE is associated with a reduction of high molecular weight
(HMW) VWF multimers and a lack of outer proteolytic bands on gel
electrophoresis, indicating reduced proteolysis. Genetic analysis of 38
such index cases identified 22 different mutations in the VWF gene, most
of them affecting cysteine residues clustered in the D3 domain. The most
common mutation was Y1146C (613160.0039), which was found in 12 (32%)
probands. In vitro expression studies indicated that the Y1146C-mutant
protein caused a severe reduction in or lack of HMW monomers and
decreased secreted VWF antigen levels. However, clinical symptoms were
heterogeneous among carriers, ranging from mild to severe bleeding.
Schneppenheim et al. (2010) suggested that several mechanisms likely act
in concert to produce subtype IIE, including decreased secretion of VWF,
the change of a cysteine residue which may impact multimerization, and
decreased half-life of the mutant protein. Altered ADAMTS13-mediated
proteolysis did not appear to be a major primary factor.

- Von Willebrand Disease Type 3

In a patient with severe type 3 von Willebrand disease (277430), Peake
et al. (1990) found a homozygous 2.3-kb deletion in the VWF gene which
included exon 42; a novel 182-bp insert was found between the
breakpoints. The patient had an alloantibody inhibitor to VWF. The
insert was detected by PCR amplification both in the patient's DNA and
in his carrier relatives.

In patients with VWD type 3, Zhang et al. (1992, 1992, 1992) identified
homozygous or compound heterozygous mutations in the VWF gene (see,
e.g., 613160.0015-613160.0017). Some heterozygous family members had a
less severe phenotype, consistent with VWD type 1.

ANIMAL MODEL

Denis et al. (1998) generated a mouse model for von Willebrand disease
by using gene targeting. VWF-deficient mice appeared normal at birth;
they were viable and fertile. Neither von Willebrand factor nor
VWF-propolypeptide (von Willebrand antigen II) was detectable in plasma,
platelets, or endothelial cells of the homozygous mutant mice. The
mutant mice exhibited defects in hemostasis with a highly prolonged
bleeding time and spontaneous bleeding events in approximately 10% of
neonates. As in the human disease, the factor VIII level in these mice
was reduced strongly as a result of the lack of protection provided by
von Willebrand factor. Defective thrombosis in mutant mice was also
evident in an in vivo model of vascular injury. In this model, the
exteriorized mesentery was superfused with ferric chloride and the
accumulation of fluorescently labeled platelets was observed by
intravascular microscopy. Denis et al. (1998) concluded that these mice
very closely mimic severe human von Willebrand disease.

Golder et al. (2010) generated transgenic mouse models of VWD type 2B by
introducing mutations R1306W (613160.0005), V1316M (613160.0007), and
R1341Q (613160.0008) into the murine Vwf gene. The mutant Vwf proteins
were expressed by the liver and only present in the plasma compartment,
not in platelets. Mutant mice showed variable thrombocytopenia, which
was most severe in V1316M mice. Blood smears from mutant mice showed
many platelet aggregates, which were not seen in wildtype mice, and
plasma samples from mutant mice showed decreased numbers of Vwf
multimers resulting from increased Adamst13-mediated proteolysis. Mice
with the V1316M mutation also had large platelets. Even though the
enhanced affinity of Vwf 2B mutant proteins to platelets could
theoretically have a thrombotic effect, ferric chloride-induced injury
to cremaster arterioles in mutant mice showed a marked reduction in
thrombus development and platelet adhesion in the presence of
circulating Vwf 2B.

Rayes et al. (2010) also generated mouse models of VWD type 2B by
introducing the R1306Q and V1316M mutations in the murine Vwf gene. Both
mutant proteins were associated with enhanced ristocetin-induced
platelet aggregation, and mutant mice developed thrombocytopenia and
circulating platelet aggregates, both of which were more pronounced for
mice with the V1316M mutation. Only the V1316M mutant showed spontaneous
platelet aggregation in vitro. Blood smears from mutant mice showed
increased platelet size compared to wildtype. Both mutant proteins had a
2- to 3-fold reduced half-life and induced a 3- to 6-fold increase in
number of giant platelets compared with wild-type Vwf. Loss of large
multimers was observed in 50% of mutant mice. In vivo hemostatic
potential of both mutants was severely impaired, even in an thrombotic
model of arterial vessel occlusion. Mice who were doubly mutant for Vwf
2B and Adamts13 deficiency had more and larger circulating platelet
aggregates and did not lack high molecular weight (HMW) multimers. The
findings confirmed that VWD type 2B is dependent upon the type of
mutation and pointed to an important role for ADAMTS13 in modulating
platelet size as well as the removal of HMW VWF.

*FIELD* AV
.0001
VON WILLEBRAND DISEASE, TYPE 2A
VWF, ILE1628THR

Goodeve (2010) noted that mutations in the VWF gene, which were
sometimes numbered from the transcription start site of the mature
protein, are now 'numbered from the first A of the ATG initiator
methionine codon (A = +1) at the start of every protein (Met = +1), with
cDNA rather than genomic DNA being commonly used as a reference
sequence.' Thus, the mutation originally designated ILE865THR is now
designated ILE1628THR (I1628T).

In affected members of a family with von Willebrand disease type 2A (see
613554), Iannuzzi et al. (1991) identified a 4883T-C transition in the
VWF gene, resulting in an ile865-to-thr (I865T) substitution. Type 2A
VWD is characterized by a qualitative defect in VWF, resulting in the
absence of large and intermediate VWF multimers, which may be caused by
increased VWF proteolysis. The I865T substitution was located
immediately adjacent to 2 other previously identified mutations that
also result in type 2A von Willebrand disease (R834W, 613160.0002 and
V844D, 613160.0003), suggesting a clustering for these mutations in a
portion of the protein critical for proteolysis.

Dent et al. (1990) noted that the I865T, R834W, and V844D mutations are
located within a 32-amino acid segment in the midportion of the
2,813-amino acid VWF coding sequence. Type IIA von Willebrand disease is
characterized by normal or only moderately decreased levels of von
Willebrand factor, the absence of large and intermediate VWF multimers,
and increased VWF proteolysis with an increase in the plasma levels of
the 176-kD VWF proteolytic fragment. The proteolytic cleavage site is
located between tyr842 and met843.

.0002
VON WILLEBRAND DISEASE, TYPE 2A
VWF, ARG1597TRP

Goodeve (2010) noted that mutations in the VWF gene, which were
sometimes numbered from the transcription start site of the mature
protein, are now 'numbered from the first A of the ATG initiator
methionine codon (A = +1) at the start of every protein (Met = +1), with
cDNA rather than genomic DNA being commonly used as a reference
sequence.' Thus, the mutation originally designated ARG834TRP is now
designated ARG1597TRP (R1597W).

In a patient with von Willebrand disease type 2A (see 613554),
characterized by selective loss of high molecular weight VWF multimers,
Ginsburg et al. (1989) identified a heterozygous 4789C-T transition in
the VWF gene, resulting in an arg834-to-trp (R834W) substitution.

.0003
VON WILLEBRAND DISEASE, TYPE 2A
VWF, VAL1607ASP

Goodeve (2010) noted that mutations in the VWF gene, which were
sometimes numbered from the transcription start site of the mature
protein, are now 'numbered from the first A of the ATG initiator
methionine codon (A = +1) at the start of every protein (Met = +1), with
cDNA rather than genomic DNA being commonly used as a reference
sequence.' Thus, the mutation originally designated VAL844ASP is now
designated VAL1607ASP (V1607D).

In a patient with von Willebrand disease type 2A (see 613554),
characterized by selective loss of high molecular weight VWF multimers,
Ginsburg et al. (1989) identified a heterozygous 4820T-A transversion in
the VWF gene, resulting in a val844-to-asp (V844D) substitution.

.0004
VON WILLEBRAND DISEASE, TYPE 2B
VWF, TRP1313CYS

Goodeve (2010) noted that mutations in the VWF gene, which were
sometimes numbered from the transcription start site of the mature
protein, are now 'numbered from the first A of the ATG initiator
methionine codon (A = +1) at the start of every protein (Met = +1), with
cDNA rather than genomic DNA being commonly used as a reference
sequence.' Thus, the mutation originally designated TRP550CYS is now
designated TRP1313CYS (W1313C).

In the patient identified as case 7 in the report by Kyrle et al. (1988)
with laboratory findings consistent with the diagnosis of type 2B von
Willebrand disease (see 613554), Ware et al. (1991) found a
trp550-to-cys (W550C) substitution. The mutation is located in the
domain of the molecule comprising residues 449 to 728 involved in the
binding to platelet glycoprotein Ib-IX receptor complex (see 606672).
This interaction is physiologically regulated so that it does not occur
between circulating VWF and platelets but, rather, only at a site of
vascular injury. The abnormal VWF found in type 2B von Willebrand
disease has a characteristically increased affinity for GP Ib and binds
to the circulating platelets.

.0005
VON WILLEBRAND DISEASE, TYPE 2B
VWF, ARG1306TRP

Goodeve (2010) noted that mutations in the VWF gene, which were
sometimes numbered from the transcription start site of the mature
protein, are now 'numbered from the first A of the ATG initiator
methionine codon (A = +1) at the start of every protein (Met = +1), with
cDNA rather than genomic DNA being commonly used as a reference
sequence.' Thus, the mutation originally designated ARG543TRP is now
designated ARG1306TRP (R1306W).

In 2 unrelated patients with VWD type 2B (see 613554), Randi et al.
(1991) identified a heterozygous 4166C-T transition in exon 28 of the
VWF gene, resulting in an arg543-to-trp (R543W) substitution in the
domain that interacts with platelet glycoprotein GP1BA (606672). Both
patients had previously been reported by Ruggeri et al. (1980) as having
VWD with a heightened interaction between platelets and VWF. Patient
plasma showed a decrease in large VWF multimers due to spontaneous
binding of VWF to platelets and subsequent clearance from the
circulation.

Donner et al. (1992) studied 20 patients from 9 unrelated families with
type 2B VWD from Denmark, Germany, and Sweden. Fifteen patients in 5
families were heterozygous for the R543W mutation. In 2 of the 5
families, it represented a de novo mutation. In one of the other
families, the father, though asymptomatic and with normal laboratory
test results, carried the mutation in heterozygous form.

.0006
VON WILLEBRAND DISEASE, TYPE 2B
VWF, ARG1308CYS

Goodeve (2010) noted that mutations in the VWF gene, which were
sometimes numbered from the transcription start site of the mature
protein, are now 'numbered from the first A of the ATG initiator
methionine codon (A = +1) at the start of every protein (Met = +1), with
cDNA rather than genomic DNA being commonly used as a reference
sequence.' Thus, the mutation originally designated ARG545CYS is now
designated ARG1308CYS (R1308C).

In 7 patients from 4 unrelated families with VWD type 2B (see 613554),
Randi et al. (1991) identified a heterozygous 4172C-T transition in exon
28 of the VWF gene, resulting in an arg545-to-cys (R545C) substitution
in the domain that interacts with platelet glycoprotein GP1BA (606672).
Patient plasma showed a decrease in large VWF multimers due to
spontaneous binding of VWF to platelets and subsequent clearance from
the circulation. Examination of the RFLP haplotype background for the
R545C mutations identified in their study permitted Randi et al. (1991)
to conclude that the mutation had occurred independently 3 times; a
fourth patient represented a new mutation.

Donner et al. (1991) reported another family with this mutation. In a
later study of 20 patients from 9 unrelated families with type 2B VWD
from Denmark, Germany, and Sweden, Donner et al. (1992) found the
arg545-to-cys mutation in heterozygous state in 4 affected persons in 3
families.

In a Japanese patient with VWD type 2B, Hagiwara et al. (1996)
identified a homozygous mutation in exon 28 of the VWF gene, resulting
in an arg1308-to-cys (R1308C) substitution.

.0007
VON WILLEBRAND DISEASE, TYPE 2B
VWF, VAL1316MET

Goodeve (2010) noted that mutations in the VWF gene, which were
sometimes numbered from the transcription start site of the mature
protein, are now 'numbered from the first A of the ATG initiator
methionine codon (A = +1) at the start of every protein (Met = +1), with
cDNA rather than genomic DNA being commonly used as a reference
sequence.' Thus, the mutation originally designated VAL553MET is now
designated VAL1316MET (V1316M).

In a patient with VWD type 2B (see 613554), Randi et al. (1991)
identified a heterozygous 4196G-A transition in exon 28 of the VWF gene,
resulting in a val553-to-met (V553M) substitution in the domain that
interacts with platelet glycoprotein GP1BA (606672). Patient plasma
showed a decrease in large VWF multimers due to spontaneous binding of
VWF to platelets and subsequent clearance from the circulation.

Murray et al. (1992) also observed this mutation in multiple members of
a family with type 2B von Willebrand disease. They showed by VWF
polymorphism analysis that the mutation originated in a VWF gene
transmitted from a phenotypically normal grandfather. Analysis of the
sperm from this individual showed that approximately 5% of the germline
contained the mutant sequence.

Jackson et al. (2009) identified a heterozygous V1316M substitution in
affected members of a large French Canadian family with VWD type 2B that
was described by Milton et al. (1984) as having the 'Montreal platelet
syndrome.' Affected individuals had lifelong bruising; some patients had
severe postoperative bleeding, postpartum hemorrhage, and
gastrointestinal bleeding. A significant proportion of platelets
occurred in microaggregates typically containing 2 to 6 platelets, and
the aggregation could be increased by stirring. Affected family members
had macrothrombocytopenia, borderline to normal VWF antigen, low
ristocetin cofactor activity, and normal factor VIII coagulant activity,
all consistent with VWD type 2B.

.0008
VON WILLEBRAND DISEASE, TYPE 2B
VWF, ARG1341GLN

Goodeve (2010) noted that mutations in the VWF gene, which were
sometimes numbered from the transcription start site of the mature
protein, are now 'numbered from the first A of the ATG initiator
methionine codon (A = +1) at the start of every protein (Met = +1), with
cDNA rather than genomic DNA being commonly used as a reference
sequence.' Thus, the mutation originally designated ARG578GLN is now
designated ARG1341GLN (R1341Q).

In a patient with VWD type 2B (see 613554), Cooney et al. (1991)
identified a heterozygous 4022G-A transition in the VWF gene, resulting
in an arg578-to-gln (R578Q) substitution within the putative GP1BA
(606672)-binding domain.

.0009
VON WILLEBRAND DISEASE, TYPE 2A
VWF, SER1613PRO

Goodeve (2010) noted that mutations in the VWF gene, which were
sometimes numbered from the transcription start site of the mature
protein, are now 'numbered from the first A of the ATG initiator
methionine codon (A = +1) at the start of every protein (Met = +1), with
cDNA rather than genomic DNA being commonly used as a reference
sequence.' Thus, the mutation originally designated SER850PRO is now
designated SER1613PRO (S1613P).

Randi et al. (1991) suggested that mutations causing type IIA von
Willebrand disease are clustered in the A2 domain of the VWF gene. The
ser850-to-pro (S850P) mutation, designated S1613P based on a different
numbering system, is in the A2 region of the gene (Goodeve, 2010).

.0010
VON WILLEBRAND FACTOR POLYMORPHISM
VWF, ARG1399HIS

Goodeve (2010) noted that mutations in the VWF gene, which were
sometimes numbered from the transcription start site of the mature
protein, are now 'numbered from the first A of the ATG initiator
methionine codon (A = +1) at the start of every protein (Met = +1), with
cDNA rather than genomic DNA being commonly used as a reference
sequence.' Thus, the polymorphism originally designated ARG636HIS is now
designated ARG1399HIS (R1399H).

Cooney et al. (1991) found a rare sequence polymorphism at nucleotide
4196 of the VWF gene. A 4196G-A transition led to an arg636-to-his
(R636H) substitution. The allele frequency was estimated to be about
0.015. Although the change was within the region involved in binding to
platelet glycoprotein receptor and the region mutant in von Willebrand
disease type 2B (see 613554), no hematologic abnormality was associated
with the change.

.0011
VON WILLEBRAND DISEASE, TYPE 2N
VWF, THR791MET

Goodeve (2010) noted that mutations in the VWF gene, which were
sometimes numbered from the transcription start site of the mature
protein, are now 'numbered from the first A of the ATG initiator
methionine codon (A = +1) at the start of every protein (Met = +1), with
cDNA rather than genomic DNA being commonly used as a reference
sequence.' Thus, the mutation originally designated THR28MET is now
designated THR791MET (T791M).

In a 50-year-old French woman, born of consanguineous parents, with the
Normandy type of VWD (VWD2N; see 613554) reported by Mazurier et al.
(1990), Gaucher et al. (1991) identified a homozygous 791C-T transition
in exon 18 of the VWF gene, resulting in a thr28-to-met (T28M)
substitution in the mature VWF subunit. The woman had a lifelong history
of excessive bleeding, and laboratory data showed decreased factor VIII
(300841), subnormal bleeding time, and normal VWF multimers. VWF
isolated from patient plasma was unable to bind factor VIII. Gaucher et
al. (1991) noted that the phenotype resembled hemophilia A, or F8
deficiency, but showed autosomal recessive instead of X-linked
inheritance.

By functional expression studies, Tuley et al. (1991) showed that the
T28M mutation occurred in the factor VIII binding site of the VWF
molecule. The corresponding mutant recombinant molecule formed normal
multimers and had normal ristocetin cofactor activity, but had a defect
in factor VIII binding.

Wise et al. (1993) reported a family with VWD type 2N ascertained
through a female patient with low levels of factor VIII activity. The
patient was homozygous for the thr28-to-met mutation, which was
heterozygous in both parents.

.0012
VON WILLEBRAND DISEASE, TYPE 2N
VWF, ARG816TRP

Goodeve (2010) noted that mutations in the VWF gene, which were
sometimes numbered from the transcription start site of the mature
protein, are now 'numbered from the first A of the ATG initiator
methionine codon (A = +1) at the start of every protein (Met = +1), with
cDNA rather than genomic DNA being commonly used as a reference
sequence.' Thus, the mutation originally designated ARG53TRP is now
designated ARG816TRP (R816W).

In a family with the Normandy type of von Willebrand disease (VWD2N; see
613554), Gaucher et al. (1991) demonstrated homozygosity for a C-to-T
transition resulting in an arg53-to-trp (R53W) substitution in the
mature protein. Although there was no known parental consanguinity, both
parents originated from the same village in Portugal. The 2 alleles
showed sequence variation within the intron 40 VNTR and might have
arisen after the arg53-to-trp mutation occurred.

.0013
VON WILLEBRAND DISEASE, TYPE 2N
VON WILLEBRAND DISEASE, TYPE 1, INCLUDED
VWF, ARG854GLN

Goodeve (2010) noted that mutations in the VWF gene, which were
sometimes numbered from the transcription start site of the mature
protein, are now 'numbered from the first A of the ATG initiator
methionine codon (A = +1) at the start of every protein (Met = +1), with
cDNA rather than genomic DNA being commonly used as a reference
sequence.' Thus, the mutation originally designated ARG91GLN is now
designated ARG854GLN (R854Q).

In a patient with the Normandy type of von Willebrand disease (VWD2N;
see 613554), Gaucher et al. (1991) demonstrated compound heterozygosity
for the arg53-to-trp mutation (193400.0012) and another C-to-T
transition that resulted in a substitution of glutamine for arginine-91.
The patient's parents were related as second cousins.

Hilbert et al. (2004) reported 2 unrelated French patients with type 2N
VWD who were compound heterozygous for R854Q and another pathogenic
mutation (Y795C, 613160.0031 and C804F, 613160.0032, respectively).

Peerlinck et al. (1992) identified a heterozygous A-to-G transition in
exon 20 of the VWF gene, resulting in an arg854-to-gln (R854Q)
substitution, in a 23-year-old woman with a lifelong history of bleeding
and low VWF levels, consistent with von Willebrand disease type 1
(193400). Laboratory studies showed disproportionately low factor VIII
(F8; 300841) and decreased binding capacity of VWF for F8. The R854Q
substitution occurred in the putative factor VIII-binding domain. All
VWF multimers were normal. Neither parent was clinically affected, but
laboratory studies showed that the father had partially increased
bleeding time and partially decreased VWF antigen. Restriction enzyme
analysis indicated that the unaffected mother was also heterozygous for
the R854Q mutation, and that the patient had inherited a hypomorphic
'silent' VWF allele from her father. Peerlinck et al. (1992) noted that
the inheritance pattern in this family was difficult to determine, but
concluded that the presence of the 'silent' allele allowed the clinical
expression of the mutated second allele, resulting in a recessive
phenotype in the proband. Peerlinck et al. (1992) commented that
although the phenotype was similar to that of the 'Normandy' type 2N
variant (see 613554), the patient also had quantitatively low VWF and
was thus classified as having VWD type 1.

.0014
MOVED TO 613160.0013
.0015
VON WILLEBRAND DISEASE, TYPE 3
VON WILLEBRAND DISEASE, TYPE 1, INCLUDED
VWF, ARG1659TER

In a patient with von Willebrand disease type 3 (277480), Zhang et al.
(1992) identified a homozygous C-to-T transition in exon 28 of the VWF
gene, resulting in an arg1659-to-ter (R1659X) substitution. Both parents
carried the heterozygous mutation; the clinical features of the family
were not reported.

Zhang et al. (1992) identified the R1659X mutation in affected members
of 3 families from western Finland with VWD type 3. Severely affected
individuals were either homozygous or presumed to be compound
heterozygous with another pathogenic mutation. In 1 family, heterozygous
mutation carriers had a less severe phenotype, consistent with type 1
VWD (193400).

.0016
VON WILLEBRAND DISEASE, TYPE 3
VON WILLEBRAND DISEASE, TYPE 1, INCLUDED
VWF, ARG1852TER

In a Swedish patient with VWD type 3 (277430) and pronounced bleeding
tendency, Zhang et al. (1992) identified homozygous C-to-T transition in
exon 32 of the VWF gene, resulting in an arg1852-to-ter (R1852X)
substitution. Two additional Swedish patients with type 3 were
heterozygous for the mutation, but were predicted to be compound
heterozygous for another mutation because their phenotype was more
severe than other family members, who had type 1 disease (193400).

.0017
VON WILLEBRAND DISEASE, TYPE 3
VWF, ARG2635TER

In a patient with severe VMD type 3 (277480), Zhang et al. (1992)
identified a C-to-T transition in exon 45 of the VWF gene, resulting in
an arg2635-to-ter (R2635X) substitution. Although the patient was
heterozygous for this mutation, he was thought to be a compound
heterozygote for another, as yet unidentified mutation, since he had
severe disease.

.0018
VON WILLEBRAND DISEASE, TYPE 2M
VWF, GLY1324SER

Goodeve (2010) noted that mutations in the VWF gene, which were
sometimes numbered from the transcription start site of the mature
protein, are now 'numbered from the first A of the ATG initiator
methionine codon (A = +1) at the start of every protein (Met = +1), with
cDNA rather than genomic DNA being commonly used as a reference
sequence.' Thus, the mutation originally designated GLY561SER is now
designated GLY1324SER (G1324S).

In a patient with VWD type 2M (see 613554), Rabinowitz et al. (1992)
identified a heterozygous mutation in exon 28 of the VWF gene, resulting
in a gly561-to-ser (G561S) substitution within the GP1BA
(606672)-binding domain of the mature protein. Laboratory studies of
patient plasma showed normal botrocetin-induced binding but no
ristocetin-induced binding to platelet glycoprotein Ib. The patient's
plasma VWF contained a full range of multimers. The mutant recombinant
protein formed normal multimers, but exhibited the same functional
defect as the patient's plasma VWF. The patient was originally described
by Howard et al. (1984) and Andrews et al. (1989).

.0019
VON WILLEBRAND DISEASE, TYPE 2A
VWF, CYS1272ARG

Goodeve (2010) noted that mutations in the VWF gene, which were
sometimes numbered from the transcription start site of the mature
protein, are now 'numbered from the first A of the ATG initiator
methionine codon (A = +1) at the start of every protein (Met = +1), with
cDNA rather than genomic DNA being commonly used as a reference
sequence.' Thus, the mutation originally designated CYS509ARG is now
designated CYS1272ARG (C1272R).

In a patient with type 2A von Willebrand disease (see 613554), Lavergne
et al. (1992) found a 3814T-C transition in the 5-prime end of exon 28
of the VWF gene, resulting in a cys509-to-arg (C509R) substitution. This
mutation eliminated an intramolecular disulfide bridge formed by cys509
and cys695. The bridge is important to maintenance of the configuration
of VWF functional domains that interact with platelet glycoprotein
Ib-IX. However, it appeared that this bridge also affects the processing
and composition of VWF multimers, since the patient had a type 2A
phenotype. The amino acid substitution was the result of a 381T-C
transition. The findings suggested a broader pathogenic mechanism for
VWF type 2A.

.0020
VON WILLEBRAND DISEASE, TYPE 2B
VWF, VAL1314LEU

Goodeve (2010) noted that mutations in the VWF gene, which were
sometimes numbered from the transcription start site of the mature
protein, are now 'numbered from the first A of the ATG initiator
methionine codon (A = +1) at the start of every protein (Met = +1), with
cDNA rather than genomic DNA being commonly used as a reference
sequence.' Thus, the mutation originally designated VAL551LEU is now
designated VAL1314LEU (V1314L).

In 1 of 20 patients from 9 unrelated families with type 2B VWD (see
613554) from Denmark, Germany, and Sweden, Donner et al. (1992) found
heterozygosity for a de novo val551-to-leu (V551L) mutation. In most of
the patients with type 2B VWD, spontaneous thrombocytopenia had been
recorded on at least one occasion. The patient with the val551-to-leu
substitution and 5 patients with the arg543-to-trp (613160.0005)
substitution had had bleeding associated with thrombocytopenia in the
neonatal period or early infancy.

.0021
VON WILLEBRAND DISEASE, TYPE 3
VWF, 1-BP DEL, EX18, C

Among 24 patients with von Willebrand disease type 3 (277480), Zhang et
al. (1992) found that 24 of the 48 chromosomes harbored a 1-bp deletion
in a stretch of 6 cytosines at position 2679-2684 in exon 18 of the VWF
gene. Nine patients were homozygous and 6 were heterozygous for the
mutation. The deletion interrupted the reading frame and resulted in a
translational stop codon at position V842 in the amino acid sequence.
Translation of the mutant mRNA would yield only a severely truncated
mature VWF (48 of 2,050 amino acids) after removal of the propeptide.

Zhang et al. (1993) demonstrated that deletion of 1 cytosine in exon 18
was the mutation in the Aland family (family S) in which the disease was
first reported by von Willebrand (1926). They reported studies of
descendants of the original family; only heterozygotes were found
surviving. The proposita was a 5-year-old girl, who later bled to death
during her fourth menstrual period. She had a normal coagulation time,
but the bleeding time was prolonged, despite a normal platelet count.
All but 1 of her 11 sibs had bleeding symptoms, as did both of her
parents, who were third cousins, and many members of her family on both
sides. Four of the proband's sisters had died of uncontrolled bleeding
in early childhood; 3 died from gastrointestinal bleeding and 1 from
bleeding after she bit her tongue in a fall. The predominant symptoms
were bleeding from mucous membranes, such as from the nose, the gingivae
after tooth extractions, the uterus, and the gastrointestinal tract. In
contrast to hemophilia, hemarthroses seemed to be rare. All 5 of the
girls who died from uncontrolled bleeding were probably homozygous for
the deletion.

Mertes et al. (1993) found that the single cytosine deletion in exon 18
observed in half the alleles of 24 Swedish VWD type 3 patients (Zhang et
al., 1992) occurred uncommonly in German patients with type 3 VWD; only
1 out of 24 alleles carried the delta-C mutation. A founder effect might
explain the higher frequency in Sweden.

.0022
VON WILLEBRAND DISEASE, TYPE 2A
VWF, PHE1514CYS

Goodeve (2010) noted that mutations in the VWF gene, which were
sometimes numbered from the transcription start site of the mature
protein, are now 'numbered from the first A of the ATG initiator
methionine codon (A = +1) at the start of every protein (Met = +1), with
cDNA rather than genomic DNA being commonly used as a reference
sequence.' Thus, the mutation originally designated PHE751CYS is now
designated PHE1514CYS (F1514C).

In 8 patients from a large type 2A (see 613554) von Willebrand disease
family, Gaucher et al. (1993) found a heterozygous T-to-G transversion
resulting in a phe751-to-cys (F751C) substitution in the mature subunit.
Type 2A is a variant form of von Willebrand disease characterized by the
absence of high molecular weight VWF multimers in plasma. Gaucher et al.
(1993) noted that most of the candidate missense mutations potentially
responsible for type 2A VWD have been found clustered within a short
segment of VWF, lying between gly742 and glu875 of the mature subunit.
Gaucher et al. (1993) suggested that the mutation may induce a
conformational change of the VWF subunit affecting either its
sensitivity to proteolytic cleavage or, more likely, its intracellular
transport as suggested by the abnormal multimeric pattern of platelet
VWF observed in these patients.

.0023
VON WILLEBRAND DISEASE, TYPE 2A
VWF, GLY550ARG

In a German woman with von Willebrand disease type 2 (613554), referred
to as type IIC, Schneppenheim et al. (1995) identified a homozygous
1898G-A transition in exon 14 of the VWF gene, resulting in a
gly550-to-arg (G550R) substitution in the D2 domain. The proband had
frequent epistaxis, easy bruising, and menorrhagia, and laboratory
studies showed decreased VWF activity and decreased levels of high
molecular weight multimers. The subtype of VWD was originally referred
to as 'type IIC,' which shows recessive inheritance and an altered
multimer pattern. Further family members were heterozygous for the
mutation and were phenotypically normal or only mildly affected, in
accordance with the recessive pattern of inheritance.

Sadler et al. (2006) stated that the subtype previously known as VWD IIC
is due to mutations in the VWF propeptide that prevent multimerization
of VWF in the Golgi apparatus. This form is now referred to as VWD type
2A.

.0024
VON WILLEBRAND DISEASE, TYPE 2A
VWF, CYS2773ARG

Goodeve (2010) noted that mutations in the VWF gene, which were
sometimes numbered from the transcription start site of the mature
protein, are now 'numbered from the first A of the ATG initiator
methionine codon (A = +1) at the start of every protein (Met = +1), with
cDNA rather than genomic DNA being commonly used as a reference
sequence.' Thus, the mutation originally designated CYS2010ARG is now
designated CYS2773ARG (C2773R).

In 2 unrelated patients with VWD type 2 (613554), Schneppenheim et al.
(1996) identified a heterozygous cys2010-to-arg (C2010R) mutation in the
mature VWF protein. Recombinant expression of mutant VWF fragments
demonstrated that the mutation was responsible for defective disulfide
bonding of the C-terminal domains, thus impairing dimer formation. In 1
family, both alleles were normal in the parents and 1 sister; thus, the
mutation originated de novo in the proposita. The phenotype of what was
then called type IID von Willebrand disease includes autosomal dominant
inheritance of a moderate to severe hemorrhagic diathesis, prolonged
bleeding time, normal factor VIII procoagulant and VWF antigen levels,
but markedly reduced ristocetin cofactor activity due to the lack of
large VWF multimers in plasma.

Sadler et al. (2006) stated that the subtype previously known as VWD IID
is due to heterozygous mutations in the C-terminal domain of VWF that
prevent VWF dimerization in the endoplasmic reticulum. This form is now
referred to as VWD type 2A.

.0025
MOVED TO 613160.0006
.0026
VON WILLEBRAND DISEASE, TYPE 2A
VWF, 6-BP INS, NT1212

Holmberg et al. (1998) found that a patient with type 2 VWD (613554)
reported by Ruggeri et al. (1982) was compound heterozygous for 2
mutations in the VWF gene: a null mutation and a 6-nucleotide insertion,
1212ins6 (AATCCC), in exon 11, predicting the insertion of the amino
acids asparagine and proline between phenylalanine-404 and threonine-405
of the von Willebrand propeptide. The patient was originally classified
as type IIC, since laboratory studies showed absence of the high
molecular weight multimers and a marked increase of the smallest
multimer (the protomer) in both plasma and platelets. The IIC phenotype
showed recessive inheritance.

Sadler et al. (2006) stated that the subtype previously known as VWD IIC
is due to mutations in the VWF propeptide that prevent multimerization
of VWF in the Golgi apparatus. This form is now referred to as VWD type
2A.

.0027
VON WILLEBRAND DISEASE, TYPE 1
VON WILLEBRAND FACTOR VICENZA
VWF, ARG1205HIS

The arg1205-to-his mutation (R1205H) in the VWF gene is sometimes
referred to as VWF Vicenza.

In affected members of 7 Italian families and in 1 German patient with
von Willebrand disease (193400) 'Vicenza,' Schneppenheim et al. (2000)
identified a heterozygous 3864G-A transition in exon 27 of the VWF gene,
resulting in an R1205H substitution in the D3 domain. The mutation was
not found in unaffected family members or in 100 control chromosomes.
Haplotype identity, with minor deviations in 1 Italian family, suggested
a common but not very recent genetic origin of R1205H. Von Willebrand
disease 'Vicenza' was originally described in patients living in the
region of Vicenza in Italy (Mannucci et al., 1988). Randi et al. (1993)
demonstrated that the clinical disorder in Italian patients is linked to
the VWF gene. A number of additional families were identified in Germany
by Zieger et al. (1997). The phenotype was characterized by these groups
as showing autosomal dominant inheritance and low levels of VWF antigen
in the presence of high molecular weight and ultra high molecular weight
multimers, so-called 'supranormal' multimers, similar to those seen in
normal plasma after infusion of desmopressin.

Casonato et al. (2002) identified 4 additional families with the R1205H
variant. Affected individuals showed a mild bleeding tendency and
significant decrease in plasma VWF antigen and ristocetin cofactor
activity, but normal platelet VWF levels. Larger than normal VWF
multimers were also observed. However, VWF multimers disappeared rapidly
from the circulation after desmopressin, indicating reduced survival of
the mutant VWF protein. Since ristocetin-induced platelet aggregation
was normal, Casonato et al. (2002) attributed the phenotype to reduced
survival of normally synthesized VWF, which is consistent with type 1
VWF.

In Wales, Lester et al. (2006) investigated 7 kindreds with VWD Vicenza
R1205H. All affected individuals had been diagnosed with moderate to
severe type 1 VWD. Among all families with highly penetrant type 1 VWD
investigated in the center, heterozygosity for the R1205H mutation was
found to be the most common underlying defect. A severe laboratory
phenotype associated with a bleeding history that was milder than
expected was commonly observed. Lester et al. (2006) provided evidence
that the R1205H mutation can arise de novo.

Cumming et al. (2006) identified the Vicenza variant in 4 (12.5%) of 32
UK patients with type 1 VWD. These authors stated that the R1205H
substitution resulted from a 3614G-A transition in exon 27. The mutation
was highly penetrant and consistently associated with moderate to severe
type I disease. VWF multimer studies did not show the presence of
ultralarge multimers in any affected individuals; the authors thus
classified the Vicenza variant to be a type 1 quantitative defect,
rather than a type 2M qualitative defect as had been suggested by
Castaman et al. (2002). Three of the 4 families reported by Cumming et
al. (2006) shared the same haplotype, suggesting a common origin of the
mutation.

In a review, Sadler et al. (2006) noted that the Vicenza VWF variant has
increased clearance compared to wildtype VWF. Sadler et al. (2006) also
noted that the Vicenza variant has been classified as VWD type 2M due to
the presence of high molecular weight multimers. However, since VWF
antigen and functional activity are decreased proportionately, it is
better classified as VWD type 1.

.0028
VON WILLEBRAND DISEASE, TYPE 1
VWF, CYS1149ARG

Eikenboom et al. (1996) described a family in the Netherlands in which 3
affected members with type 1 von Willebrand disease (193400) and VWF
levels 10 to 15% of normal were heterozygous for a mutation in exon 26
of the VWF gene, resulting in a cys1149-to-arg (C1149R) substitution in
the D3 domain (numbered from the initiation codon, or cys386-to-arg,
numbered from the N terminus of the mature subunit). The mutation
resulted in a decrease in the secretion of coexpressed normal VWF, and
the mutation was proposed to cause intracellular retention of pro-VWF
heterodimers. The multimer pattern remained nearly normal and consistent
with a dominant VWD type 1 phenotype.

Bodo et al. (2001) performed experiments supporting the hypothesis that
normal and C1149R mutant subunits formed heterodimers that, like
homodimers of C1149R, were retained in the endoplasmic reticulum. Such a
mechanism would explain the dominant-negative effect of the C1149R
mutation on VWF secretion, and the authors suggested that a similar
dominant-negative mechanism could cause quantitative deficiencies of
other multisubunit proteins.

.0029
VON WILLEBRAND DISEASE, TYPE 1, SUSCEPTIBILITY TO
VWF, TYR1584CYS

O'Brien et al. (2003) addressed the molecular basis of type 1 von
Willebrand disease (193400) in a comprehensive manner through a Canadian
population-based study. In 10 Canadian families and 2 families from the
UK with type 1 VWD, O'Brien et al. (2003) identified a heterozygous
4751A-G transition in exon 28 of the VWF gene, resulting in a
tyr1584-to-cys (Y1584C) substitution. The Y1584C variant was found in 1
of 100 controls, but this individual had low VWF antigen levels,
suggesting an affected status. One study participant with the mutation
had a normal VWF antigen level and no history of bleeding, suggesting
incomplete penetrance, and another who was homozygous for the mutation
had significantly decreased VWF antigen levels. The mutation was
associated with a common haplotype in a significant portion of patients
with the disorder and was in-phase with a splice site variation
(5312-19A-C) in some families. In vitro functional expression studies
showed that the mutation resulted in increased intracellular retention
of the VWF protein, resulting in a quantitative defect. Molecular
dynamic simulation on a homology model of the VWF-A2 domain containing
the Y1584C mutation showed that no significant structural changes
occurred as a result of the substitution, but that a new solvent-exposed
reactive thiol group was apparent.

Bowen and Collins (2004) described a patient with type 1 von Willebrand
disease in whom the von Willebrand factor showed increased
susceptibility to proteolysis by ADAMTS13 (604134). Investigation of
additional family members indicated that increased susceptibility was
heritable, but it did not track uniquely with type 1 VWD. Sequence
analysis showed that increased susceptibility to proteolysis tracked
with the Y1584C substitution. A prospective study of 200 individuals
yielded 2 Y1584C heterozygotes; for both, plasma VWF showed increased
susceptibility to proteolysis.

Bowen et al. (2005) identified heterozygosity for the Y1584C variant in
19 (25%) of 76 UK patients with type 1 VWD. This corresponded to 8 (27%)
of 30 total families studied. However, the Y1584C variant did not
segregate with disease in 4 families: 5 unaffected individuals carried
the variant, whereas 3 affected individuals did not. These findings
indicated that Y1584C is not solely causative of type 1 VWD. Eighteen of
the 19 patients were ABO blood group (110300) type O, suggesting there
may be an interaction between C1584 and blood group O. In vitro studies
of plasma showed that Y1584C VWF had increased susceptibility to
proteolysis by ADAMTS13, even in those who did not have VWD. Bowen et
al. (2005) proposed a mechanism in which Y1584C VWF undergoes increased
proteolysis, which may increase bleeding risk in carriers. However,
presence for the variant is not causative for the disorder, and may
instead represent a risk factor.

Cumming et al. (2006) identified heterozygosity for the Y1584C variant
in 8 (25%) of 32 UK families and in 19 (17%) of 119 related individuals
with type 1 VWD. Eighteen (95%) of the 19 individuals were blood group
O. Heterozygosity for Y1584C segregated with VWD in 3 families, did not
segregate with VWD in 4 families, and showed equivocal results in 2
families. Cumming et al. (2006) concluded that Y1594C is a polymorphism
that is frequently associated with type 1 VWD, but shows incomplete
penetrance and does not consistently segregate with the disease. The
association with blood group type O may be related to the fact that both
blood group O and Y1584C are associated with increased proteolysis of
VWF by ADAMTS13.

.0030
VON WILLEBRAND DISEASE, TYPE 2M
VWF, SER1285PHE

In a French mother and son with VWD type 2M (see 613554), Stepanian et
al. (2003) identified a heterozygous 3854C-T transition in exon 28 of
the VWF gene, resulting in a ser1285-to-phe (S1285F) substitution in the
A1 loop of the protein. In vitro functional expression studies in COS-7
cells showed that the mutant VWF had markedly reduced ristocetin-induced
binding to platelets via GP1BA (606672), consistent with a loss of
function. The findings indicated that the S1285F mutation altered the
folding of the A1 loop and prevented the correct exposure of VWF binding
sites to GP1BA. Both patients had a moderate bleeding syndrome with
epistaxis and easy bruising. Laboratory studies showed mildly decreased
VWF antigen levels, normal multimers, and severely decreased VWF
functional activity. Factor VIII (F8; 300841) was mildly decreased and
platelet counts were normal.

.0031
VON WILLEBRAND DISEASE, TYPE 2N
VWF, TYR795CYS

In a French patient with VWD type 2N (see 613554), Hilbert et al. (2004)
identified compound heterozygosity for 2 mutations in the VWF gene: a
2384A-G transition in exon 18 resulting in a tyr795-to-cys (Y795C)
substitution in the D-prime domain, and R854Q (613160.0013). In vitro
functional expression assays showed that the mutant VWF protein had
decreased binding to factor VIII (300841), and resulted in an abnormal
multimeric pattern consistent with ultralarge multimers. Hilbert et al.
(2004) suggested that the effect on the cysteine residue may alter
protein conformation.

.0032
VON WILLEBRAND DISEASE, TYPE 2N
VWF, CYS804PHE

In a French patient with VWD type 2N (see 613554), Hilbert et al. (2004)
identified compound heterozygosity for 2 mutations in the VWF gene: a
2411G-T transversion in exon 18 resulting in a cys804-to-phe (C804F)
substitution in the D-prime domain, and R854Q (613160.0013). In vitro
functional expression assays showed that the mutant VWF protein had
decreased binding to factor VIII (300841), and resulted in an abnormal
multimeric pattern consistent with loss of ultralarge multimers. Hilbert
et al. (2004) suggested that the effect on the cysteine residue may
alter protein conformation.

.0033
VON WILLEBRAND DISEASE, TYPE 2B
WVF, PRO1266LEU

Goodeve (2010) noted that mutations in the VWF gene, which were
sometimes numbered from the transcription start site of the mature
protein, are now 'numbered from the first A of the ATG initiator
methionine codon (A = +1) at the start of every protein (Met = +1), with
cDNA rather than genomic DNA being commonly used as a reference
sequence.' Thus, the mutation originally designated PRO503LEU is now
designated PRO1266LEU (P1266L).

In affected members of a Swedish family (Holmberg et al., 1986) and a
German family with a variant of VWD type 2B (see 613554), Holmberg et
al. (1993) identified a heterozygous C-to-T transition in the VWF gene,
resulting in a pro503-to-leu (P503L) substitution in the mature subunit.
The phenotype was unique in that there was a mild bleeding disorder, and
laboratory studies showed that platelets aggregated at much lower
ristocetin concentrations than normal. The bleeding time was variously
prolonged, and VWF:Ag, VWF activity, and F8 were decreased. All VWF
multimers were present, and there was no thrombocytopenia. The defect in
this family, inherited as an autosomal dominant trait, resembled that of
type 2B because of the response to ristocetin, but differed because all
VWF multimers were present. Holmberg et al. (1986) referred to it as
'type 2 Malmo.' Weiss and Sussman (1985) reported a similarly affected
family, and referred to this variant as 'type I New York' (Sadler et
al., 2006). Wylie et al. (1988) also described this variant and noted
that there was no spontaneous aggregation of platelets.

Sadler et al. (2006) emphasized that this variant is a form of VWD type
2B with increased sensitivity to ristocetin in vivo.

.0034
VON WILLEBRAND DISEASE, TYPE 3
VWF, CYS2362PHE

In several patients from northern Italy with VWD type 3 (277430),
Eikenboom et al. (1998) identified a homozygous mutation in the VWF
gene, resulting in a cys2362-to-phe (C2362F) substitution. Haplotype
analysis indicated a founder effect.

Tjernberg et al. (2006) demonstrated that recombinant C2362F expressed
in 293T human kidney cells resulted in significantly decreased
expression of the mutant protein (8% of controls), although there was
similar production. The findings indicated increased intracellular
retention of the mutant protein. The mutant protein produced showed less
of the multimeric structure, suggesting that the loss of a cysteine on
an interchain bond impaired normal multimerization, since there was no
difference in subunit size from the wildtype. There was also no evidence
of a dominant-negative effect, suggesting that the ultimate effects of
the C2362F mutation were similar to that of a null allele.

.0035
VON WILLEBRAND DISEASE, TYPE 2N
VWF, TYR357TER

In a 20-year-old French woman with VWD type 2N (see 613554), Mazurier et
al. (2002) identified compound heterozygosity for 2 mutations in the VWF
gene: a 1071C-A transversion in exon 9, resulting in a tyr357-to-ter
(Y357X) substitution, and a 3178T-C transition in exon 24, resulting in
a cys1060-to-arg (C1060R; 613160.0036) substitution. The authors noted
that the Y357X mutation is a type 3 mutation (277480) presumably because
it represents a truncating mutation and lack of protein expression. The
patient had very low levels of VWF and F8, and absent binding of VWF to
F8. She had epistaxis, hematomas, and hematemesis throughout childhood.
The diagnosis was complicated at first because 2 male first cousins had
F8 deficiency (306700) due to a hemizygous mutation in the F8 gene
(C179G; 300841.0268).

.0036
VON WILLEBRAND DISEASE, TYPE 2N
VWF, CYS1060ARG

See 613160.0035 and Mazurier et al. (2002).

.0037
VON WILLEBRAND DISEASE, TYPE 2A
VWF, ASN528SER

In 3 Turkish boys, born of consanguineous parents, with VWD type 2A (see
613554), Haberichter et al. (2010) identified a homozygous 1583A-G
transition in exon 14 of the VWF gene, resulting in an asn528-to-ser
(N528S) substitution in the D2 domain of the propeptide. The phenotype
was characterized by significant mucocutaneous bleeding beginning in
childhood; 1 patient had joint bleeding. The patients had decreased
plasma and platelet VWF antigen and decreased platelet VWF binding to
collagen, with only slightly reduced F8 activity. There was a poor VWF
response to desmopressin infusion, indicating lack of VWF storage in
endothelial cells. The VWF multimer pattern lacked both high molecular
weight multimers and medium-sized multimers particularly severe in
platelets, consistent with VWD type 2A and the historical
subclassification of type IIC. In vitro functional expression studies in
mammalian cells showed that the N528S mutation introduced into a
full-length VWF expression vector resulted in decreased VWF secretion
(7.5% of controls) with an abnormal multimer pattern lacking both high
molecular weight and medium-sized multimers, and lack of proper
trafficking to storage granules. Detailed studies using coexpression of
the mutant and wildtype propeptide with mutant and wildtype full-length
VWF indicated a defective interaction of VWF with its intracellular
propeptide chaperone, resulting in loss of regulated storage of VWF.
Heterozygous expression of the mutant and wildtype alleles resulted in
normal VWF secretion and multimerization, confirming the recessive
nature of this mutation.

.0038
VON WILLEBRAND DISEASE, TYPE 3
VON WILLEBRAND DISEASE, TYPE 1, INCLUDED
VWF, 8.6-KB DEL, EX4-5

In 3 Caucasian British patients, including 2 sibs, with VWD type 3
(277480), Sutherland et al. (2009) identified a homozygous 8,631-bp
deletion in the VWF gene, resulting in an in-frame deletion of exons 4
and 5. The deletion spanned from within intron 3 to within intron 5, and
the breakpoints occurred in inverted AluY repeat elements. Analysis of
other patients with VWD type 3 showed that 4 were compound heterozygous
for the exon 4-5 deletion and another pathogenic mutation, and 1 was
heterozygous for the deletion but with no second mutation detected. In
total, 7 of 12 white patients with VWD type 3 carried this deletion,
which was not found in 9 patients of Asian origin. Haplotype analysis
confirmed a founder effect in the white British population.
Heterozygosity for this deletion was found in 2 of 34 probands with VWD
type 1 (193400), their affected family members, and 1 unaffected family
member, indicating reduced penetrance. An unrelated patient with VWD
type 1 was also found to carry a heterozygous deletion. In vitro
functional expression studies showed that the deletion resulted in
significantly decreased protein secretion, with a 98% decrease in the
homozygous state and an 86% decrease in the heterozygous state,
consistent with a dominant-negative effect. Expression of the homozygous
mutation, but not of the heterozygous mutation, resulted in defective
multimer production. The mutation was not found in 200 control alleles.

.0039
VON WILLEBRAND DISEASE, TYPE 2A/IIE
VWF, TYR1146CYS

In 12 (32%) of 38 probands with von Willebrand disease type 2A/IIE (see
613554), Schneppenheim et al. (2010) identified a heterozygous 3437A-C
transversion in exon 26 of the VWF gene, resulting in a tyr1146-to-cys
(Y1146C) substitution in the D3 domain. Plasma from patients showed
complete absence of large VWF multimers, and in vitro expression studies
indicated that the Y1146C-mutant protein caused a severe reduction in or
lack of high molecular weight monomers. and decreased secreted VWF
antigen levels. However, clinical symptoms were heterogeneous among
carriers, ranging from mild to severe bleeding. Schneppenheim et al.
(2010) suggested several mechanisms acting in concert, including
decreased secretion of VWF, the change affecting a cysteine residue
which may impact multimerization, and decreased half-life of the mutant
protein. Altered ADAMTS13-mediated proteolysis did not appear to be a
primary factor.

.0040
VON WILLEBRAND DISEASE, TYPE 2CB
VWF, TRP1745CYS

In an elderly woman with von Willebrand disease type 2CB (see 613554),
Riddell et al. (2009) identified compound heterozygosity for 2 mutations
in the VWF gene: a 5235G-T transversion in exon 30, resulting in a
trp1745-to-cys (W1745C) substitution in the A3 domain, and R760H
(613160.0041). She had a lifelong history of severe bleeding episodes,
including epistaxis, ecchymosis, menorrhagia, and bleeding after dental
extractions. The proband had 2 offspring, each of whom was heterozygous
for 1 of the mutations and showed minor bleeding symptoms not requiring
treatment. Both persons with the W1745C mutation had markedly reduced
ratios of VWF collagen-binding activity to VWF antigen (CB:Ag) against
type III collagen and type I collagen. There were normal values of
VWF:RCo to VWF:Ag (RCo:Ag), normal VWF multimer analysis, and normal
ristocetin-induced platelet aggregation. Treatment of the mother with
DDAVP resulted in a good functional response with a rise in VWF:CB
resulting from an overall increase in the amount of circulating VWF,
even though the qualitative defect in collagen binding remained. These
findings and in vitro expression studies indicated that the
W1745C-mutant protein caused a specific defect in collagen binding,
which Riddell et al. (2009) suggested represented a novel classification
subtype termed 'VWF 2CB.'

.0041
VON WILLEBRAND DISEASE, TYPE 1
VWF, ARG760HIS

In a patient with a mild bleeding tendency and laboratory studies
consistent with VWD type 1 (193400), Riddell et al. (2009) identified a
heterozygous 2279G-A transition in the VWF gene, resulting in an
arg760-to-his (R760H; 613160.0041) substitution. Laboratory studies
showed a concordant reduction in VWF:Ag, VWF:RCo, and VWF:CB, with a
normal multimer pattern.

.0042
VON WILLEBRAND DISEASE, TYPE 2CB
VWF, SER1783ALA

In a mother and son with VWD type 2CB (see 613554), Riddell et al.
(2009) identified a heterozygous 5347T-G transversion in exon 31 of the
VWF gene, resulting in a ser1783-to-ala (S1783A) substitution in the A3
domain. Laboratory studies showed normal VWF:Ag, VWF:RCo, and multimers,
but decreased binding to both collagen I and collagen III. Defective
collagen binding was confirmed by in vitro expression studies. Treatment
with DDAVP resulted in a good functional response with a rise in VWF:CB
resulting from an overall increase in the amount of circulating VWF,
even though the qualitative defect in collagen binding remained. These
findings indicated that the S1783A-mutant protein caused a specific
defect in collagen binding, which Riddell et al. (2009) suggested
represented a novel classification subtype termed 'VWF 2CB.'

*FIELD* SA
Bahou et al. (1988); Bonthron et al. (1986); Castaman et al. (1999);
Cumming et al. (1992); Fay et al. (1986); Ginsburg (1999); Hoyer
(1981); Mazurier et al. (1990); Meyer et al. (1978); Nachman et al.
(1980); Ngo et al. (1988); Ruggeri et al. (1982); Ruggeri and Zimmerman
(1980); Saba et al. (1985); Verweij et al. (1985)
*FIELD* RF
1. Andrews, R. K.; Booth, W. J.; Gorman, J. J.; Castaldi, P. A.; Berndt,
M. C.: Purification of botrocetin from Bothrops jararaca venom: analysis
of the botrocetin-mediated interaction between von Willebrand factor
and the human platelet membrane glycoprotein Ib-IX complex. Biochemistry 28:
8317-8326, 1989.

2. Bahou, W. F.; Bowie, E. J. W.; Fass, D. N.; Ginsburg, D.: Molecular
genetic analysis of porcine von Willebrand disease: tight linkage
to the von Willebrand factor locus. Blood 72: 308-313, 1988.

3. Barrow, L. L.; Simin, K.; Mohlke, K.; Nichols, W. C.; Ginsburg,
D.; Meisler, M. H.: Conserved linkage of neurotrophin-3 and von Willebrand
factor on mouse chromosome 6. Mammalian Genome 4: 343-345, 1993.

4. Bernardi, F.; Marchetti, G.; Guerra, S.; Casonato, A.; Gemmati,
D.; Patracchini, P.; Ballerini, G.; Conconi, F.: A de novo and heterozygous
gene deletion causing a variant of von Willebrand disease. Blood 75:
677-683, 1990.

5. Bodo, I.; Katsumi, A.; Tuley, E. A.; Eikenboom, J. C. J.; Dong,
Z.; Sadler, J. E.: Type 1 von Willebrand disease mutation cys1149-to-arg
causes intracellular retention and degradation of heterodimers: a
possible general mechanism for dominant mutations of oligomeric proteins. Blood 98:
2973-2979, 2001.

6. Bonthron, D.; Orr, E. C.; Mitsock, L. M.; Ginsburg, D.; Handin,
R. I.; Orkin, S. H.: Nucleotide sequence of pre-pro-von Willebrand
factor cDNA. Nucleic Acids Res. 14: 7125-7127, 1986.

7. Bonthron, D. T.; Handin, R. I.; Kaufman, R. J.; Wasley, L. C.;
Orr, E. C.; Mitsock, L. M.; Ewenstein, B.; Loscalzo, J.; Ginsburg,
D.; Orkin, S. H.: Structure of pre-pro-von Willebrand factor and
its expression in heterologous cells. Nature 324: 270-273, 1986.

8. Bowen, D. J.; Collins, P. W.: An amino acid polymorphism in von
Willebrand factor correlates with increased susceptibility to proteolysis
by ADAMTS13. Blood 103: 941-947, 2004.

9. Bowen, D. J.; Collins, P. W.; Lester, W.; Cumming, A. M.; Keeney,
S.; Grundy, P.; Enayat, S. M.; Bolton-Maggs, P. H. B.; Keeling, D.
M.; Khair, K.; Tait, R. C.; Wilde, J. T.; Pasi, K. J.; Hill, F. G.
: The prevalence of the cysteine 1584 variant of von Willebrand factor
is increased in type 1 von Willebrand disease: co-segregation with
increased susceptibility to ADAMTS13 proteolysis but not clinical
phenotype. Brit. J. Haemat. 128: 830-836, 2005.

10. Cao, W.; Krishnaswamy, S.; Camire, R. M.; Lenting, P. J.; Zheng,
X. L.: Factor VIII accelerates proteolytic cleavage of von Willebrand
factor by ADAMTS13. Proc. Nat. Acad. Sci. 105: 7416-7421, 2008.

11. Casonato, A.; Pontara, E.; Sartorello, F.; Cattini, M. G.; Sartori,
M. T.; Padrini, R.; Girolami, A.: Reduced von Willebrand factor survival
in type Vicenza von Willebrand disease. Blood 99: 180-184, 2002.

12. Castaman, G.; Eikenboom, J. C. J.; Bertina, R. M.; Rodeghiero,
F.: Inconsistency of association between type 1 von Willebrand disease
phenotype and genotype in families identified in an epidemiological
investigation. Thromb. Haemost. 82: 1065-1070, 1999.

13. Castaman, G.; Rodeghiero, F.; Mannucci, P. M.: The elusive pathogenesis
of von Willebrand disease Vicenza. (Letter) Blood 99: 4243-4244,
2002.

14. Collins, C. J.; Underdahl, J. P.; Levene, R. B.; Ravera, C. P.;
Morin, M. J.; Dombalagian, M. J.; Ricca, G.; Livingston, D. M.; Lynch,
D. C.: Molecular cloning of the human gene for von Willebrand factor
and identification of the transcription initiation site. Proc. Nat.
Acad. Sci. 84: 4393-4397, 1987.

15. Cooney, K. A.; Nichols, W. C.; Bruck, M. E.; Bahou, W. F.; Shapiro,
A. D.; Bowie, E. J. W.; Gralnick, H. R.; Ginsburg, D.: The molecular
defect in type IIB von Willebrand disease: identification of four
potential missense mutations within the putative GpIb binding domain. J.
Clin. Invest. 87: 1227-1233, 1991.

16. Cumming, A.; Grundy, P.; Keeney, S.; Lester, W.; Enayat, S.; Guilliatt,
A.; Bowen, D.; Pasi, J.; Keeling, D.; Hill, F.; Bolton-Maggs, P. H.;
Hay, C.; Collins, P. B.: An investigation of the von Willebrand factor
genotype in UK patients diagnosed to have type 1 von Willebrand disease. Thromb.
Haemost. 96: 630-641, 2006.

17. Cumming, A. M.; Armstrong, J. G.; Pendry, K.; Burn, A. M.; Wensley,
R. T.: Polymerase chain reaction amplification of two polymorphic
simple repeat sequences within the von Willebrand factor gene: application
to family studies in von Willebrand disease. Hum. Genet. 89: 194-198,
1992.

18. Denis, C.; Methia, N.; Frenette, P. S.; Rayburn, H.; Ullman-Cullere,
M.; Hynes, R. O.; Wagner, D. D.: A mouse model of severe von Willebrand
disease: defects in hemostasis and thrombosis. Proc. Nat. Acad. Sci. 95:
9524-9529, 1998.

19. Dent, J. A.; Berkowitz, S. D.; Ware, J.; Kasper, C. K.; Ruggeri,
Z. M.: Identification of a cleavage site directing the immunochemical
detection of molecular abnormalities in type IIA von Willebrand factor. Proc.
Nat. Acad. Sci. 87: 6306-6310, 1990. Note: Erratum: Proc. Nat. Acad.
Sci. 87: 9508 only, 1990.

20. Donner, M.; Andersson, A.-M.; Kristoffersson, A.-C.; Nilsson,
I. M.; Dahlback, B.; Holmberg, L.: An arg545-to-cys substitution
mutation of the von Willebrand factor in type IIB von Willebrand's
disease. Europ. J. Haemat. 47: 342-345, 1991.

21. Donner, M.; Kristoffersson, A. C.; Lenk, H.; Scheibel, E.; Dahlback,
B.; Nilsson, I. M.; Holmberg, L.: Type IIB von Willebrand's disease:
gene mutations and clinical presentation in nine families from Denmark,
Germany and Sweden. Brit. J. Haemat. 82: 58-65, 1992.

22. Eikenboom, J. C. J.; Castaman, G.; Vos, H. L.; Bertina, R. M.;
Rodeghiero, F.: Characterization of the genetic defects in recessive
type 1 and type 3 von Willebrand disease patients of Italian origin. Thromb.
Haemost. 79: 709-717, 1998.

23. Eikenboom, J. C. J.; Matsushita, T.; Reitsma, P. H.; Tuley, E.
A.; Castaman, G.; Briet, E.; Sadler, J. E.: Dominant type 1 von Willebrand
disease caused by mutated cysteine residues in the D3 domain of von
Willebrand factor. Blood 88: 2433-2441, 1996.

24. Eikenboom, J. C. J.; Vink, T.; Briet, E.; Sixma, J. J.; Reitsma,
P. H.: Multiple substitutions in the von Willebrand factor gene that
mimic the pseudogene sequence. Proc. Nat. Acad. Sci. 91: 2221-2224,
1994.

25. Fay, P. J.; Kawai, Y.; Wagner, D. D.; Ginsburg, D.; Bonthron,
D.; Ohlsson-Wilhelm, B. M.; Chavin, S. I.; Abraham, G. N.; Handin,
R. I.; Orkin, S. H.; Montgomery, R. R.; Marder, V. J.: Propolypeptide
of von Willebrand factor circulates in blood and is identical to von
Willebrand antigen II. Science 232: 995-998, 1986.

26. Flood, V. H.; Gill, J. C.; Morateck, P. A.; Christopherson, P.
A.; Friedman, K. D.; Haberichter, S. L.; Branchford, B. R.; Hoffmann,
R. G.; Abshire, T. C.; Di Paola, J. A.; Hoots, W. K; Leissinger, C.;
Lusher, J. M.; Ragni, M. V.; Shapiro, A. D.; Montgomery, R. R. Common
VWF exon 28 polymorphisms in African Americans affecting the VWF activity
assay by ristocetin cofactor. Blood 116: 280-286, 2010.

27. Gaucher, C.; Hanss, M.; Dechavanne, M.; Mazurier, C.: Substitution
of cysteine for phenylalanine 751 in mature von Willebrand factor
is a novel candidate mutation in a family with type IIA von Willebrand
disease. Brit. J. Haemat. 83: 94-99, 1993.

28. Gaucher, C.; Jorieux, S.; Mercier, B.; Oufkir, D.; Mazurier, C.
: The 'Normandy' variant of von Willebrand disease: characterization
of a point mutation in the von Willebrand factor gene. Blood 77:
1937-1941, 1991.

29. Gaucher, C.; Mercier, B.; Jorieux, S.; Oufkir, D.; Mazurier, C.
: Identification of two point mutations in the von Willebrand factor
gene of three families with the 'Normandy' variant of von Willebrand
disease. Brit. J. Haemat. 78: 506-514, 1991.

30. Ginsburg, D.: Molecular genetics of von Willebrand disease. Thromb.
Haemat. 82: 585-591, 1999.

31. Ginsburg, D.; Handin, R. I.; Bonthron, D. T.; Donlon, T. A.; Bruns,
G. A. P.; Latt, S. A.; Orkin, S. H.: Human von Willebrand factor
(vWF): isolation of complementary DNA (cDNA) clones and chromosomal
localization. Science 228: 1401-1406, 1985.

32. Ginsburg, D.; Konkle, B. A.; Gill, J. C.; Montgomery, R. R.; Bockenstedt,
P. L.; Johnson, T. A.; Yang, A. Y.: Molecular basis of human von
Willebrand disease: analysis of platelet von Willebrand factor mRNA. Proc.
Nat. Acad. Sci. 86: 3723-3727, 1989.

33. Ginsburg, D.; Sadler, J. E.: Von Willebrand disease: a database
of point mutations, insertions, and deletions. Thromb. Haemost. 69:
177-184, 1993.

34. Golder, M.; Pruss, C. M.; Hegadorn, C.; Mewburn, J.; Laverty,
K.; Sponagle, K.; Lillicrap, D.: Mutation-specific hemostatic variability
in mice expressing common type 2B von Willebrand disease substitutions. Blood 115:
4862-4869, 2010.

35. Goodeve, A. C.: The genetic basis of von Willebrand disease. Blood
Rev. 24: 123-134, 2010.

36. Haberichter, S. L.; Budde, U.; Obser, T.; Schneppenheim, S.; Wermes,
C.; Schneppenheim, R.: The mutation N528S in the von Willebrand factor
(VWF) propeptide causes defective multimerization and storage of VWF. Blood 115:
4580-4587, 2010.

37. Hagiwara, T.; Inaba, H.; Yoshida, S.; Nagaizumi, K.; Arai, M.;
Hanabusa, H.; Fukutake, K.: A novel mutation gly1672-to-arg in type
2A and a homozygous mutation in type 2B von Willebrand disease. Thromb.
Haemost. 76: 253-257, 1996.

38. Hilbert, L.; Jorieux, S.; Fontenay-Roupie, M.; Guicheteau, M.;
Fressinaud, E.; Meyer, D.; Mazurier, C.; the INSERM Network on Molecular
Abnormalities in von Willebrand Disease: Expression of two type
2N von Willebrand disease mutations identified in exon 18 of von Willebrand
factor gene. Brit. J. Haematol. 127: 184-189, 2004.

39. Holmberg, L.; Berntorp, E.; Donner, M.; Nilsson, I. M.: von Willebrand's
disease characterised by increased ristocetin sensitivity and the
presence of all von Willebrand factor multimers. Blood 68: 668-672,
1986.

40. Holmberg, L.; Dent, J. A.; Schneppenheim, R.; Budde, U.; Ware,
J.; Ruggeri, Z. M.: von Willebrand factor mutation enhancing interaction
with platelets in patients with normal multimeric structure. J. Clin.
Invest. 91: 2169-2177, 1993.

41. Holmberg, L.; Karpman, D.; Isaksson, C.; Kristoffersson, A. C.;
Lethagen, S.; Schneppenheim, R.: Ins405-asn-pro mutation in the von
Willebrand factor propeptide in recessive type 2A (IIC) von Willebrand's
disease. Thromb. Haemost. 79: 718-722, 1998.

42. Howard, M. A.; Perkin, J.; Salem, H. H.; Firkin, B. G.: The agglutination
of human platelets by botrocetin: evidence that botrocetin and ristocetin
act at different sites on the factor VIII molecule and platelet membrane. Brit.
J. Haemat. 57: 25-35, 1984.

43. Hoyer, L. W.: The factor VIII complex: structure and function. Blood 58:
1-13, 1981.

44. Huizinga, E. G.; Tsuji, S.; Romijn, R. A. P.; Schiphorst, M. E.;
de Groot, P. G.; Sixma, J. J.; Gros, P.: Structures of glycoprotein
Ib-alpha and its complex with von Willebrand factor A1 domain. Science 297:
1176-1179, 2002.

45. Iannuzzi, M. C.; Hidaka, N.; Boehnke, M.; Bruck, M. E.; Hanna,
W. T.; Collins, F. S.; Ginsburg, D.: Analysis of the relationship
of von Willebrand disease (vWD) and hereditary hemorrhagic telangiectasia
and identification of a potential type IIA vWD mutation (ile865-to-thr). Am.
J. Hum. Genet. 48: 757-763, 1991.

46. Jackson, S. C.; Sinclair, G. D.; Cloutier, S.; Duan, Z.; Rand,
M. L.; Poon, M.-C.: The Montreal platelet syndrome kindred has type
2B von Willebrand disease with the VWF V1316M mutation. Blood 113:
3348-3351, 2009.

47. Kokame, K.; Matsumoto, M.; Fujimura, Y.; Miyata, T.: VWF73, a
region from D1596 to R1668 of von Willebrand factor, provides a minimal
substrate for ADAMTS-13. Blood 103: 607-612, 2004.

48. Kyrle, P. A.; Niessner, H.; Dent, J.; Panzer, S.; Brenner, B.;
Zimmerman, T. S.; Lechner, K.: IIB von Willebrand's disease: pathogenetic
and therapeutic studies. Brit. J. Haemat. 69: 55-59, 1988.

49. Lavergne, J.-M.; De Paillette, L.; Bahnak, B. R.; Ribba, A.-S.;
Fressinaud, E.; Meyer, D.; Pietu, G.: Defects in type IIA von Willebrand
disease: a cysteine 509 to arginine substitution in the mature von
Willebrand factor disrupts a disulphide loop involved in the interaction
with platelet glycoprotein Ib-IX. Brit. J. Haemat. 82: 66-72, 1992.

50. Lester, W. A.; Guilliatt, A. M.; Surdhar, G. K.; Enayat, S. M.;
Wilde, J. T.; Willoughby, S.; Grundy, P.; Cumming, A. M.; Collins,
P. W.; Hill, F. G. H.: Inherited and de novo von Willebrand disease
'Vicenza' in UK families with the R1205H mutation: diagnostic pitfalls
and new insights. Brit. J. Haemat. 135: 91-96, 2006.

51. Lynch, D. C.; Zimmerman, T. S.; Collins, C. J.; Morin, M. J.;
Ling, E. H.; Livingston, D. M.: Molecular cloning of mRNA for human
von Willebrand factor. (Abstract) Clin. Res. 33: 548, 1985.

52. Lynch, D. C.; Zimmerman, T. S.; Ruggeri, Z. M.: Von Willebrand
factor, now cloned. (Annotation). Brit. J. Haemat. 64: 15-20, 1986.

53. Mancuso, D. J.; Tuley, E. A.; Westfield, L. A.; Lester-Mancuso,
T. L.; Le Beau, M. M.; Sorace, J. M.; Sadler, J. E.: Human von Willebrand
factor gene and pseudogene: structural analysis and differentiation
by polymerase chain reaction. Biochemistry 30: 253-269, 1991.

54. Mancuso, D. J.; Tuley, E. A.; Westfield, L. A.; Worrall, N. K.;
Shelton-Inloes, B. B.; Sorace, J. M.; Alevy, Y. G.; Sadler, J. E.
: Structure of the gene for human von Willebrand factor. J. Biol.
Chem. 264: 19514-19527, 1989.

55. Mannucci, P. M.; Lombardi, R.; Castaman, G.; Dent, J. A.; Lattuada,
A.; Rodeghiero, F.; Zimmerman, T. S.: Von Willebrand disease 'Vicenza'
with larger-than-normal (supranormal) von Willebrand factor multimers. Blood 71:
65-70, 1988.

56. Mazurier, C.; Dieval, J.; Jorieux, S.; Delobel, J.; Goudemand,
M.: A new von Willebrand factor (vWF) defect in a patient with factor
VIII (FVIII) deficiency but with normal levels and multimeric patterns
of both plasma and platelet vWF: characterization of abnormal vWF/FVIII
interaction. Blood 75: 20-26, 1990.

57. Mazurier, C.; Gaucher, C.; Jorieux, S.; Parquet-Gernez, A.; Goudemand,
M.: Evidence for a von Willebrand factor defect in factor VIII binding
in three members of a family previously misdiagnosed mild haemophilia
A and haemophilia A carriers: consequences for therapy and genetic
counselling. Brit. J. Haemat. 76: 372-379, 1990.

58. Mazurier, C.; Parquet-Gernez, A.; Gaucher, C.; Lavergne, J.-M.;
Goudemand, J.: Factor VIII deficiency not induced by FVIII gene mutation
in a female first cousin of two brothers with haemophilia A. Brit.
J. Haemat. 119: 390-392, 2002.

59. Mertes, G.; Ludwig, M.; Schwaab, R.; Brackmann, H.-H.; Olek, K.
: Delta-C in exon 18 of the von Willebrand gene is uncommon in German
VWD type III patients. (Letter) Semin. Thromb. Hemost. 19: 1064-1065,
1993.

60. Meyer, D.; McKee, P. A.; Hoyer, L. W.; Zimmerman, T. S.; Gralnick,
H. R.: Molecular biology of factor VIII--von Willebrand factor. Thromb.
Haemost. 40: 245-251, 1978.

61. Michaux, G.; Abbitt, K. B.; Collinson, L. M.; Haberichter, S.
L.; Norman, K. E.; Cutler, D. F.: The physiological function of von
Willebrand's factor depends on its tubular storage in endothelial
Weibel-Palade bodies. Dev. Cell 10: 223-232, 2006.

62. Milton, J. G.; Frojmovic, M. M.; Tang, S. S.; White, J. G.: Spontaneous
platelet aggregation in a hereditary giant platelet syndrome (MPS). Am.
J. Path. 114: 336-345, 1984.

63. Murray, E. W.; Giles, A. R.; Lillicrap, D.: Germ-line mosaicism
for a valine-to-methionine substitution at residue 553 in the glycoprotein
Ib-binding domain of von Willebrand factor, causing type IIB von Willebrand
disease. Am. J. Hum. Genet. 50: 199-207, 1992.

64. Nachman, R. L.; Jaffe, E. A.; Miller, C.; Brown, W. T.: Structural
analysis of factor VIII antigen in von Willebrand disease. Proc.
Nat. Acad. Sci. 77: 6832-6836, 1980.

65. Ngo, K. Y.; Glotz, V. T.; Koziol, J. A.; Lynch, D. C.; Gitschier,
J.; Ranieri, P.; Ciavarella, N.; Ruggeri, Z. M.; Zimmerman, T. S.
: Homozygous and heterozygous deletions of the von Willebrand factor
gene in patients and carriers of severe von Willebrand disease. Proc.
Nat. Acad. Sci. 85: 2753-2757, 1988.

66. NIH/CEPH Collaborative Mapping Group: A comprehensive genetic
linkage map of the human genome. Science 258: 67-86, 1992.

67. O'Brien, L. A.; James, P. D.; Othman, M.; Berber, E.; Cameron,
C.; Notley, C. R. P.; Hegadorn, C. A.; Sutherland, J. J.; Hough, C.;
Rivard, G. E.; O'Shaunessey, D.; Association of Hemophilia Clinic
Directors of Canada; Lillicrap, D.: Founder von Willebrand factor
haplotype associated with type I von Willebrand disease. Blood 102:
549-557, 2003.

68. Patracchini, P.; Marchetti, G.; Aiello, V.; Croci, G.; Calzolari,
E.; Bernardi, F.: Characterization and mapping of the 5-prime portion
of von Willebrand factor pseudogene. Hum. Genet. 90: 297-298, 1992.

69. Peake, I. R.; Liddell, M. B.; Moodie, P.; Standen, G.; Mancuso,
D. J.; Tuley, E. A.; Westfield, L. A.; Sorace, J. M.; Sadler, J. E.;
Verweij, C. L.; Bloom, A. L.: Severe type III von Willebrand's disease
caused by deletion of exon 42 of the von Willebrand factor gene: family
studies that identify carriers of the condition and a compound heterozygous
individual. Blood 75: 654-661, 1990.

70. Peerlinck, K.; Eikenboom, J. C. J.; Ploos Van Amstel, H. K.; Sangtawesin,
W.; Arnout, J.; Reitsma, P. H.; Vermylen, J.; Briet, E.: A patient
with von Willebrand's disease characterized by a compound heterozygosity
for a substitution of arg-854 by gln in the putative factor-VIII-binding
domain of von Willebrand factor (vWF) on one allele and very low levels
of mRNA from the second vWF allele. Brit. J. Haemat. 80: 358-363,
1992.

71. Rabinowitz, I.; Tuley, E. A.; Mancuso, D. J.; Randi, A. M.; Firkin,
B. G.; Howard, M. A.; Sadler, J. E.: Von Willebrand disease type
B: a missense mutation selectively abolishes ristocetin-induced von
Willebrand factor binding to platelet glycoprotein Ib. Proc. Nat.
Acad. Sci. 89: 9846-9849, 1992.

72. Randi, A. M.; Rabinowitz, I.; Mancuso, D. J.; Mannucci, P. M.;
Sadler, J. E.: Molecular basis of von Willebrand disease type IIB:
candidate mutations cluster in one disulfide loop between proposed
platelet glycoprotein Ib binding sequences. J. Clin. Invest. 87:
1220-1226, 1991.

73. Randi, A. M.; Sacchi, E.; Castaman, G. C.; Rodeghiero, F.; Mannucci,
P. M.: The genetic defect of type I von Willebrand disease 'Vicenza'
is linked to the von Willebrand factor gene. Thromb. Haemost. 69:
173-176, 1993.

74. Rayes, J.; Hollestelle, M. J.; Legendre, P.; Marx, I.; de Groot,
P. G.; Christophe, O. D.; Lenting, P. J.; Denis, C. V.: Mutation
and ADAMTS13-dependent modulation of disease severity in a mouse model
for von Willebrand disease type 2B. Blood 115: 4870-4877, 2010.

75. Riddell, A. F.; Gomez, K.; Millar, C. M.; Mellars, G.; Gill, S.;
Brown, S. A.; Sutherland, M.; Laffan, M. A.; McKinnon, T. A.: Characterization
of W1745C and S1783A: 2 novel mutations causing defective collagen
binding in the A3 domain of von Willebrand factor. Blood 114: 3489-3496,
2009.

76. Ruggeri, Z. M.: Von Willebrand factor. J. Clin. Invest. 99:
559-564, 1997. Note: Erratum: J. Clin. Invest. 100: 237 only, 1997.

77. Ruggeri, Z. M.; Lombardi, R.; Gatti, L.; Bader, R.; Valsecchi,
C.; Zimmerman, T. S.: Type IIB von Willebrand's disease: differential
clearance of endogenous versus transfused large multimer von Willebrand
factor. Blood 60: 1453-1456, 1982.

78. Ruggeri, Z. M.; Nilsson, I. M.; Lombardi, R.; Holmberg, L.; Zimmerman,
T. S.: Aberrant multimeric structure of von Willebrand factor in
a new variant of von Willebrand's disease (type IIC). J. Clin. Invest. 70:
1124-1127, 1982.

79. Ruggeri, Z. M.; Pareti, F. I.; Mannucci, P. M.; Ciavarella, N.;
Zimmerman, T. S.: Heightened interaction between platelets and factor
VIII von Willebrand factor in a new subtype of von Willebrand's disease. New
Eng. J. Med. 302: 1047-1051, 1980.

80. Ruggeri, Z. M.; Zimmerman, T. S.: Variant von Willebrand's disease:
characterization of two subtypes by analysis of multimeric composition
of factor VIII-von Willebrand factor in plasma and platelets. J.
Clin. Invest. 65: 1318-1325, 1980.

81. Saba, H. I.; Saba, S. R.; Dent, J.; Ruggeri, Z. M.; Zimmerman,
T. S.: Type IIB Tampa: a variant of von Willebrand disease with chronic
thrombocytopenia, circulating platelet aggregates, and spontaneous
platelet aggregation. Blood 66: 282-286, 1985.

82. Sadler, J. E.; Budde, U.; Eikenboom, J. C. J.; Favaloro, E. J.;
Hill, F. G. H.; Holmberg, L.; Ingerslev, J.; Lee, C. A.; Lillicrap,
D.; Mannucci, P. M.; Mazurier, C.; Meyer, D.; and 9 others: Update
on the pathophysiology and classification of von Willebrand disease:
a report of the Subcommittee on von Willebrand Factor. J. Thromb.
Haemost. 4: 2103-2114, 2006.

83. Sadler, J. E.; Ginsburg, D.: A database of polymorphisms in the
von Willebrand factor gene and pseudogene. Thromb. Haemost. 69:
185-191, 1993.

84. Sadler, J. E.; Shelton-Inloes, B. B.; Sorace, J. M.; Harlan, J.
M.; Titani, K.; Davie, E. W.: Cloning and characterization of two
cDNAs coding for human von Willebrand factor. Proc. Nat. Acad. Sci. 82:
6394-6398, 1985.

85. Schneppenheim, R.; Brassard, J.; Krey, S.; Budde, U.; Kunicki,
T. J.; Holmberg, L.; Ware, J.; Ruggeri, Z. M.: Defective dimerization
of von Willebrand factor subunits due to a cys-to-arg mutation in
type IID von Willebrand disease. Proc. Nat. Acad. Sci. 93: 3581-3586,
1996.

86. Schneppenheim, R.; Federici, A. B.; Budde, U.; Castaman, G.; Drewke,
E.; Krey, S.; Mannucci, P. M.; Riesen, G.; Rodeghiero, F.; Zieger,
B.; Zimmermann, R.: Von Willebrand disease type 2M 'Vicenza' in Italian
and German patients: identification of the first candidate mutation
(G3864A; R1205H) in 8 families. Thromb. Haemost. 82: 136-140, 2000.

87. Schneppenheim, R.; Michiels, J. J.; Obser, T.; Oyen, F.; Pieconka,
A.; Schneppenheim, S.; Will, K.; Zieger, B.; Budde, U. A cluster
of mutations in the D3 domain of von Willebrand factor correlates
with a distinct subgroup of von Willebrand disease: type 2A/IIE. Blood 115:
4894-4901, 2010.

88. Schneppenheim, R.; Thomas, K. B.; Krey, S.; Budde, U.; Jessat,
U.; Sutor, A. H.; Zieger, B.: Identification of a candidate missense
mutation in a family with von Willebrand disease type IIC. Hum. Genet. 95:
681-686, 1995.

89. Shelton-Inloes, B. B.; Chehab, F. F.; Mannucci, P. M.; Federici,
A. B.; Sadler, J. E.: Gene deletions correlate with the development
of alloantibodies in von Willebrand disease. J. Clin. Invest. 79:
1459-1465, 1987.

90. Sporn, L. A.; Marder, V. J.; Wagner, D. D.: Von Willebrand factor
released from Weibel-Palade bodies binds more avidly to extracellular
matrix than that secreted constitutively. Blood 69: 1531-1534, 1987.

91. Stepanian, A.; Ribba, A.-S.; Lavergne, J.-M.; Fressinaud, E.;
Juhan-Vague, I.; Mazurier, C.; Girma, J.-P.; Meyer, D.: A new mutation,
S1285F, within the A1 loop of von Willebrand factor induces a conformational
change in A1 loop with abnormal binding to platelet GPIb and botrocetin
causing type 2M von Willebrand disease. Brit. J. Haemat. 120: 643-651,
2003.

92. Sutherland, M. S.; Cumming, A. M.; Bowman, M.; Bolton-Maggs, P.
H. B.; Bowen, D. J.; Collins, P. W.; Hay, C. R. M.; Will, A. M.; Keeney,
S.: A novel deletion mutation is recurrent in von Willebrand disease
types 1 and 3. Blood 114: 1091-1098, 2009.

93. Titani, K.; Kumar, S.; Takio, K.; Ericsson, L. H.; Wade, R. D.;
Ashida, K.; Walsh, K. A.; Chopek, M. W.; Sadler, J. E.; Fujikawa,
K.: Amino acid sequence of human von Willebrand factor. Biochemistry 25:
3171-3184, 1986.

94. Tjernberg, P.; Castaman, G.; Vos, H. L.; Bertina, R. M.; Eikenboom,
J. C.: Homozygous C2362F von Willebrand factor induces intracellular
retention of mutant von Willebrand factor resulting in autosomal recessive
severe von Willebrand disease. Brit. J. Haemat. 133: 409-418, 2006.

95. Tuley, E. A.; Gaucher, C.; Jorieux, S.; Worrall, N. K.; Sadler,
J. E.; Mazurier, C.: Expression of von Willebrand factor 'Normandy':
an autosomal mutation that mimics hemophilia A. Proc. Nat. Acad.
Sci. 88: 6377-6381, 1991.

96. Verweij, C. L.; de Vries, C. J. M.; Distel, B.; van Zonneveld,
A.-J.; Geurts van Kessel, A.; van Mourik, J. A.; Pannekoek, H.: Construction
of cDNA coding for human von Willebrand factor using antibody probes
for colony-screening and mapping of the chromosomal gene. Nucleic
Acids Res. 13: 4699-4717, 1985.

97. Verweij, C. L.; Hofker, M.; Quadt, R.; Briet, E.; Pannekoek, H.
: RFLP for a human von Willebrand factor (vWF) cDNA clone, pvWF1100. Nucleic
Acids Res. 13: 8289 only, 1985. Note: Erratum: Nucleic Acids Res.
14: 1930 only, 1986.

98. von Willebrand, E. A.: Hereditar pseudohemofili. Finska Lakar.
Hand. 68: 87-112, 1926.

99. Wagner, D. D.; Saffaripour, S.; Bonfanti, R.; Sadler, J. E.; Cramer,
E. M.; Chapman, B.; Mayadas, T. N.: Induction of specific storage
organelles by von Willebrand factor propolypeptide. Cell 64: 403-413,
1991.

100. Ware, J.; Dent, J. A.; Azuma, H.; Sugimoto, M.; Kyrle, P. A.;
Yoshioka, A.; Ruggeri, Z. M.: Identification of a point mutation
in type IIB von Willebrand disease illustrating the regulation of
von Willebrand factor affinity for the platelet membrane glycoprotein
Ib-IX receptor. Proc. Nat. Acad. Sci. 88: 2946-2950, 1991.

101. Weiss, J. G.; Sussman, I. I.: Increased ristocetin-induced platelet
aggregation (RIPA) and plasma von Willebrand factor (VWF) containing
all VWF multimers (type I--New York). Blood 66 (suppl. 1): 329,
1985.

102. Wise, R. J.; Ewenstein, B. M.; Gorlin, J.; Narins, S. C.; Jesson,
M.; Handin, R. I.: Autosomal recessive transmission of hemophilia
A due to a von Willebrand factor mutation. Hum. Genet. 91: 367-372,
1993.

103. Wu, J.-J.; Fujikawa, K.; McMullen, B. A.; Chung, D. W.: Characterization
of a core binding site for ADAMTS-13 in the A2 domain of von Willebrand
factor. Proc. Nat. Acad. Sci. 103: 18470-18474, 2006.

104. Wylie, B.; Gibson, J.; Uhr, E.; Kronenberg, H.: Von Willebrand's
disease characterized by increased ristocetin sensitivity and the
presence of all von Willebrand factor multimers in plasma: a new subtype. Pathology 20:
62-63, 1988.

105. Zhang, Z. P.; Blomback, M.; Nyman, D.; Anvret, M.: Mutations
of von Willebrand factor gene in families with von Willebrand disease
in the Aland Islands. Proc. Nat. Acad. Sci. 90: 7937-7940, 1993.

106. Zhang, Z. P.; Falk, G.; Blomback, M.; Egberg, N.; Anvret, M.
: Identification of a new nonsense mutation in the von Willebrand
factor gene in patients with von Willebrand disease type III. Hum.
Molec. Genet. 1: 61-62, 1992.

107. Zhang, Z. P.; Falk, G.; Blomback, M.; Egberg, N.; Anvret, M.
: A single cytosine deletion in exon 18 of the von Willebrand factor
gene is the most common mutation in Swedish vWD type III patients. Hum.
Molec. Genet. 1: 767-768, 1992.

108. Zhang, Z. P.; Lindstedt, M.; Falk, G.; Blomback, M.; Egberg,
N.; Anvret, M.: Nonsense mutations of the von Willebrand factor gene
in patients with von Willebrand disease type III and type I. Am.
J. Hum. Genet. 51: 850-858, 1992.

109. Zieger, B.; Budde, U.; Jessat, U.; Zimmermann, R.; Simon, M.;
Katzel, R.; Sutor, A. H.: New families with von Willebrand disease
type 2M (Vicenza). Thromb. Res. 87: 57-64, 1997.

*FIELD* CN
Cassandra L. Kniffin - updated: 4/29/2013
Cassandra L. Kniffin - updated: 5/10/2011
Cassandra L. Kniffin - updated: 12/27/2010
Cassandra L. Kniffin - updated: 10/8/2010

*FIELD* CD
Cassandra L. Kniffin: 12/1/2009

*FIELD* ED
alopez: 05/03/2013
ckniffin: 4/29/2013
carol: 4/18/2013
terry: 4/4/2013
terry: 8/9/2012
carol: 7/6/2011
wwang: 6/13/2011
ckniffin: 5/10/2011
carol: 4/7/2011
terry: 1/7/2011
wwang: 1/5/2011
ckniffin: 12/27/2010
wwang: 11/2/2010
ckniffin: 10/8/2010
carol: 10/5/2010
carol: 10/4/2010
ckniffin: 9/29/2010
ckniffin: 12/4/2009

MIM 613554
*RECORD*
*FIELD* NO
613554
*FIELD* TI
#613554 VON WILLEBRAND DISEASE, TYPE 2; VWD2
;;VON WILLEBRAND DISEASE, TYPE II;;
VWD, TYPE 2
read moreVON WILLEBRAND DISEASE, TYPE 2A, INCLUDED; VWD2A, INCLUDED;;
VON WILLEBRAND DISEASE, TYPE 2B, INCLUDED; VWD2B, INCLUDED;;
VON WILLEBRAND DISEASE, TYPE 2M, INCLUDED; VWD2M, INCLUDED;;
VON WILLEBRAND DISEASE, TYPE 2N, INCLUDED; VWD2N, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because von Willebrand disease
(VWD) type 2 is caused by mutation in the gene encoding von Willebrand
factor (VWF; 613160), which maps to chromosome 12p13.

DESCRIPTION

Von Willebrand disease is the most common inherited bleeding disorder.
It is characterized clinically by mucocutaneous bleeding, such as
epistaxis and menorrhagia, and prolonged bleeding after surgery or
trauma. It results from a defect in platelet aggregation due to defects
in the von Willebrand factor. Von Willebrand factor is a large,
multimeric protein that plays a role in platelet adhesion and also
serves as a carrier for the thrombotic protein factor VIII (F8; 300841).
F8 is mutated in hemophilia A (306700) (review by Goodeve, 2010).

Whereas von Willebrand disease types 1 (193400) and 3 (277480) are
characterized by quantitative defects in the VWF gene, von Willebrand
disease type 2, which is divided in subtypes 2A, 2B, 2M, and 2N, is
characterized by qualitative abnormalities of the VWF protein. The
mutant VWF protein in types 2A, 2B, and 2M are defective in their
platelet-dependent function, whereas the mutant protein in type 2N is
defective in its ability to bind F8. VWD2 accounts for 20 to 30% of
cases of VWD (Mannucci, 2004; Sadler et al., 2006; Lillicrap, 2009;
Goodeve, 2010).

For a general discussion and a classification of the types of von
Willebrand disease, see VWD type 1 (193400).

CLINICAL FEATURES

Von Willebrand disease type 2, like VWD type 1, is characterized by
excessive mucocutaneous bleeding, such as epistaxis and menorrhagia, and
prolonged bleeding after surgery (Mannucci, 2004). The delineation of
different subtypes of VWD type 2 does not reflect clinical differences,
but rather different mutant VWF protein phenotypes, which may affect
diagnosis, treatment, and counseling (Sadler et al., 2006).

INHERITANCE

Inheritance of VWD type 2 is generally autosomal dominant, although some
cases are characterized by autosomal recessive transmission (Mannucci,
2004).

PATHOGENESIS

- Von Willebrand Disease Type 2A

The mutant VWF protein in von Willebrand disease type 2A has decreased
platelet adhesion due to a selective deficiency of high molecular weight
multimers. The decrease in large multimers can be due to (1) a failure
to synthesize the multimers ('group 1') or (2) enhanced ADAMTS13
(604134)-mediated proteolysis of the secreted high molecular weight
protein ('group 2'). Regardless of mechanism in type 2A, the loss of
large multimers is associated with decreased VWF-platelet interactions
and/or decreased VWF-connective tissue interactions (reviews by Sadler
et al., 2006 and Lillicrap, 2009).

Historically, type 2A was subclassified into types IIA, IIC, IID, and
IIE. The mutant VWF in type IIA showed increased proteolysis by
ADAMTS13; type IIC showed impaired multimerization in the Golgi
apparatus due to mutation in the VWF propeptide (Zimmerman and Ruggeri,
1987); type IID showed impaired dimerization in the endoplasmic
reticulum due to mutations in the C-terminal domain; and type IIE showed
impaired intersubunit disulfide bond formation in the Golgi apparatus
(Sadler et al., 2006) and a lack of outer proteolytic bands on gel
electrophoresis, indicating reduced proteolysis (Zimmerman et al.,
1986). All these subtypes showed dominant inheritance except for IIC,
which showed recessive inheritance. These subtypes of type 2A are no
longer used because the discrimination has not shown clinical utility;
all are now referred to as type 2A (Sadler et al., 2006).

Gralnick et al. (1985) found that in VWD type 2A, inhibition of a
calcium-dependent protease in vitro resulted in correction of the
abnormal multimeric structure. This suggested that an abnormal VWF
protein synthesized in this disorder is susceptible to proteolytic
degradation, a process which may play an important role in phenotypic
expression of the disease.

- Von Willebrand Disease Type 2B

The mutant VWF protein in VWD type 2B shows increased affinity to
platelet GP1BA (606672), resulting in increased platelet aggregation,
and increased proteolysis of VWF subunits causing a decrease of large
VWF multimers. Patients often have secondary thrombocytopenia due to
platelet consumption (Sadler et al., 2006).

Othman and Favaloro (2008) reviewed the complexity of VWD type 2B,
noting that atypical forms with complete VWF monomers, no mutations in
the A1 domain, or with giant platelets have also been reported,
suggesting the presence of phenotypic modifiers.

Saba et al. (1985) found chronic thrombocytopenia, in vivo platelet
aggregate formation, and spontaneous platelet aggregation in vitro in
affected members of a family with VWD type 2B. The 4 affected family
members identified were a man and 2 sons and a daughter by 2 different
wives.

Holmberg et al. (1986) reported a Swedish family in which 8 members had
a variant of VWD type 2B, referred to as 'type 2 Malmo.' There was a
mild bleeding disorder, and laboratory studies showed that platelets
aggregated at much lower ristocetin concentrations than normal. The
bleeding time was variously prolonged, and VWF:Ag, VWF activity, and F8
were decreased. All VWF multimers were present, and there was no
thrombocytopenia. The defect in this family, inherited as an autosomal
dominant, resembled that of type 2B because of the response to
ristocetin, but differed because all VWF multimers were present. Weiss
and Sussman (1986) reported a similarly affected family, and referred to
this variant as 'type I New York' (Sadler et al., 2006). Wylie et al.
(1988) also described this variant and noted that there was no
spontaneous aggregation of platelets. Holmberg et al. (1993) reviewed
the family reported by Holmberg et al. (1986) and reported another
affected German family. Affected individuals had only mild bleeding.
Sadler et al. (2006) emphasized that the variant reported by Wylie et
al. (1988) and others was a form of VWD type 2B, with increased
sensitivity to ristocetin in vivo.

Donner et al. (1987) described 2 families with an apparently autosomal
recessive form of type 2B von Willebrand disease. The patients presented
in infancy with thrombocytopenia.

Murray et al. (1991) found evidence of gonadal mosaicism in the father
of 2 sibs with VWD type 2B who had inherited the same VWF gene, as
marked by polymorphisms, i.e., haplotype, as did 7 unaffected sibs.

Jackson et al. (2009) identified a heterozygous V1316M substitution
(613160.0007) in affected members of a large French Canadian family with
VWD type 2B that had been described originally by Lacombe and D'Angelo
(1963); Milton and Frojmovic (1979), and Milton et al. (1984) referred
to the disorder in the family as 'Montreal platelet syndrome.' Affected
individuals had lifelong bruising; some patients had severe
postoperative bleeding, postpartum hemorrhage, and gastrointestinal
bleeding. A significant proportion of platelets occurred in
microaggregates typically containing 2 to 6 platelets, and the
aggregation could be increased by stirring. Milton and Frojmovic (1979)
suggested that the appearance of abnormally large platelets was related
to a defect in the mechanism that regulates platelet size and shape
during shape change. Jackson et al. (2009) found that affected family
members had macrothrombocytopenia, borderline to normal VWF antigen, low
ristocetin cofactor activity, and normal factor VIII coagulant activity,
all consistent with VWD type 2B.

- Von Willebrand Disease Type 2M

The mutant VWF protein in VWD type 2M shows decreased platelet adhesion
without a deficiency of high molecular weight multimers. This functional
defect is caused by mutations that disrupt VWF binding to platelets or
to subendothelium, consistent with a loss of function (Sadler et al.,
2006).

Stepanian et al. (2003) reported a French mother and son with VWD type
2M. Both patients had a moderate bleeding syndrome with epistaxis and
easy bruising. Laboratory studies showed mildly decreased VWF antigen
levels, normal multimers, and severely decreased VWF functional
activity. Factor VIII was mildly decreased and platelet counts were
normal.

- Von Willebrand Disease Type 2N

The mutant VWF protein in VWD type 2N shows markedly decreased binding
affinity for factor VIII, and this may be confused with mild hemophilia
A (306700) (Sadler et al., 2006). The phenotype is characterized by a
disproportionate decrease in F8 compared to VWF:Ag. VWD type 2N usually
shows autosomal recessive inheritance (Sadler et al., 2006). Gaucher et
al. (1991) noted that the phenotype resembled hemophilia A, or F8
deficiency, but showed autosomal recessive instead of X-linked
inheritance.

Mazurier et al. (1990) reported a 50-year-old French woman, born of
consanguineous parents, with VWD type 2N (previously designated the
'Normandy' variant). She had a lifelong history of excessive bleeding,
and laboratory data showed decreased factor VIII, subnormal bleeding
time, and normal VWF multimers. VWF isolated from patient plasma was
unable to bind factor VIII. Lopez-Fernandez et al. (1992) described a
brother and sister with VWD characterized by abnormal binding of von
Willebrand factor to factor VIII. They were presumably homozygous for a
recessive VWF defect. Hilbert et al. (2004) reported 2 unrelated French
patients with VWD type 2N. Both were adults with lifelong histories of
mucocutaneous bleeding and menorrhagia. Laboratory studies showed a
dramatic decrease in VWF F8-binding capacity.

- Von Willebrand Disease Type 2CB

Riddell et al. (2009) proposed a new subtype of VWF characterized by
clinically significant bleeding episodes due to a mutant VWF protein
with defective collagen binding, termed 'VWF 2CB.' Laboratory studies
showed normal values of VWF:RCo to VWF:Ag (RCo:Ag), normal VWF multimer
analysis, and normal ristocetin-induced platelet aggregation, but
markedly reduced ratios of VWF collagen-binding activity to VWF antigen
(CB:Ag) against type III collagen and type I collagen. Riddell et al.
(2009) concluded that the defect was distinct from VWF type 2M, in that
type 2M is also characterized by impaired binding to platelet GP1BA and
can show a full range of associated VWF multimers.

OTHER FEATURES

An association between aortic stenosis and hemorrhage from
gastrointestinal angiodysplasia has long been recognized. Remarkably,
aortic valve replacement, rather than bowel resection, corrects the
bleeding. Warkentin et al. (1992) pointed out that aortic stenosis can
be complicated by acquired von Willebrand disease type 2A which is
corrected by valve replacement, and hypothesized that acquired VWD was
the link. They suggested that in patients with aortic stenosis there is
an accelerated clearance of the largest VWF multimers as a result of
accelerated platelet/VWF interactions in blood flowing through the
stenotic aortic valve.

Chey et al. (1992) described gastric angiodysplasia in association with
type 2B VWD. Endoscopic electrocautery performed acutely and followed by
long-term estrogen/progesterone therapy was accompanied by no recurrence
of bleeding during 11 months of follow-up. Lavabre-Bertrand et al.
(1994) corroborated the usefulness of estrogen-progesterone therapy for
the bleeding of digestive angiodysplasia on the basis of observations in
a 59-year-old man with VWD and life-threatening digestive bleeding.

CLINICAL MANAGEMENT

Von Willebrand disease is often treated with the vasopressin analog
desmopressin acetate (1-desamino-8-D-arginine vasopressin; dDAVP), which
raises the level of factor VIII/von Willebrand factor in plasma.
Holmberg et al. (1983) showed that dDAVP is contraindicated in type 2B
VWD because it produces thrombocytopenia in such patients by release of
an abnormal factor VIII/von Willebrand factor with platelet-aggregating
properties.

Hall et al. (1987) described 3 monoclonal antibodies produced against
von Willebrand factor antigen by conventional hybridoma technique. These
antibodies inhibited factor VIII ristocetin cofactor activity but did
not inhibit factor VIII coagulant activity. Hall et al. (1987) found
that the antibodies were useful in differentiating types 1 and 2 VWD.
Since desmopressin may be ineffective or even contraindicated in
treating patients with type 2 VWD, the differentiation is of clinical
importance.

In a review of VWD type 2N, Mazurier (1992) stated that the deficiency
of factor VIII could be corrected by infusion of a VWF concentrate
almost devoid of factor VIII coagulant activity, and that this treatment
was more effective than infusion of factor VIII itself.

Riddell et al. (2009) noted that patients with VWF type 2CB, which is
characterized by clinically significant bleeding episodes due to a
mutant VWF protein with defective collagen binding, show good functional
response to treatment with DDAVP. DDAVP causes a rise in VWF:CB
resulting from an overall increase in the amount of circulating VWF,
even though the qualitative defect in collagen binding remains.

MAPPING

Verweij et al. (1988) used RFLPs to demonstrate that the mutation in von
Willebrand disease type 2A is in the gene for von Willebrand factor on
chromosome 12p13.

MOLECULAR GENETICS

- Von Willebrand Disease Type 2A

Mutations causing the enhanced proteolysis phenotype lie within or near
domain A2 (exon 28) of the VWF gene, which is the site of the ADAMTS13
(604134) cleavage sequence between residues tyr1605 and met1606.
Mutations interfering with multimerization occur in regions involved in
dimer or multimer assembly, such as the VWF propeptide, the N-terminal
D3 domain, the A2 domain, and the C terminus (James and Lillicrap,
2008).

In affected members of a family with von Willebrand disease type 2A,
Iannuzzi et al. (1991) identified a 4883T-C heterozygous mutation in the
VWF (I865T; 613160.0001). The I865R substitution was located immediately
adjacent to 2 other previously identified mutations that also result in
type 2A von Willebrand disease (R834W, 613160.0002 and V844D,
613160.0003; Ginsburg et al., 1989), suggesting a clustering for these
mutations in a portion of the protein critical for proteolysis.

Dent et al. (1990) noted that the I865T, R834W, and V844D mutations are
located within a 32-amino acid segment in the midportion of the
2,813-amino acid VWF coding sequence. Type 2A von Willebrand disease is
characterized by normal or only moderately decreased levels of von
Willebrand factor, the absence of large and intermediate VWF multimers,
and increased VWF proteolysis with an increase in the plasma levels of
the 176-kD VWF proteolytic fragment. The ADAMTS13 (604134)
proteolytic-cleavage site is located between tyr842 and met843
(numbering based on the mature protein).

- Von Willebrand Disease Type 2A/IIE

Schneppenheim et al. (2010) reported a high frequency (29%) of VWD type
2A subtype IIE among patients with type 2A studied in their laboratory.
Type IIE is associated with a reduction of high molecular weight (HMW)
VWF multimers and a lack of outer proteolytic bands on gel
electrophoresis, indicating reduced proteolysis. Genetic analysis of 38
such index cases identified 22 different mutations in the VWF gene, most
of them affecting cysteine residues clustered in the D3 domain. The most
common mutation was Y1146C (613160.0039), which was found in 12 (32%)
probands. In vitro expression studies indicated that the Y1146C-mutant
protein caused a severe reduction in or lack of HMW monomers and
decreased secreted VWF antigen levels. However, clinical symptoms were
heterogeneous among carriers, ranging from mild to severe bleeding.
Schneppenheim et al. (2010) suggested that several mechanisms likely act
in concert to produce subtype IIE, including decreased secretion of VWF,
the change of a cysteine residue which may impact multimerization, and
decreased half-life of the mutant protein. Altered ADAMTS13-mediated
proteolysis did not appear to be a major primary factor.

- Von Willebrand Disease Type 2B

Mutations causing VWD type 2B tend to cluster within or near the A1
domain of the VWF gene, which mediates platelet GP1BA (606672) binding.
The mutations appear to enhance platelet binding of VWF by stabilizing
the bound conformation (Sadler et al., 2006).

In patients with VWD type 2B, Randi et al. (1991) identified 3 different
heterozygous mutations in exon 28 of the VWF gene
(613160.0005-613160.0007) within the domain that interacts with platelet
glycoprotein GP1BA, resulting in a loss of function. Patient plasma
showed a decrease in large VWF multimers due to spontaneous binding of
VWF to platelets and subsequent clearance from the circulation. The
region of VWF that binds to GP1BA has been localized to a peptide
including amino acids 480 to 718 of the mature subunit that is encoded
by exon 28.

In affected members of a Swedish family (Holmberg et al., 1986) and a
German family with a variant of VWD type 2B, Holmberg et al. (1993)
identified a heterozygous mutation in the VWF gene (P1266L;
613160.0033). The phenotype was unique in that there was a mild bleeding
disorder, and laboratory studies showed that platelets aggregated at
much lower ristocetin concentrations than normal.

- Von Willebrand Disease Type 2M

In a French mother and son with VWD type 2M, Stepanian et al. (2003)
identified a heterozygous mutation in the VWF gene (S1285F; 613160.0030)
that altered the folding of the A1 loop and prevented the correct
exposure of VWF binding sites to GP1BA. The findings were consistent
with a loss of function.

- Von Willebrand Disease Type 2N

Mutations that cause VWD type 2N usually occur in the F8-binding site of
VWF, which lies between ser764 and arg1035. However, mutations outside
of this region have also been reported (Hilbert et al., 2004).

In a 50-year-old French woman with VWD type 2N reported by Mazurier et
al. (1990), Gaucher et al. (1991) identified a homozygous mutation in
the VWF gene (T28M in the mature subunit; 613160.0011).

Mazurier et al. (2002) reported a 20-year-old French woman with VWD type
2N who was compound heterozygosity for 2 mutations in the VWF gene
(Y357X, 613160.0035 and C1060R, 613160.0036). She had very low levels of
VWF and F8, and absent binding of VWF to F8. Clinical features included
epistaxis, hematomas, and hematemesis throughout childhood. The
diagnosis was complicated at first because 2 male first cousins had F8
deficiency (306700) due to a hemizygous mutation in the F8 gene (C179G;
300841.0268).

Hilbert et al. (2004) reported 2 unrelated French patients with type 2N
VWD who were compound heterozygous for R854Q (613160.0014) and another
pathogenic mutation (Y795C, 613160.0031 and C804F, 613160.0032,
respectively).

- Von Willebrand Disease Type 2CB

In affected members of 2 unrelated families with von Willebrand disease
type 2CB, Riddell et al. (2009) identified heterozygous mutations in the
collagen-binding A3 domain of the VWF gene (W1745C; 613160.0040 and
S1783A; 613160.0042, respectively). The authors noted that VWD type 2M
is associated with mutations in the A1 domain of VWF.

ANIMAL MODEL

Rayes et al. (2010) and Golder et al. (2010) independently developed
mouse models of VWD type 2B that recapitulated the human phenotype.

*FIELD* SA
Asakura et al. (1987); Cooney et al. (1991); Donner et al. (1991);
Donner et al. (1992); Kyrle et al. (1988); Lavergne et al. (1992);
Mazurier et al. (1990); Montgomery et al. (1982); Montgomery and Zimmerman
(1978); Murray et al. (1992); Ruggeri et al. (1982); Ruggeri et al.
(1982); Ruggeri et al. (1980); Ruggeri and Zimmerman (1980); Saba
et al. (1985); Schneppenheim et al. (1996); Schneppenheim et al. (2000);
Schneppenheim et al. (1995); Takahashi et al. (1980); Tuley et al.
(1991); Weinger et al. (1981); Zieger et al. (1997)
*FIELD* RF
1. Asakura, A.; Harrison, J.; Gomperts, E.; Abildgaard, C.: Type
IIA von Willebrand disease with apparent recessive inheritance. Blood 69:
1419-1420, 1987.

2. Chey, W. D.; Hasler, W. L.; Bockenstedt, P. L.: Angiodysplasia
and von Willebrand's disease type IIB treated with estrogen/progesterone
therapy. Am. J. Hemat. 41: 276-279, 1992.

3. Cooney, K. A.; Nichols, W. C.; Bruck, M. E.; Bahou, W. F.; Shapiro,
A. D.; Bowie, E. J. W.; Gralnick, H. R.; Ginsburg, D.: The molecular
defect in type IIB von Willebrand disease: identification of four
potential missense mutations within the putative GpIb binding domain. J.
Clin. Invest. 87: 1227-1233, 1991.

4. Dent, J. A.; Berkowitz, S. D.; Ware, J.; Kasper, C. K.; Ruggeri,
Z. M.: Identification of a cleavage site directing the immunochemical
detection of molecular abnormalities in type IIA von Willebrand factor. Proc.
Nat. Acad. Sci. 87: 6306-6310, 1990. Note: Erratum: Proc. Nat. Acad.
Sci. 87: 9508 only, 1990.

5. Donner, M.; Andersson, A.-M.; Kristoffersson, A.-C.; Nilsson, I.
M.; Dahlback, B.; Holmberg, L.: An arg545-to-cys substitution mutation
of the von Willebrand factor in type IIB von Willebrand's disease. Europ.
J. Haemat. 47: 342-345, 1991.

6. Donner, M.; Holmberg, L.; Nilsson, I. M.: Type IIB von Willebrand's
disease with probable autosomal recessive inheritance and presenting
as thrombocytopenia in infancy. Brit. J. Haemat. 66: 349-354, 1987.

7. Donner, M.; Kristoffersson, A. C.; Lenk, H.; Scheibel, E.; Dahlback,
B.; Nilsson, I. M.; Holmberg, L.: Type IIB von Willebrand's disease:
gene mutations and clinical presentation in nine families from Denmark,
Germany and Sweden. Brit. J. Haemat. 82: 58-65, 1992.

8. Gaucher, C.; Jorieux, S.; Mercier, B.; Oufkir, D.; Mazurier, C.
: The 'Normandy' variant of von Willebrand disease: characterization
of a point mutation in the von Willebrand factor gene. Blood 77:
1937-1941, 1991.

9. Ginsburg, D.; Konkle, B. A.; Gill, J. C.; Montgomery, R. R.; Bockenstedt,
P. L.; Johnson, T. A.; Yang, A. Y.: Molecular basis of human von
Willebrand disease: analysis of platelet von Willebrand factor mRNA. Proc.
Nat. Acad. Sci. 86: 3723-3727, 1989.

10. Golder, M.; Pruss, C. M.; Hegadorn, C.; Mewburn, J.; Laverty,
K.; Sponagle, K.; Lillicrap, D.: Mutation-specific hemostatic variability
in mice expressing common type 2B von Willebrand disease substitutions. Blood 115:
4862-4869, 2010.

11. Goodeve, A. C.: The genetic basis of von Willebrand disease. Blood
Rev. 24: 123-134, 2010.

12. Gralnick, H. R.; Williams, S. B.; McKeown, L. P.; Rick, M. E.;
Maisonneuve, P.; Jenneau, C.; Sultan, Y.: Von Willebrand's disease
with spontaneous platelet aggregation induced by an abnormal plasma
von Willebrand factor. J. Clin. Invest. 76: 1522-1529, 1985.

13. Hall, J. D.; Willis, D. W.; Evatt, B. L.; Jackson, D. W.: Using
a monoclonal antibody to identify patients with type I and type II
von Willebrand's disease. Thromb. Haemost. 57: 332-336, 1987.

14. Hilbert, L.; Jorieux, S.; Fontenay-Roupie, M.; Guicheteau, M.;
Fressinaud, E.; Meyer, D.; Mazurier, C.; the INSERM Network on Molecular
Abnormalities in von Willebrand Disease: Expression of two type
2N von Willebrand disease mutations identified in exon 18 of von Willebrand
factor gene. Brit. J. Haemat. 127: 184-189, 2004.

15. Holmberg, L.; Berntorp, E.; Donner, M.; Nilsson, I. M.: Von Willebrand's
disease characterised by increased ristocetin sensitivity and the
presence of all von Willebrand factor multimers. Blood 68: 668-672,
1986.

16. Holmberg, L.; Dent, J. A.; Schneppenheim, R.; Budde, U.; Ware,
J.; Ruggeri, Z. M.: Von Willebrand factor mutation enhancing interaction
with platelets in patients with normal multimeric structure. J. Clin.
Invest. 91: 2169-2177, 1993.

17. Holmberg, L.; Nilsson, I. M.; Borge, L.; Gunnarsson, M.; Sjorin,
E.: Platelet aggregation induced by 1-desamino-8-D-arginine vasopressin
(DDAVP) in type IIB von Willebrand's disease. New Eng. J. Med. 309:
816-821, 1983.

18. Iannuzzi, M. C.; Hidaka, N.; Boehnke, M.; Bruck, M. E.; Hanna,
W. T.; Collins, F. S.; Ginsburg, D.: Analysis of the relationship
of von Willebrand disease (vWD) and hereditary hemorrhagic telangiectasia
and identification of a potential type IIA vWD mutation (ile865-to-thr). Am.
J. Hum. Genet. 48: 757-763, 1991.

19. Jackson, S. C.; Sinclair, G. D.; Cloutier, S.; Duan, Z.; Rand,
M. L.; Poon, M.-C.: The Montreal platelet syndrome kindred has type
2B von Willebrand disease with the VWF V1316M mutation. Blood 113:
3348-3351, 2009.

20. James, P.; Lillicrap, D.: The role of molecular genetics in diagnosing
von Willebrand disease. Semin. Thromb. Hemost. 34: 502-508, 2008.

21. Kyrle, P. A.; Niessner, H.; Dent, J.; Panzer, S.; Brenner, B.;
Zimmerman, T. S.; Lechner, K.: IIB von Willebrand's disease: pathogenetic
and therapeutic studies. Brit. J. Haemat. 69: 55-59, 1988.

22. Lacombe, M.; D'Angelo, G.: Etudes sur une thrombopathie familiale. Nouv.
Rev. Fr. Hematol. 3: 611-614, 1963.

23. Lavabre-Bertrand, T.; Navarro, M.; Blanc, P.; Larrey, D.; Michel,
H.; Rouanet, C.: Von Willebrand's disease, digestive angiodysplasia,
and estrogen-progesterone treatment. (Letter) Am. J. Hemat. 46:
254-255, 1994.

24. Lavergne, J.-M.; De Paillette, L.; Bahnak, B. R.; Ribba, A.-S.;
Fressinaud, E.; Meyer, D.; Pietu, G.: Defects in type IIA von Willebrand
disease: a cysteine 509 to arginine substitution in the mature von
Willebrand factor disrupts a disulphide loop involved in the interaction
with platelet glycoprotein Ib-IX. Brit. J. Haemat. 82: 66-72, 1992.

25. Lillicrap, D.: Genotype/phenotype association in von Willebrand
disease: is the glass half full or empty? J. Thromb. Haemost. 7
(suppl. 1): 65-70, 2009.

26. Lopez-Fernandez, M. F.; Blanco-Lopez, M. J.; Castineira, M. P.;
Batlle, J.: Further evidence for recessive inheritance of von Willebrand
disease with abnormal binding of von Willebrand factor to factor VIII. Am.
J. Hemat. 40: 20-27, 1992.

27. Mannucci, P. M.: Treatment of von Willebrand's disease. New
Eng. J. Med. 351: 683-694, 2004.

28. Mazurier, C.: Von Willebrand disease masquerading as haemophilia
A. Thromb. Haemost. 67: 391-396, 1992.

29. Mazurier, C.; Dieval, J.; Jorieux, S.; Delobel, J.; Goudemand,
M.: A new von Willebrand factor (vWF) defect in a patient with factor
VIII (FVIII) deficiency but with normal levels and multimeric patterns
of both plasma and platelet vWF: characterization of abnormal vWF/FVIII
interaction. Blood 75: 20-26, 1990.

30. Mazurier, C.; Gaucher, C.; Jorieux, S.; Parquet-Gernez, A.; Goudemand,
M.: Evidence for a von Willebrand factor defect in factor VIII binding
in three members of a family previously misdiagnosed mild haemophilia
A and haemophilia A carriers: consequences for therapy and genetic
counselling. Brit. J. Haemat. 76: 372-379, 1990.

31. Mazurier, C.; Parquet-Gernez, A.; Gaucher, C.; Lavergne, J.-M.;
Goudemand, J.: Factor VIII deficiency not induced by FVIII gene mutation
in a female first cousin of two brothers with haemophilia A. Brit.
J. Haemat. 119: 390-392, 2002.

32. Milton, J. G.; Frojmovic, M. M.: Shape-changing agents produce
abnormally large platelets in a hereditary 'giant platelets syndrome
(MPS)'. J. Lab. Clin. Med. 93: 154-161, 1979.

33. Milton, J. G.; Frojmovic, M. M.; Tang, S. S.; White, J. G.: Spontaneous
platelet aggregation in a hereditary giant platelet syndrome (MPS). Am.
J. Path. 114: 336-345, 1984.

34. Montgomery, R. R.; Hathaway, W. E.; Johnson, J.; Jacobson, L.;
Muntean, W.: A variant of von Willebrand's disease with abnormal
expression of factor VIII procoagulant activity. Blood 60: 201-207,
1982.

35. Montgomery, R. R.; Zimmerman, T. S.: Von Willebrand's disease
antigen II: a new plasma and platelet antigen deficient in severe
von Willebrand's disease. J. Clin. Invest. 61: 1498-1507, 1978.

36. Murray, E. W.; Giles, A. R.; Bridge, P. J.; Peake, I. R.; Lillicrap,
D. P.: Cosegregation of von Willebrand factor gene polymorphisms
and possible germinal mosaicism in type IIB von Willebrand disease. Blood 77:
1476-1483, 1991.

37. Murray, E. W.; Giles, A. R.; Lillicrap, D.: Germ-line mosaicism
for a valine-to-methionine substitution at residue 553 in the glycoprotein
Ib-binding domain of von Willebrand factor, causing type IIB von Willebrand
disease. Am. J. Hum. Genet. 50: 199-207, 1992.

38. Othman, M.; Favaloro, E. J.: Genetics of type 2B von Willebrand
disease: 'true 2B,' 'tricky 2B,' or 'not 2B.' What are the modifiers
of the phenotype? Semin. Thromb. Hemost. 34: 520-531, 2008.

39. Randi, A. M.; Rabinowitz, I.; Mancuso, D. J.; Mannucci, P. M.;
Sadler, J. E.: Molecular basis of von Willebrand disease type IIB:
candidate mutations cluster in one disulfide loop between proposed
platelet glycoprotein Ib binding sequences. J. Clin. Invest. 87:
1220-1226, 1991.

40. Rayes, J.; Hollestelle, M. J.; Legendre, P.; Marx, I.; de Groot,
P. G.; Christophe, O. D.; Lenting, P. J.; Denis, C. V.: Mutation
and ADAMTS13-dependent modulation of disease severity in a mouse model
for von Willebrand disease type 2B. Blood 115: 4870-4877, 2010.

41. Riddell, A. F.; Gomez, K.; Millar, C. M.; Mellars, G.; Gill, S.;
Brown, S. A.; Sutherland, M.; Laffan, M. A.; McKinnon, T. A.: Characterization
of W1745C and S1783A: 2 novel mutations causing defective collagen
binding in the A3 domain of von Willebrand factor. Blood 114: 3489-3496,
2009.

42. Ruggeri, Z. M.; Lombardi, R.; Gatti, L.; Bader, R.; Valsecchi,
C.; Zimmerman, T. S.: Type IIB von Willebrand's disease: differential
clearance of endogenous versus transfused large multimer von Willebrand
factor. Blood 60: 1453-1456, 1982.

43. Ruggeri, Z. M.; Nilsson, I. M.; Lombardi, R.; Holmberg, L.; Zimmerman,
T. S.: Aberrant multimeric structure of von Willebrand factor in
a new variant of von Willebrand's disease (type IIC). J. Clin. Invest. 70:
1124-1127, 1982.

44. Ruggeri, Z. M.; Pareti, F. I.; Mannucci, P. M.; Ciavarella, N.;
Zimmerman, T. S.: Heightened interaction between platelets and factor
VIII von Willebrand factor in a new subtype of von Willebrand's disease. New
Eng. J. Med. 302: 1047-1051, 1980.

45. Ruggeri, Z. M.; Zimmerman, T. S.: Variant von Willebrand's disease:
characterization of two subtypes by analysis of multimeric composition
of factor VIII-von Willebrand factor in plasma and platelets. J.
Clin. Invest. 65: 1318-1325, 1980.

46. Saba, H. I.; Saba, S. R.; Dent, J.; Ruggeri, Z. M.; Zimmerman,
T. S.: Type IIB Tampa: a variant of von Willebrand disease with chronic
thrombocytopenia, circulating platelet aggregates, and spontaneous
platelet aggregation. Blood 66: 282-286, 1985.

47. Saba, H. I.; Saba, S. R.; Dent, J.; Ruggeri, Z. M.; Zimmerman,
T. S.: Type IIB Tampa: a variant of von Willebrand disease with chronic
thrombocytopenia, circulating platelet aggregates, and spontaneous
platelet aggregation. Blood 66: 282-286, 1985.

48. Sadler, J. E.; Budde, U.; Eikenboom, J. C. J.; Favaloro, E. J.;
Hill, F. G. H.; Holmberg, L.; Ingerslev, J.; Lee, C. A.; Lillicrap,
D.; Mannucci, P. M.; Mazurier, C.; Meyer, D.; and 9 others: Update
on the pathophysiology and classification of von Willebrand disease:
a report of the Subcommittee on von Willebrand Factor. J. Thromb.
Haemost. 4: 2103-2114, 2006.

49. Schneppenheim, R.; Brassard, J.; Krey, S.; Budde, U.; Kunicki,
T. J.; Holmberg, L.; Ware, J.; Ruggeri, Z. M.: Defective dimerization
of von Willebrand factor subunits due to a cys-to-arg mutation in
type IID von Willebrand disease. Proc. Nat. Acad. Sci. 93: 3581-3586,
1996.

50. Schneppenheim, R.; Federici, A. B.; Budde, U.; Castaman, G.; Drewke,
E.; Krey, S.; Mannucci, P. M.; Riesen, G.; Rodeghiero, F.; Zieger,
B.; Zimmermann, R.: Von Willebrand disease type 2M 'Vicenza' in Italian
and German patients: identification of the first candidate mutation
(G3864A; R1205H) in 8 families. Thromb. Haemost. 82: 136-140, 2000.

51. Schneppenheim, R.; Michiels, J. J.; Obser, T.; Oyen, F.; Pieconka,
A.; Schneppenheim, S.; Will, K.; Zieger, B.; Budde, U. A cluster
of mutations in the D3 domain of von Willebrand factor correlates
with a distinct subgroup of von Willebrand disease: type 2A/IIE. Blood 115:
4894-4901, 2010.

52. Schneppenheim, R.; Thomas, K. B.; Krey, S.; Budde, U.; Jessat,
U.; Sutor, A. H.; Zieger, B.: Identification of a candidate missense
mutation in a family with von Willebrand disease type IIC. Hum. Genet. 95:
681-686, 1995.

53. Stepanian, A.; Ribba, A.-S.; Lavergne, J.-M.; Fressinaud, E.;
Juhan-Vague, I.; Mazurier, C.; Girma, J.-P.; Meyer, D.: A new mutation,
S1285F, within the A1 loop of von Willebrand factor induces a conformational
change in A1 loop with abnormal binding to platelet GPIb and botrocetin
causing type 2M von Willebrand disease. Brit. J. Haemat. 120: 643-651,
2003.

54. Takahashi, H.; Sakuragawa, N.; Shibata, A.: Von Willebrand disease
with an increased ristocetin-induced platelet aggregation and a qualitative
abnormality of the factor VIII protein. Am. J. Hemat. 8: 299-308,
1980.

55. Tuley, E. A.; Gaucher, C.; Jorieux, S.; Worrall, N. K.; Sadler,
J. E.; Mazurier, C.: Expression of von Willebrand factor 'Normandy':
an autosomal mutation that mimics hemophilia A. Proc. Nat. Acad.
Sci. 88: 6377-6381, 1991.

56. Verweij, C. L.; Quadt, R.; Briet, E.; Dubbeldam, K.; van Ommen,
G. B.; Pannekoek, H.: Genetic linkage of two intragenic restriction
fragment length polymorphisms with von Willebrand's disease type IIA:
evidence for a defect in the von Willebrand factor gene. J. Clin.
Invest. 81: 1116-1121, 1988.

57. Warkentin, T. E.; Moore, J. C.; Morgan, D. G.: Aortic stenosis
and bleeding gastrointestinal angiodysplasia: is acquired von Willebrand's
disease the link? Lancet 340: 35-37, 1992.

58. Weinger, R. S.; Cimo, P. L.; Moake, J. L.; Olson, J. D.; Heller,
M. S.: Type IIB von Willebrand's disease: unusual response to cryoprecipitate
infusion. Ann. Intern. Med. 94: 47-50, 1981.

59. Weiss, J. G.; Sussman, I. I.: A new von Willebrand variant (type
I, New York): increased ristocetin-induced platelet aggregation and
plasma von Willebrand factor containing the full range of multimers. Blood 68:
149-156, 1986.

60. Wylie, B.; Gibson, J.; Uhr, E.; Kronenberg, H.: Von Willebrand's
disease characterized by increased ristocetin sensitivity and the
presence of all von Willebrand factor multimers in plasma: a new subtype. Pathology 20:
62-63, 1988.

61. Zieger, B.; Budde, U.; Jessat, U.; Zimmermann, R.; Simon, M.;
Katzel, R.; Sutor, A. H.: New families with von Willebrand disease
type 2M (Vicenza). Thromb. Res. 87: 57-64, 1997.

62. Zimmerman, T. S.; Dent, J. A.; Ruggeri, Z. M.; Nannini, L. H.
: Subunit composition of plasma von Willebrand factor. Cleavage is
present in normal individuals, increased in IIA and IIB von Willebrand
disease, but minimal in variants with aberrant structure of individual
oligomers (types IIC, IID, and IIE). J. Clin. Invest. 77: 947-951,
1986.

63. Zimmerman, T. S.; Ruggeri, Z. M.: Von Willebrand disease. Hum.
Path. 18: 140-152, 1987.

*FIELD* CS
INHERITANCE:
Autosomal dominant;
Autosomal recessive

HEAD AND NECK:
[Nose];
Epistaxis

SKIN, NAILS, HAIR:
[Skin];
Easy bruising

HEMATOLOGY:
Prolonged bleeding due to a qualitative defect in the VWF protein;
Defect in platelet aggregation;
Mucocutaneous bleeding;
Menorrhagia;
Patients with type 2B develop thrombocytopenia

LABORATORY ABNORMALITIES:
Decreased levels of plasma factor VIII in patients with type 2N

MISCELLANEOUS:
There are several subtypes;
Variable severity;
Most types show autosomal dominant inheritance;
Type 2N shows autosomal recessive inheritance;
Type 2A is characterized by deficiency of high molecular weight monomers;
Type 2B is characterized by increased affinity for platelet glycoprotein
1B;
Type 2M is characterized by decreased platelet adhesion in the presence
of high molecular weight monomers;
Type 2N is characterized by decreased binding affinity for factor
VIII;
Type 2CB is characterized by defective binding affinity for collagen
types I and III

MOLECULAR BASIS:
Caused by mutation in the von Willebrand factor gene (VWF, 613160.0001)

*FIELD* CD
Cassandra L. Kniffin: 9/29/2010

*FIELD* ED
joanna: 07/17/2012
ckniffin: 5/10/2011
ckniffin: 12/27/2010

*FIELD* CN
Cassandra L. Kniffin - updated: 4/29/2013
Cassandra L. Kniffin - updated: 5/10/2011
Cassandra L. Kniffin - updated: 10/8/2010

*FIELD* CD
Cassandra L. Kniffin: 9/8/2010

*FIELD* ED
alopez: 05/03/2013
ckniffin: 5/1/2013
ckniffin: 4/29/2013
terry: 8/9/2012
wwang: 6/13/2011
ckniffin: 5/10/2011
carol: 4/7/2011
terry: 1/7/2011
terry: 11/24/2010
wwang: 11/2/2010
ckniffin: 10/8/2010
terry: 10/8/2010
carol: 10/4/2010
ckniffin: 9/29/2010