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Thromb Haemost 2000; 84(04): 536-540
DOI: 10.1055/s-0037-1614063
Review Article
Schattauer GmbH

Molecular Characterization of a Multiethnic Group of 21 Patients with Type 3 von Willebrand Disease

Luciano Baronciani
2   From the Angelo Bianchi Bonomi Hemophilia and Thrombosis Center and Fondazione Luigi Villa, IRCCS Maggiore Hospital and University of Milan, Italy
,
Giovanna Cozzi
2   From the Angelo Bianchi Bonomi Hemophilia and Thrombosis Center and Fondazione Luigi Villa, IRCCS Maggiore Hospital and University of Milan, Italy
,
Maria Teresa Canciani
2   From the Angelo Bianchi Bonomi Hemophilia and Thrombosis Center and Fondazione Luigi Villa, IRCCS Maggiore Hospital and University of Milan, Italy
,
Flora Peyvandi
2   From the Angelo Bianchi Bonomi Hemophilia and Thrombosis Center and Fondazione Luigi Villa, IRCCS Maggiore Hospital and University of Milan, Italy
,
Alok Srivastava
1   Department of Hematology, Christian Medical College Hospital, Vellore, India
,
Augusto Bramante Federici
2   From the Angelo Bianchi Bonomi Hemophilia and Thrombosis Center and Fondazione Luigi Villa, IRCCS Maggiore Hospital and University of Milan, Italy
,
Pier Mannuccio Mannucci
2   From the Angelo Bianchi Bonomi Hemophilia and Thrombosis Center and Fondazione Luigi Villa, IRCCS Maggiore Hospital and University of Milan, Italy
› Author AffiliationsWe would like to thank Dr. P. V. Jenkins (Royal Free Hospital, London, UK) for helpful criticism and advice. The financial support of the Foundation Angelo Bianchi Bonomi and Foundation Luigi Villa is gratefully acknowledged.
Further Information

Publication History

Received 12 April 2000

Accepted after revision 06 July 2000

Publication Date:
11 December 2017 (online)

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Summary

Type 3 von Willebrand disease is a rare autosomal disorder characterized by unmeasurable levels of von Willebrand factor and severe hemorrhagic symptoms. We studied a multiethnic group of 37 patients, from Italy (n = 14), Iran (n = 10) and India (n = 13) to identify the molecular defects and to evaluate genetic heterogeneity among these populations. Twenty-one patients (6 Italians, 9 Iranians and 6 Indians) were fully characterized at the molecular level. Twenty-four different gene alterations were identified, 20 of which have not been described previously. The majority of the mutations caused null alleles, 11 being nonsense mutations (Q218*, W222*, R365*, R373*, E644*, Q706*, S1338*, Q1346*, Y1542*, R1659*, E2129*), 4 small deletions (437delG, 2680delC, 6431delT, del 8491-8499), 3 possible splice site mutations [IVS9(-1)g→a, IVS29(+10)c→t, IVS40(-1)g → c], 3 candidate missense mutations (C275S, C2174G, C2804Y), 2 small insertions (7375insC, 7921insC) and 1 large gene deletion. The latter mutation was associated with the development of alloantibodies to VWF, but this complication was also found in a patient homozygous for a nonsense mutation (Q1346*). Due to the ethnic origin of the patients most of them were the offspring of consanguineous marriages and so were homozygous for the mutations found (18/21). Our results indicate that molecular defects responsible for type 3 VWD are scattered throughout the entire VWF gene (from exon 3 to 52), and that there is no prevalent and common gene defect in the three populations studied by us.

Keywords

von Willebrand factor - type 3 von Willebrand disease - gene analysis - mutation
 

  • References

  • 1 Ruggeri ZM, Zimmerman TS. von Willebrand factor and von Willebrand disease. Blood 1987; 70: 895-904.
    PubMedGoogle Scholar
  • 2 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 1989; 264: 19514-27.
    PubMedGoogle Scholar
  • 3 Mannucci PM, Bloom AL, Larrieu MJ, Nilsson IM, West RR. Atherosclerosis and von Willebrand factor I. Prevalence of severe von Willebrand’s disease in western Europe and Israel. Br J Haematol 1984; 57: 163-9.
    CrossrefPubMedGoogle Scholar
  • 4 Shelton-Inloes BB, Chehab FF, Mannucci PM, Federici AB, Sadler JE. Gene deletions correlate with the development of alloantibodies in von Willebrand disease. J Clin Invest 1987; 79: 1459-65.
    CrossrefPubMedGoogle Scholar
  • 5 Ngo KY, Glotz VT, Koziol JA, Lynch DC, Gitschier J, Ranieri P, Ciavarella N, Ruggeri ZM, Zimmerman TS. Homozygous and heterozygous deletions of the von Willebrand factor gene in patients and carriers of severe von Willebrand diease. Proc Natl Acad Sci USA 1988; 85: 2753-7.
    CrossrefPubMedGoogle Scholar
  • 6 Peake IR, Liddell MB, Moodie P, Standen G, Mancuso DJ, Tuley EA, Westfield LA, Sorace JM, Sadler JE, Verweij CL, Bloom AL. 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: 654-61.
    PubMedGoogle Scholar
  • 7 Mancuso DJ, Tuley EA, Castillo R, de Bosch N, Mannucci PM, Sadler JE. Characterization of partial gene deletions in type III von Willebrand disease with alloantibody inhibitors. Thromb Haemost 1994; 72: 180-5.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 8 Schneppenheim R, Krey S, Bergmann F, Bock D, Budde U, Lange M, Linde R, Mittler U, Meili E, Mertes G, Olek K, Plendl H, Simeoni E. Genetic heterogeneity of severe von Willebrand disease type III in the German population. Hum Genet 1994; 94: 640-52.
    PubMedGoogle Scholar
  • 9 Eikenboom JCJ, Castaman G, Vos HL, Bertina RM, Rodeghiero F. Characterization of the genetic defects in recessive type 1 and type 3 von Willebrand disease patients of Italian origin. Thromb Haemost 1998; 79: 709-17.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 10 Abuzenadah AM, Gursel T, Ingerslev J, Nesbitt IM, Peake IR, Goodeve AC. Mutational analysis of the von Willebrand factor gene in 27 families from Turkey with von Willebrand disease. Thromb Haemost 1999; 82 (Suppl) 283.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 11 Surdhar GK, Enayat MS, Lawson S, Williams MD, Hill FGH. Multiple mutations in vWF gene of boy with severe von Willebrand disease. Thromb Haemost 1999; 82 (Suppl) 583.
    PubMedGoogle Scholar
  • 12 Zhang ZP, Falk G, Blombäck 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 von Willebrand disease type III patients. Hum Molec Gen 1992; 01: 767-8.
    PubMedGoogle Scholar
  • 13 Zhang ZP, Blombäck M, Egberg N, Falk G, Anvret M. Characterization of the von Willebrand factor gene (vWF) in von Willebrand disease type III patients from 24 families of Swedish and Finnish origin. Genomics 1994; 21: 188-93.
    CrossrefPubMedGoogle Scholar
  • 14 Bahnak BR, Lavergne JM, Rothschild C, Meyer D. A stop codon in a patient with severe type III von Willebrand disease. Blood 1991; 78: 1148-9.
    PubMedGoogle Scholar
  • 15 Zhang ZP, Lindstedt M, Falk G, Blombäck 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 1992; 51: 850-8.
    PubMedGoogle Scholar
  • 16 Eikenboom JCJ, Ploos van HKAmstel, Reitsma PH, Briët E. Mutations in severe type III von Willebrand’s disease in the Dutch population: candidate missense and nonsense mutations associated with reduced levels of von Willebrand factor messenger RNA. Thromb Haemost 1992; 68: 448-54.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 17 Hagiwara T, Inaba H, Yoshida S, Nagaizumi K, Arai M, Hanabusa H, Fukutake K. A novel mutation Gly 1672→Arg in type 2A and a homozygous mutation in type 2B von Willebrand disease. Thromb Haemost 1996; 76: 253-7.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 18 Schneppenheim R, Brassard J, Budde U, Krey S, Schwaab R, Oldenburg J. Defective dimerization of von Willebrand factor – A new class of mutations in vWD type 2 and type 3. Thromb Haemost 1997; 77 (Suppl) 389.
    PubMedGoogle Scholar
  • 19 Montgomery RR, Jozwiak MA, Hutter JJ, Endres JL, Foster PA, Friedman KD. A homozygous variant of the von Willebrand factor (VWF) that fails to c-terminal dimerize resulting in loss of VWF multimers larger than dimer. Blood 1999; 94 (Suppl. 01) 443a.
    PubMedGoogle Scholar
  • 20 Casana P, Martinez F, Lorenzo JI, Haya S, Espinos C, Tavares A, Aznar JA. New mutations detected in patients with different types of von Willebrand disease. Thromb Haemost 1999; 82 (Suppl) 614.
    PubMedGoogle Scholar
  • 21 Gazda H, Budde U, Krey S, Rokicka-Milewska RSchneppenheim. Delta C in exon 18 of the von Willebrand factor gene is the most common mutation in patients with severe von Willebrand disease type 3 in Poland. Blood 1997; 90 (Suppl. 01) 94b.
    PubMedGoogle Scholar
  • 22 Federici AB, Tombesi S, Coppola R, Colibretti ML, Gobbi M, Albertini A, Mannucci PM. Preliminary results on the characterization of monoclonal antibodies to von Willebrand factor. In: Biotecnol Plasma Proteins; 1990: 56.
    Google Scholar
  • 23 Mannucci PM, Meyer D, Ruggeri ZM, Koutts J, Ciavarella N, Lavergne JM. Precipitating antibodies in von Willebrand’s disease. Nature 1976; 262: 141-2.
    CrossrefPubMedGoogle Scholar
  • 24 Ruggeri ZM, Ciavarella N, Mannucci PM, Molinari A, Dammacco F, Lavergne JM, Meyer D. Familial incidence of precipitating antibodies in von Willebrand disease: a study of four cases. J Lab Clin Med 1979; 94: 60-75.
    PubMedGoogle Scholar
  • 25 Mannucci PM, Ruggeri ZM, Ciavarella N, Kazatchkine MD, Mowbray JF. Precipitating antibodies to factor VIII/von Willebrand factor in von Willebrand’s disease: effects on replacement therapy. Blood 1981; 57: 25-31.
    PubMedGoogle Scholar
  • 26 Sambrook J, Fritsch EF, Maniatis T. Molecular cloning: A laboratory manual. 2 ed. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press; 1989
    Google Scholar
  • 27 Sadler JE. A revised classification of von Willebrand disease. Thromb Haemost 1994; 71: 520-5.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 28 Heker KH, Roux KH. High and low annealing temperatures increase both specificity and yield in TD and SD PCR. BioTechniques 1996; 20: 478-85.
    CrossrefPubMedGoogle Scholar
  • 29 Orita M, Iwahana H, Kanazawa H, Hayashi K, Sekiya T. Detection of polymorphisms of human DNA by gel electrophoresis as single-strand conformation polymorphisms. Proc Natl Acad Sci USA 1989; 86: 2766-70.
    CrossrefPubMedGoogle Scholar
  • 30 Mannucci PM, Federici AB. Antibodies to von Willebrand factor in von Willebrand disease. In: Inhibitors to coagulation factors. Aledort LM, Hoyer LW, Reisner HM, White II GC. (eds) New York: Plenum Press; 1995: 87-92.
    Google Scholar
  • 31 Eikenboom JCJ, Briët E, Reitsma PH, Ploos van HKAmstel. Severe type III von Willebrand’s disease in the Dutch population is often associated with the absence of von Willebrand factor messenger RNA. Thromb Haemost 1991; 65: 1127.
    PubMedGoogle Scholar
  • 32 Wise RJ, Pittman DD, Handin RI, Kaufman RJ, Orkin SH. The propeptide of von Willebrand factor independently mediates the assembly of von Willebrand multimers. Cell 1988; 52: 229-36.
    CrossrefPubMedGoogle Scholar
  • 33 Mayadas TN, Wagner DD. In vitro multimerization of von Willebrand factor is triggered by low pH: importance of the propolypeptide and free sulfhydryls. J Biol Chem 1989; 264: 13497-503.
    PubMedGoogle Scholar
  • 34 Allen S, Abuzenadah AM, Daly ME, Goodeve AC, Gursel T, Ingerslev J, Peake IR. Arg273Trp mutation in the Von Willebrand factor propeptide results in impaired secretion. Thromb Haemost 1999; 82 (Suppl) 687.
    PubMedGoogle Scholar
  • 35 Budde U, Obser T, Brassard J, Drewke E, Krey S, Oldenburg J, Ruggeri ZM, Schwaab R, Ware J. Von Willebrand factor dimerization defects cause different types of Von Willebrand disease. Blood 1999; 94 (Suppl. 01) 453a.
    PubMedGoogle Scholar