DNA encoding canine von willebrand factor and methods of use

Details DNA encoding canine von willebrand factor and methods of use DNA encoding canine von willebrand factor and methods of use

2000-09-15

2004-08-24

Whisenant, Ethan (Department: 1637)

Chemistry: molecular biology and microbiology

Measuring or testing process involving enzymes or...

Involving nucleic acid

C435S091200, C435S252300, C435S325000, C536S022100, C536S024300

Reexamination Certificate

active

06780583

ABSTRACT:

FIELD OF THE INVENTION
This invention relates generally to canine von Willebrand factor (vWF), and more particularly, to the gene encoding vWF as well as a genetic defect that causes canine von Willebrand's disease.
BACKGROUND OF THE INVENTION
In both dogs and humans, von Willebrand's disease (vWD) is a bleeding disorder of variable severity that results from a quantitative or qualitative defect in von Willebrand factor (vWF) (Ginsburg, D. et al.,
Blood
79:2507-2519 (1992); Ruggeri, Z. M., et al.,
FASEB J
7:308-316 (1993); Dodds, W. J.,
Mod Vet Pract
681-686 (1984); Johnson, G. S. et al.,
JAVMA
176:1261-1263 (1988); Brooks, M.,
Probl In Vet Med
4:636-646 (1992)). This clotting factor has two known functions, stabilization of Factor VIII (hemophilic factor A) in the blood, and aiding the adhesion of platelets to the subendothelium, which allows them to provide hemostasis more effectively. If the factor is missing or defective, the patient, whether human or dog, may bleed severely.
The disease is the most common hereditary bleeding disorder in both species, and is genetically and clinically heterogenous. Three clinical types, called 1, 2, and 3 (formerly I, II, and II; see Sadler, J. E. et al.,
Blood
84:676-679 (1994) for nomenclature changes), have been described. Type 1 vWD is inherited in a dominant, incompletely penetrant fashion. Bleeding appears to be due to the reduced level of vWF rather than a qualitative difference. Although this is the most common form of vWD found in most mammals, and can cause serious bleeding problems, it is generally less severe than the other two types. In addition, a relatively inexpensive vasopressin analog (DDAVP) can help alleviate symptoms (Kraus, K. H. et al.,
Vet Surg
18:103-109 (1989)).
In Type 2 vWD, patients may have essentially normal levels of vWF, but the factor is abnormal as determined by specialized tests (Ruggeri, Z. M., et al.,
FASEB J
7:308-316 (1993); Brooks, M.,
Probl In Vet Med
4:636-446 (1992)). This type is also inherited in a dominant fashion and has only rarely been described in dogs (Turrentine, M. A., et al.,
Vet Clin North Am Small Anim Pract
18:275 (1988)).
Type 3 vWD is the most severe form of the disease. It is inherited as an autosomal recessive trait, and affected individuals have no detectable vWF in their blood. Serious bleeding episodes require transfusions of blood or cryoprecipitate to supply the missing vWF. Heterozygous carriers have moderately reduced factor concentrations, but generally appear to have normal hemostasis.
Scottish terriers have Type 3 vWD (Dodds, W. J.,
Mod Vet Pract
681-686 (1984); Johnson, G. S. et al.,
JAVMA
176:1261-1263 (1988)). Homozygotes have no detectable vWF and have a severe bleeding disorder. Heterozygotes have reduced levels of the factor, and are clinically normal (Brooks, M. et al.,
JAVMA
200:1123-1127 (1992)). The prevalence of vWD among Scottish terriers including both heterozygotes and homozygotes has been variously estimated from 27-31% (Stokol, T. et al.,
Res. Vet. Sci
. 59:152-155 (1995); Brooks, M.,
Proc
. 9
th ACVIM Forum
89-91 (1991)).
Currently, detection of affected and carrier Scottish terrier dogs is done by vWF antigen testing (Benson, R. E. et al.,
Am J Vet Res
44:399-403 (1983); Stokol, T. et al.,
Res. Vet. Sci
. 59:152-155 (1995)) or by coagulation assays (Rosborough, T. K. et al.,
J. Lab. Clin. Med
. 96:47-56 (1980); Read, M. S. et al.,
J. Lab. Clin. Med
. 101:74-82 (1983)). These procedures yield variable results, as the protein-based tests can be influenced by such things as sample collection, sample handling, estrous, pregnancy vaccination, age, and hypothyroidism (Strauss, H. S. et al.,
New Eng J Med
269:1251-1252 (1963); Bloom, A. L.,
Mayo Clin Proc
66:743-751 (1991); Stirling, Y. et al.,
Thromb Haemostasis
52:176-182 (1984); Mansell, P. D. et al.,
Br. Vet. J
. 148:329-337 (1992); Avgeris, S. et al.,
JAVMA
196:921-924 (1990); Panciera, D. P. et al.,
JAVMA
205:1550-1553 (1994)). Thus, for example, a dog that tests within the normal range on one day, can test within the carrier range on another day. It is therefore difficult for breeders to use this information.
It would thus be desirable to provide the nucleic acid sequence encoding canine vWF. It would also be desirable to provide the genetic defect responsible for canine vWD. It would further be desirable to obtain the amino acid sequence of canine vWF. It would also be desirable to provide a method for detecting carriers of the defective vWF gene based on the nucleic acid sequence of the normal and defective vWF gene.
SUMMARY OF THE INVENTION
The present invention provides a novel purified and isolated nucleic acid sequence encoding canine vWF. Nucleic acid sequences containing the mutations that cause vWD in Scottish terriers, Doberman pinschers, Shetland sheepdogs, Manchester terriers and Poodles are also provided. The nucleic acid sequences of the present invention may be used in methods for detecting carriers of the mutation that causes vWD. Such methods may be used by breeders to reduce the frequency of the disease-causing allele and the incidence of disease. In addition, the nucleic acid sequence of the canine vWF provided herein may be used to determine the genetic defect that causes vWD in other breeds as well as other species.
Additional objects, advantages and features of the present invention will become apparent from the following description, taken in conjunction with the accompanying drawings.


REFERENCES:
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patent: WO 96/15262 (1996-05-01), None
patent: WO 98/03683 (1998-01-01), None
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Avgeris, S. et al. “Plasma von Willebrand Factor Concentration and Thyroid Function in Dogs”JAVMA196:921-92 (1990).
Bakhshi, M.R. et al. Sequencing of the Primary Adhesion Domain of Bovine von Willebrand Factor:Biochem. Biophys. Acta1132:325-28 (1992).
Benson, R.E. et al. “Efficiency and Precision of Electroimmunoassay for Canine Factor VIII-Related Antigen”Am. J. Vet. Res.44:399-403 (1983).
Bergenhem, N.C.H. et al. “Mutation Creates an Open Reading Frame within the 5′ Untranslated Region of Macaque Erythrocyte Carbonic Anhydrase (CA) I mRNA that Suppresses CA I Expression and Supports the Scanning Model for Translation”Proc. Natl. Acad. Sci. USA89:8789-8802 (1992).
Bloom, A.L. “Von Willebrand Factor: Clinical Features of Inherited and Acquired Disorders”Mayo Clin. Proc.66:743-51 (1991).
Bonthron, D. et al. “Nucleotide Sequence of Pre-Pro-von Willebrand Factor cDNA”Nucleic Acids Res.14:7125-27 (1986).
Brinkhous, K.M. et al. “Pathophysiology of Platelet-Aggregating von Willebrand Factor: Applications of the Venom Coagglutinin vWF Assay”Ann. New York Acad. Sci.370:191-204 (1981).
Brooks, M. “Clinical Features of Canine von Willebrand's Disease”Proc. 9thACVIM Forum:89-91 (1991).
Brooks, M. “Management of Canine von Willebrand's Disease”Probl. In Vet. Med.4:636-46 (1992).
Brooks, M. et al. “Epidemiologic Features of von Willebrand's Disease in Doberman Pinschers, Scottish Terriers, and Shetland Sheepdogs: 260 Cases (1984-1988)”JAVMA200:1123-27 (1992).
Dodds, W.J. “Von Willebrand's Disease in Dogs”Mod. Vet. Pract.618-686 (1984).
Database entry CTLVWC Accession No. 7622 Story S.J. et al., Canis familiaris complete cds.
Ginsberg, D. et al. “Molecular Genetics of von Willebrand Disease”Blood79:2507-19 (1992).
Holmes, N. et al., “Von Wille-brand's disease in UK dobermanns: possible correlation of a polymorphic DNA marker with disease status,”J. Small Anim. Pract.,Jul. 1996;37(7):307-8.
Janel, N. et al. “Comparison of the 5′-Flanking Sequences of the Human and Bovine von Willebrand Factor-Encoding Genes Reveals Alternation of Highly Homologous Domains with Species-Specific Alu-Type Repeats”Gene167:291-95 (1995).
Johnson, G.S. et al. “A Bleeding Disease (von Willebrand's Disease) in a Chesapeake Bay Retriever”JAVMA176:1261-63 (19

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