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Thromb Haemost 1998; 80(02): 332-337
DOI: 10.1055/s-0037-1615197
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Schattauer GmbH

Identification of Mutations in the Canine von Willebrand Factor Gene Associated with Type III von Willebrand Disease

M. Rieger
1   Department of Laboratory Medicine, Molecular Biology Division, University of Vienna, Medical School, Vienna, Austria
2   Hyland/Immuno, Division of Baxter Healthcare, Vienna, Austria
,
H. P. Schwarz
2   Hyland/Immuno, Division of Baxter Healthcare, Vienna, Austria
,
P. L. Turecek
2   Hyland/Immuno, Division of Baxter Healthcare, Vienna, Austria
,
F. Dorner
2   Hyland/Immuno, Division of Baxter Healthcare, Vienna, Austria
,
van J. A. Mourik
3   Central Laboratory of the Netherlands Red Cross Blood Transfusion Center, Amsterdam, The Netherlands
,
C. Mannhalter
1   Department of Laboratory Medicine, Molecular Biology Division, University of Vienna, Medical School, Vienna, Austria
› Author Affiliations
Further Information

Publication History

Received 09 January 1998

Accepted after revision 15 April 1998

Publication Date:
08 December 2017 (online)

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Summary

In humans, type III von Willebrand disease is caused by deletions or nonsense mutations. In dogs, the underlying genetic defects have not been determined yet. We searched for the genetic defect in four related type III deficient Dutch Kooiker dogs obtained from one breeder. Mutation analysis was performed with total RNA isolated from platelets or whole blood. The complete coding region of the vWf gene was amplified by RT-PCR and sequenced by the cycle sequencing technique. Two homozygous mutations were found, a G→A transition at the first position of the donor splice site sequence of intron 16 (TGgtaagt→TGataagt) and a missense mutation at nt 208 (G→A) (1). The splice site defect resulted in the generation of a transcript containing 46bp of intron sequence and a stop codon at amino acid position 729 in the propeptide region of the vWf protein. This mutation seems to be causative for the type III phenotype. The effect of the missense mutation in exon 3 which causes a change of Val to Ile on the vWD phenotype is unclear. Probably, this transition represents a polymorphism occurring in Dutch Kooiker dogs. Both mutations were not present in 5 healthy mongrel dogs.

Parts of this paper were presented at the 39th annual meeting of the American Society of Hematology (ASH), December 5-9, San Diego, USA

 

  • References

  • 1 Rieger M, Schwarz HP, Turecek PL, Dorner F, van Mourik JA, Mannhalter C. Identification of the genetic defect in type III von Willebrand factor deficient Dutch Kooiker dogs. Blood 1997; 90 (Suppl. 01) 2079 (abstr.).
    PubMedGoogle Scholar
  • 2 Ruggeri ZM, Ware J. von Willebrand factor. FASEB J 1993; 7: 308-16.
    CrossrefPubMedGoogle Scholar
  • 3 Ruggeri ZM. von Willebrand factor. J Clin. Invest 1997; 99: 559-64.
    CrossrefPubMedGoogle Scholar
  • 4 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: 1401-6.
    CrossrefPubMedGoogle Scholar
  • 5 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
  • 6 Verweij CL, Diergaarde PJ, Hart M, Pannekoek H. Full length von Willebrand factor (vWF) cDNA encodes a highly repititive protein, considerably larger than mature vWF. EMBO J 1986; 5: 183-9.
    PubMedGoogle Scholar
  • 7 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. Biochem 1986; 25: 3164-71.
    CrossrefPubMedGoogle Scholar
  • 8 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. Biochem 1991; 30: 235-69.
    PubMedGoogle Scholar
  • 9 McCarrol DR, Lothrop SA, Dolan MC, McDonald TP. Canine von Willebrand factor expresses a multimeric composition similar to human von Willebrand factor. Exp Hematol 1987; 15: 1060-7.
    PubMedGoogle Scholar
  • 10 Montgomery RR, Fahs S, Montgomery MW, Mancuso DJ. Cloning and sequencing of canine von Willebrand factor. Blood 1996; 88 (Suppl. 01) 1295 (abstr.).
    PubMedGoogle Scholar
  • 11 Stoy SJ, Shibuya H, Nonneman DJ, Holzhauer J, Mohammed IC, Johnson GS. Canine vWF cDNA sequence. Unpublished 1996, Genbank accession: L76227.
    PubMed
  • 12 Shibuya H, Collins BK, Huang THM, Johnson GS. A polymorphic (AGGAAT)n tandem repeat in an intron of the canine von Willebrand factor gene. Anim Gen 1994; 25: 122.
    PubMedGoogle Scholar
  • 13 Montgomery RR, Coller BS. von Willebrand disease. In: Hemostasis and Thrombosis: Basic Principles and Clinical Practice. Third Edition, Colman RW, Hirsh J, Marder VJ, Salzman EW, eds. Philadelphia: J. B. Lippincott Company; 1994
    Google Scholar
  • 14 Eikenboom JCJ, Matsushita T, Reitsma PH, Tuley EA, Castaman G, Briet E, Sadler JE. Dominant type I von Willebrand disease caused by mutated cysteine residues in the D3 domain of von Willebrand factor. Blood 1996; 88: 2433-41.
    PubMedGoogle Scholar
  • 15 Kroner PA, Foster PA, Fahs SA, Montgomery RR. The defective interaction between von Willebrand factor and factor VIII in a patient with type I von Willebrand disease is caused by substitution of Arg19 and His54 in mature von Willebrand factor. Blood 1996; 87: 1013-21.
    PubMedGoogle Scholar
  • 16 Sadler JE, Matsushita T, Dong Z, Tuley EA, Westfield LA. Molecular mechanism and classification of von Willebrand disease. Thromb Haemost 1995; 74: 161-6.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 17 Gu J, Jorieux S, Lavergne JM, Ruan C, Mazurier C, Meyer D. A patient with type 2N von Willebrand disease is heterozygous for a new mutation: Gly22Glu. Demonstration of a defective expression of the second allele by the use of monoclonal antibodies. Blood 1997; 89: 3263-9.
    PubMedGoogle Scholar
  • 18 Meyer D, Fressinaud E, Gaucher C, Lavergne JM, Hilbert L, Ribba AS, Jorieux S, Mazurier C. Gene defects in 150 unrelated french cases with type II von Willebrand disease: from the patient to the gene. Thromb Haemost 1997; 78: 451-6.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 19 Ginsburg D, Sadler JE. Von Willebrand disease: A database of point mutations, insertions, and deletions. Thromb Haemost 1993; 69: 177-84.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 20 Stokol T, Parry BW. Canine von Willebrand disease: A Review. Aust Vet Practit 1993; 23: 94-103.
    PubMedGoogle Scholar
  • 21 Slappendel RJ. von Willebrand`s disease in Dutch Kooiker dogs. Vet Quart 1995; 17: 21-2.
    PubMedGoogle Scholar
  • 22 Thomas JS. von Willebrand disease in the dog and cat. Vet Clin North Am Small Anim Pract 1996; 26: 1089-110.
    CrossrefPubMedGoogle Scholar
  • 23 Stokol T, Parry BW, Mansell PD. Factor VIII activity in canine von Willebrand disease. Vet Clin Pathol 1995; 24: 81-90.
    CrossrefPubMedGoogle Scholar
  • 24 Sambrook T, Fritsch EF, Maniatis J. In: Molecular cloning: A Laboratory Manual. 1989 Cold Spring Harbor Laboratory, Cold Spring Harbor; NY.:
    Google Scholar
  • 25 Maurer J, Janssen JWG, Thiel E, van Denderen J, Ludwig WD, Aydemir Ü, Heinze B, Fonatsch C, Harbott J, Reiter A, Riehm H, Hoelzer D, Bartram CR. Detection of chimeric BCR-ABL genes in acute lymphoblastic leukemia by the polymerase chain reaction. Lancet 1991; 337: 1055-62.
    CrossrefPubMedGoogle Scholar
  • 26 Sadler JE. von Willebrand factor. J Biol Chem 1991; 266: 22777-80.
    PubMedGoogle Scholar
  • 27 Ginsburg D, Konkle BA, Gill JC, Montgomery RR, Blockenstedt PL, Johnson TA, Yang AY. Molecular basis of human von Willebrand disease: analysis of platelet von Willebrand factor mRNA. Proc Natl Acad Sci USA 1989; 86: 3723-7.
    CrossrefPubMedGoogle Scholar
  • 28 Mustafa S, Pabinger I, Mannhalter C. Protein S deficiency type I: identification of point mutations in 9 of 10 families. Blood 1995; 86: 3444-51.
    PubMedGoogle Scholar
  • 29 Kanno H, Fujii H, Wie DC, Chan LC, Hirono A, Tsukimoto I, Miwa S. Frame shift mutation, exon skipping, and a two-codon deletion caused by splice site mutations account for pyruvate kinase deficiency. Blood 1997; 89: 4213-8.
    PubMedGoogle Scholar
  • 30 Okubo M, Hasegawa Y, Aoyama Y, Murase T. A G+1 to C mutation in a donor splice site of intron 2 in the apolipoprotein (apo) C-II gene in a patient with apo C-II deficiency. A possible interaction between apo C-II deficiency and apo E4 in a severly hypertrigyceridemic patient. Arthero-sclerosis 1997; 130: 153-60.
    CrossrefPubMedGoogle Scholar
  • 31 Bahnak BB, Lavergne JM, Rothschild C, Meyer D. A stop codon in a patient with severe type III von Willebrand disease. Blood 1991; 78: 1148 (letter).
    PubMedGoogle Scholar
  • 32 Eikenboom JCJ, Ploos van Amstel HK, Reitsma PH, Briet 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
  • 33 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’s disease types III and I. Am J Hum Genet 1992; 51: 870-8.
    PubMedGoogle Scholar
  • 34 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
  • 35 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 heterogenity of severe von Willebrand disease Type III in the german population. Hum Genet 1994; 94: 640652.
    PubMedGoogle Scholar
  • 36 Turecek PL, Gritsch H, Richter G, Auer W, Pichler L, Schwarz HP. Assessment of bleeding for the evaluation of therapeutic preparations in small animal models of antibody-induced hemophilia and von Willebrand disease. Thromb Haemost 1997; 77: 591-9.
    Article in Thieme ConnectPubMedGoogle Scholar