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von Willebrand disease phenotype and von Willebrand factor marker genotype in Doberman Pinschers

Marjory B. Brooks DVM1, Hollis N. Erb DVM, PhD2, Polly A. Foureman DVM, PhD3,4, and Kunal Ray PhD5
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  • 1 Comparative Coagulation Section, Diagnostic Laboratory, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853.
  • | 2 Department of Population Medicine and Diagnostic Science, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853.
  • | 3 Comparative Coagulation Section, Diagnostic Laboratory, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853.
  • | 4 Present address is Section of Medical Genetics, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104.
  • | 5 Division of Human Genetics and Genomics, Indian Institute of Chemical Biology, Calcutta, India.

Abstract

Objective—To define the relationship between clinical expression of a type-1 von Willebrand disease phenotype and genotype at 2 von Willebrand factor marker loci in Doberman Pinschers.

Animals—102 client-owned Doberman Pinschers.

Procedures—Dogs were recruited on the basis of plasma von Willebrand factor concentration, clinical history, and pedigree. Blood samples and response to a history questionnaire were obtained for each dog. Plasma von Willebrand factor concentration was measured by use of an ELISA, and genotyping was performed via polymerase chain reaction for 1 intragenic and 1 extragenic von Willebrand factor marker. Amplification product size was determined by use of polyacrylamide gel electrophoresis (intragenic marker) or automated sequence analysis (extragenic marker). Western blots were prepared from a subset of dogs with low plasma von Willebrand factor concentration to evaluate multimer distribution.

Results—Strong associations were detected between plasma von Willebrand factor concentration and von Willebrand factor marker genotype. Twentyfive dogs had substantial reduction in plasma von Willebrand factor concentration and multiple hemorrhagic events. All were homozygous for a 157-basepair intragenic marker allele and homozygous or compound heterozygous for 1 of 4 extragenic marker alleles. These marker genotypes were exclusively detected in dogs with low plasma von Willebrand factor concentration, although some dogs with these genotypes did not have abnormal bleeding.

Conclusions and Clinical Relevance—Type-1 von Willebrand disease in Doberman Pinschers is associated with the von Willebrand factor gene locus; however, the expression pattern in this breed appears more complex than that of a simple recessive trait. (Am J Vet Res 2001;62:364–369)