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Thromb Haemost 1993; 69(02): 185-191
DOI: 10.1055/s-0038-1651577
Original Article
Von Willebrand Disease
Schattauer GmbH Stuttgart

A Database of Polymorphisms in the von Willebrand Factor Gene and Pseudogene

For the Consortium on von Willebrand Factor Mutations and Polymorphisms [1], and the Subcommittee on von Willebrand Factor of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis
J Evan Sadler
*   The Howard Hughes Medical Institute, The Jewish Hospital of St. Louis, Departments of Medicine, and of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO
,
David Ginsburg
**   Howard Hughes Medical Institute, Departments of Medicine and Human Genetics, University of Michigan Medical School, Ann Arbor, MI, USA
› Author Affiliations
Further Information

Publication History

Received 27 April 1992

Accepted after revision 07 October 1992

Publication Date:
03 July 2018 (online)

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Summary

Nucleotide sequence polymorphisms in the von Willebrand factor (vWF) gene are useful for genetic studies in von Willebrand disease (vWD). This database describes 33 known vWF polymorphisms distributed throughout the vWF gene. DNA sequence information is available for 21 of these sites. The most informative system is a tetranucleotide repeat polymorphism in vWF intron 40. Sixteen of these polymorphisms are within vWF exons, and approximately half of them also alter the encoded amino acid sequence. Many occur close to mutations that cause vWD. The high prevalence of vWF polymorphisms must be considered in the analysis of candidate vWD mutations. In addition to the vWF gene on chromosome 12, there is a partial unprocessed vWF pseudogene on chromosome 22 that corresponds to vWF exons 23 to 34. Three polymorphisms have been assigned to the vWF pseudogene. Because the vWF gene and pseudogene have diverged only ∼3.1% in DNA sequence, correct assignment of polymorphisms to either locus can be difficult in the region of homology. This problem has been solved in some cases by comparison of the published sequences and predicted restriction maps for the gene and pseudogene.

Members of Consortium on von Willebrand Factor Mutations and Polymorphisms. Asterisks denote Steering Committee Members: Takeshi Abe, Tokyo University, Japan; Maria Anvret, Karolinska Hospital, Sweden; Javier Batlle, Hospital Teresa Herrera, Spain; Francesco Bernardi, Universita di Ferrara, Italy; David Bonthron, MRC Human Genetics Unit, Scotland; Derrick Bowen, University of Wales, Wales; Jeroen C. J. Eikenboom, University Hospital Leiden, The Netherlands; Bruce Ewenstein, Brigham and Women’s Hospital, USA; Gunnar Falk, Karolinksa Hospital, Sweden; David Ginsburg*, University of Michigan, USA; Harvey Grainick, National Institutes of Health, USA; Hiroshi Inaba*, Tokyo Medical College, Japan; Aida Inbal*, Beilinson Medical Center, Israel; David Lillicrap*, Queen’s University, Canada; David Mancuso, The Blood Center of Southeastern Wisconsin, USA; Claudine Mazurier*, Laboratoire de Recherche sur l’Hémostase, France; Dominique Meyer*, Hôpital de Bicêtre, France; Jan Michiels, Erasmus University, Rotterdam, The Netherlands; Robert Montgomery*, The Blood Center of Southeastern Wisconsin, USA; Ian Peake*, University of Sheffield, England; Anna M. Randi*, A. Bianchi Bonomi Hemophilia and Thrombosis Center, Italy; J. Evan Sadler*, Washington University, USA; Hidehiko Saito*, Nagoya University, Japan; R. Schneppenheim, Universitäts-Kinderklinik Kiel, Germany; Jan J. Sixma*, Rijksuniversiteit te Utrecht, The Netherlands; Safia Wasi, The Canadian Red Cross, Canada: Gilbert White, University of North Carolina, USA; Paul Winter, Royal Victoria Hospital, Northern Ireland.


 

  • References

  • 1 Ginsburg D, Handin RI, Bonthron DT, Donlon TA, Bruns GAP, Latt SA, Orkin SH. Human von Willebrand factor (vWF): Isolation of complementary DNA (cDNA) clones and chromosomal localization. Science 1985; 228: 1401-1406
    CrossrefPubMedGoogle Scholar
  • 2 Verweij CL, de Vries CJM, Distel B, van Zonneveld A-J, van Kessel AG, van Mourik JA, 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 1985; 13: 4699-4717
    CrossrefPubMedGoogle Scholar
  • 3 Mancuso DJ, Tuley EA, Westfield LA, Worrall NK, Shelton-Inloes BB, Sorace JM, Alevy YG, Sadler JE. Structure of the gene for human von Willebrand factor. J Biol Chem 1990; 264: 19514-19527
    PubMedGoogle Scholar
  • 4 Patracchini P, Calzolari E, Aiello V, Palazzi P, Banin P, Marchetti G, Bernardi F. Sublocalization of von Willebrand factor pseudogene to 22q11.22-q11.23 by in situ hybridization in a 46,X,t(X;22) (pter;q11.21) translocation. Hum Genet 1989; 83: 264-266
    CrossrefPubMedGoogle Scholar
  • 5 Mancuso DJ, Tuley EA, Westfield LA, Lester-Mancuso TL, Le Beau MM, Sorace JM, Sadler JE. Human von Willebrand factor gene and pseudogene: Structural analysis and differentiation by polymerase chain reaction. Biochemistry 1991; 30: 253-269
    CrossrefPubMedGoogle Scholar
  • 6 Bonthron DT, Orr EC, Mitsock LM, Ginsburg D, Handin RI, Orkin SH. Nucleotide sequence of pro-pro-von Willebrand factor cDNA. Nucleic Acids Res 1986; 14: 7125-7127
    CrossrefPubMedGoogle Scholar
  • 7 Lynch DC, Zimmerman TS, Collins CJ, Brown M, Morin MJ, Ling EH, Livingston DM. Molecular cloning of cDNA for human von Willebrand factor. Authentication by a new method. Cell 1985; 41: 49-56
    CrossrefPubMedGoogle Scholar
  • 8 Sadler JE, Shelton-Inloes BB, Sorace JM, Harlan JM, Titani K, Davie EW. Cloning and characterization of two cDNAs coding for human von Willebrand factor. Proc Natl Acad Sci USA 1985; 82: 6394-6398
    CrossrefPubMedGoogle Scholar
  • 9 Collins CJ, Underdahl JP, Levene RB, Ravera CP, Morin MJ, Dombalagian MJ, Ricca G, Livingston DM, Lynch DC. Molecular cloning of the human gene for von Willebrand factor and identification of the transcription initiation site. Proc Natl Acad Sci USA 1987; 84: 4393-4397
    CrossrefPubMedGoogle Scholar
  • 10 Assouline Z, Kerbiriou-Nabias DM, Piétu G, Thomas N, Bahnak BR, Meyer D. The human gene for von Willebrand factor. Identification of repetitive Alu sequences 5’ to the transcription initiation site. Biochem Biophys Res Commun 1988; 153: 1159-1166
    CrossrefPubMedGoogle Scholar
  • 11 Bonthron D, Orkin SH. The human von Willebrand factor gene. Structure of the 5’ region. Eur J Biochem 1988; 171: 51-57
    CrossrefPubMedGoogle Scholar
  • 12 Titani K, Kumar S, Takio K, Ericsson LH, Wade RD, Ashida K, Walsh DA, Chopek MW, Sadler JE, Fujikawa K. Amino acid sequence of human von Willebrand factor. Biochemistry 1986; 25: 3171-3184
    CrossrefPubMedGoogle Scholar
  • 13 Lavergne JM, Bahnak BR, Assouline Z, Piétu G, Kerbiriou-Nabias D, Meulien P, Pavirani A, Meyer D. A TaqI polymorphism in the 5’ region of the von Willebrand factor (vWF) gene. Nucleic Acids Res 1988; 16: 2742
    CrossrefPubMedGoogle Scholar
  • 14 Marchetti G, Sacchi E, Patracchini P, Randi AM, Sampietro M, Bernardi F. Two additional TaqI RFLPs in von Willebrand factor gene (vWF) and pseudogene. Nucleic Acids Res 1989; 17: 3329
    CrossrefPubMedGoogle Scholar
  • 15 Bernardi F, Marchetti G, Casonato A, Gemmati D, Patracchini P, Legnani C, DeRosa V, Girolami A, Conconi F. Characterization of polymorphic markers in the von Willebrand factor gene and pseudogene. Br J Haematol 1990; 74: 282-289
    CrossrefPubMedGoogle Scholar
  • 16 Inbal A, Handin RI. Two TaqI polymorphisms in the 5’ region of the von Willebrand factor (vWF) gene. Nucleic Acids Res 1989; 17: 10143
    CrossrefPubMedGoogle Scholar
  • 17 Inbal A, Handin RI. StuI polymorphisms in the vWF gene. Nucleic Acids Res 1990; 18: 4959
    PubMedGoogle Scholar
  • 18 Iannuzzi MC, Konkle BA, Ginsburg D, Collins FS. Rsal RFLP in the human von Willebrand factor gene. Nucleic Acids Res 1987; 15: 5909
    CrossrefPubMedGoogle Scholar
  • 19 Lindstedt M, Anvret M. An EcoRI polymorphism of the human von Willebrand factor cDNA (vWF). Nucleic Acids Res 1989; 17: 2882
    CrossrefPubMedGoogle Scholar
  • 20 Ewerhardt B, Ludwig M, Schwaab R, Schneppenheim R, Olek K. An EcoRI polymorphism in the human von Willebrand factor (vWF) gene. Nucleic Acids Res 1989; 17: 5416
    CrossrefPubMedGoogle Scholar
  • 21 Verweij CL, Hofker M, Quadt R, Briët E, Pannekoek H. RFLP for a human von Willebrand factor (vWF) cDNA clone, pvWF1100. Nucleic Acids Res 1989; 13: 8289
    PubMedGoogle Scholar
  • 22 Bahnak BR, Lavergne JM, Verweij CL, Rothschild C, Pannekoek H, Larrieu M-J, Meyer D. Carrier detection in severe (type III) von Willebrand disease using two intragenic restriction fragment length polymorphisms. Thromb Haemostas 1988; 60: 178-181
    PubMedGoogle Scholar
  • 23 Verweij CL, Quadt R, Briët E, Dubbeldam K, van Ommen GB, Pannekoek H. Genetic linkage of two intragenic restriction fragment length polymorphisms with von Willebrand’s disease type II A. J Clin Invest 1988; 81: 1116-1121
    CrossrefPubMedGoogle Scholar
  • 24 O’Connell P, Lathrop GM, Law M, Leppert M, Nakamura Y, Hoff M, Kumlin E, Thomas W, Eisner T, Ballard L, Goodman P, Azen E, Sadler JE, Lai GY, Lalouel J-M, White R. A primary genetic linkage map for human chromosome 12. Genomics 1987; 1: 93-102
    CrossrefPubMedGoogle Scholar
  • 25 Bernardi F, Guerra S, Patracchini P, Volinia S, Buzzoni D, Ballerini G, Casonato A, Marchetti G. Von Willebrand disease investigated by two novel RFLPs. Br J Haematol 1988; 68: 243-248
    CrossrefPubMedGoogle Scholar
  • 26 Quadt T, Verweij CL, de Vries CJM, Briët E, Pannekoek H. A polymorphic XbaI site within the human von Willebrand factor (vWF) gene identified by a vWF cDNA clone. Nucleic Acids Res 1986; 14: 7139
    CrossrefPubMedGoogle Scholar
  • 27 Lavergne J-M, Bahnak BR, Verweij CL, Pannekoek H, Meyer D. A second XbaI polymorphic site within the human von Willebrand factor (vWF) gene. Nucleic Acids Res 1987; 15: 9099
    CrossrefPubMedGoogle Scholar
  • 28 Caekebeke-Peerlinck KMJ, Bakker E, Briët E. An infrequent DNA polymorphism associated with severe von Willebrand’s disease. Br J Haematol 1990; 75: 78-81
    CrossrefPubMedGoogle Scholar
  • 29 Konkle BA, Kim S, Iannuzzi MC, Alani R, Collins FS, Ginsburg D. SacI RFLP in the human von Willebrand factor gene. Nucleic Acids Res 1987; 15: 6766
    CrossrefPubMedGoogle Scholar
  • 30 Nishino K, Lynch DC. A polymorphism of the human von Willebrand factor (vWF) gene with BamHI. Nucleic Acids Res 1986; 14: 4697
    CrossrefPubMedGoogle Scholar
  • 31 Bernardi F, Marchetti G, Bertagnolo V, Faggioli L, del Senno L. Two TaqI RFLPs in the human von Willebrand factor gene. Nucleic Acids Res 1987; 15: 1347
    CrossrefPubMedGoogle Scholar
  • 32 Strain L, Bonthron DT, Brock DJH. SmaI and HhaI polymorphisms in the 5’ region of the human von Willebrand factor gene. Nucleic Acids Res 1991; 19: 4107
    PubMedGoogle Scholar
  • 33 Verweij CL, Diergaarde PJ, Hart M, Pannekoek H. Full-length von Willebrand factor (vWF) cDNA encodes a highly repetitive protein considerably larger than the mature vWF subunit. EMBO J 1986; 5: 1839-1847
    PubMedGoogle Scholar
  • 34 Shelton-Inloes BB, Broze Jr GJ, Miletich JP, Sadler JE. Evolution of human von Willebrand factor: cDNA sequence polymorphisms, repeated domains, and relationship to von Willebrand antigen II. Biochem Biophys Res Commun 1987; 144: 657-665
    CrossrefPubMedGoogle Scholar
  • 35 Bowen DJ, Webb CE, Peake IR, Bloom AL. AatII polymorphism in von Willebrand factor gene at codon 471. Nucleic Acids Res 1991; 19: 3159
    PubMedGoogle Scholar
  • 36 Kunkel GR, Graham JB, Fowlkes DM, Lord ST. AccI polymorphism in von Willebrand factor (F8vWF) at codon 516. Nucleic Acids Res 1991; 19: 1729
    CrossrefPubMedGoogle Scholar
  • 37 Kunkel GR, Graham JB, Fowlkes DM, Lord ST. Rsal polymorphism in von Willebrand factor (vWF) at codon 789. Nucleic Acids Res 1990; 18: 4961
    PubMedGoogle Scholar
  • 38 Shelton-Inloes BB, Titani K, Sadler JE. cDNA sequences for human von Willebrand factor reveal five types of repeated domains and five possible protein sequence polymorphisms. Biochemistry 1986; 25: 3164-3171
    CrossrefPubMedGoogle Scholar
  • 39 Nichols WC, Lyons SE, Harrison JS, Cody RL, Ginsburg D. Severe von Willebrand disease due to a defect at the level of von Willebrand factor mRNA expression: Detection by exonic PCR-restriction fragment length polymorphism analysis. Proc Natl Acad Sci USA 1991; 88: 3857-3861
    CrossrefPubMedGoogle Scholar
  • 40 Mercier B, Gaucher C, Mazurier C. An MspI polymorphism in the von Willebrand factor gene. Nucleic Acids Res 1990; 18: 7467
    PubMedGoogle Scholar
  • 41 Cacheris PM, Nichols WC, Ginsburg D. Molecular characterization of a unique von Willebrand disease variant: A novel mutation affecting von Willebrand factor/factor VIII interaction. J Biol Chem 1991; 266: 13499-13502
    PubMedGoogle Scholar
  • 42 Bonthron DT, Handin RI, Kaufman RJ, Wasley LC, Orr EC, Mitsock. Ewenstein B, Loscalzo J, Ginsburg D, Orkin SH. Structure of pre-pro-von Willebrand factor and its expression in heterologous cells. Nature 1986; 324: 270-273
    CrossrefPubMedGoogle Scholar
  • 43 Donnér M, Holmberg L, Kristoffersson A-C, Nilsson IM. An HphI-polymorphism in exon 28 of the von Willebrand factor gene, and its frequency among patients with various forms of von Willebrand’s disease. Br J Haematol 1991; 78: 403-407
    CrossrefPubMedGoogle Scholar
  • 44 Cooney KA, Nichols WC, Bruck ME, Bahou WF, Shapiro AD, Bowie EJW, Gralnick HR, 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 1991; 87: 1227-1233
    CrossrefPubMedGoogle Scholar
  • 45 Lavergne JM, Ribba AS, Bahnak BR, de Paillette L, Derlon A, Meyer D, Pietu G. The use of denaturing gradient gel electrophoresis to detect base changes in the von Willebrand factor gene from type IIA von Willebrand disease patients. Thromb Haemostas 1991; 65: 645
    PubMedGoogle Scholar
  • 46 Peake IR, Liddell MB, Moodie P, Standen G, Mancuso DJ, Tuley EA, Westfield LA, Sorace JM, Sadler JE, Verweij CL, Bloom AR. 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 1990; 75: 654-661
    PubMedGoogle Scholar
  • 47 Ploos van Amstel HK, Reitsma PH. Tetranucleotide repeat polymorphism in the vWF gene. Nucleic Acids Res 1990; 18: 4957
    PubMedGoogle Scholar
  • 48 Peake IR, Bowen D, Bignell P, Liddell MB, Sadler JE, Standen G, Bloom AL. Family studies and prenatal diagnosis in severe von Willebrand disease by polymerase chain reaction amplification of a variable number tandem repeat region of the von Willebrand factor gene. Blood 1990; 76: 555-561
    PubMedGoogle Scholar
  • 49 Standen GR, Bignell P, Bowen DJ, Peake IR, Bloom AL. Family studies in von Willebrand’s disease by analysis of restriction fragment length polymorphisms and an intragenic variable number tandem repeat (VNTR) sequence. Br J Haematol 1990; 76: 242-249
    CrossrefPubMedGoogle Scholar
  • 50 Mercier B, Gaucher C, Mazurier C. Characterization of 98 alleles in 105 unrelated individuals in the F8vWF gene. Nucleic Acids Res 1991; 19: 4800
    CrossrefPubMedGoogle Scholar
  • 51 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 and carrier detection using two intragenic restriction fragment length polymorphisms. Blood Coag Fibrinol 1991; 3: 167-177
    PubMedGoogle Scholar
  • 52 Barker D, Schafer M, White R. Restriction sites containing CpG show a higher frequency of polymorphism in human DNA. Cell 1984; 36: 131-138
    CrossrefPubMedGoogle Scholar
  • 53 Saiki RK, Bugawan TL, Horn GT, Mullis KB, Erlich HA. Analysis of enzymatically amplified β-globin and HLA-DQβ DNA with allele-specific oligonucleotide probes. Nature 1986; 324: 163-166
    CrossrefPubMedGoogle Scholar
  • 54 Myers RM, Lumelsky N, Lerman LS, Maniatis T. Detection of single base substitutions in total genomic DNA. Nature 1985; 313: 495-498
    CrossrefPubMedGoogle Scholar
  • 55 Orita M, Suzuki Y, Sekiya T, Hayashi K. Rapid and sensitive detection of point mutations and DNA polymorphisms using the polymerase chain reaction. Genomics 1989; 5: 874-879
    CrossrefPubMedGoogle Scholar
  • 56 Driscoll CM, Chiu C, Hilgartner MW. A Kpnl DNA polymorphism in the human von Willebrand factor (vWF) gene. Nucleic Acids Res 1990; 18: 4968
    PubMedGoogle Scholar