The Canine von Willebrand Story  George J. Brewer, MD  University of Michigan Medical School

Summary:

Von Willebrand's disease is a bleeding disorder, common in humans and dogs, due to a reduced level, or a defect in, von Willebrand's factor (vWF). The gene was cloned in the human and many different mutations found, which explained much of the variability in the severity of the bleeding tendency. We set out to find the mutations causing canine vWD.

With collaborators from the veterinary school at Michigan State University, we originally found three mutations. The type III (severe) vWD of Scotties is an autosomal recessive mutation that completely knocks out the function of the gene. The type III vWD of Shelties is due to a different, autosomal recessive mutation that also knocks out gene function. The type I (mild) vWD of Dobermans is due to a different, autosomal recessive, splice-site mutation that cripples the gene to about five to ten percent of its normal function.  This small remaining normal function explains why the disease is milder in the Doberman.

Subsequent study has shown that the same mutation present in Dobermans accounts for vWD in Manchester Terriers, Poodles, and Pembroke Welsh Corgis.

The frequency of the vWD mutation is very high in Dobermans, such that only 20 percent of dogs are clear, while 30 percent are affected and 50 percent are carriers. This means that breeding strategies must go beyond breeding clear to clear, to avoid unduly narrowing the gene pool of the breed. Clear to carrier breeding is safe, and the mutant gene can be eliminated gradually over two to three generations. Even affected to clear breeding is safe, although gradually eliminated by breeding the carriers to clear animals.

The mutations, their frequency in the various breeds, their clinical implications, their relationship to vWF assay, and breeding strategies will be discussed.

Dr. Brewer's work is supported by the following grants from the AKC Canine Health Foundation, as well as grants from Morris Animal Foundation, and the Orthopedic Foundation for Animals:

No. 1440 (Completed): Causative Mutation for von Willebrand's Disease (Sponsored in part by the American Miniature Schnauzer Club, American Rottweiler Club and Poodle Club of America) No. 1663: Identifying the Genetic Cause of Canine Progressive Rod-Cone Disease (PRCD Type of PRA) No. 1835: Identifying the Causes of Canine Epilepsy No. 1836: Identifying the Genetic Cause of Canine Hip Dysplasia No. 1858: Identifying the Genetic Causes of Renal Dysplasia in Shih Tzu, Lhasa Apso and Soft Coated Wheaten Terriers (Supported in part by the American Lhasa Apso Club, American Shih Tzu Club and the Soft Coated Wheaten Terrier Club of America)

Biographical Profile

George J. Brewer, MD, went to undergraduate school (Pharmacy) at Purdue University, and to medical school at Indiana University and the University of Chicago. He did residency training at the University of Chicago, and then did a postdoctoral fellowship in Human Genetics at the University of Michigan. He has been on the faculty at the University of Michigan since 1967, and is a Professor of Human Genetics and a Professor of Internal Medicine.

Dr. Brewer's research has involved human genetic diseases, such as sickle cell anemia and Wilson's disease (human copper toxicosis). Over the last fifteen years he has worked extensively in the molecular genetics of canine diseases, such as copper toxicosis, von Willebrand's disease, renal dysplasia, hip dysplasia, cataract, epilepsy and others. He is one of the founders of VetGen, LLC, an Ann Arbor-based company offering a variety of DNA tests for canine diseases and traits.