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FAQ's about vWD in Doberman Pinschers

Email correspondence between Dr. Patrick Venta and James Anable Jr.

Posted on [DOBERWORLD-L] listserv
Date: Tue, 19 Nov 1996 12:17:14 -0800
From: "James W. Anable, Jr."
Subject: READ THIS--Dr. Venta's response to vWD questions List members

Hi Jim,

My colleagues finally had a chance to comment and make changes to this letter to you, and so it is now a joint effort. So here it is.

As you know, VetGen is now offering DNA tests for von Willebrand's disease (vWD) in Scotties, Shelties, and Dobes, and Kristi, of VetGen, is beginning to post information about these tests. The responses indicate some confusion, particularly about the Doberman. You have asked me, as one of the investigators who discovered the mutation, to clarify the genetics and usefulness of the new DNA tests. This is a fairly long letter, and I will apologize for its length now, but I felt that much of what is presented is information that you and other interested parties will want. I have not followed the posts for the lists, so I hope that you will forgive me if I might repeat something that has already been said a million times.

A key part of this message that you must understand is that we now know the precise DNA mutations and why and how they cause vWD in these three breeds. So all past hypotheses and speculations in the Merck Vet Manual and elsewhere, which were based upon the old protein-based factor assay, are out the window. Ignore them--they are past history. Now that we have the mutations in Scotties, Shelties, and Dobes, we can speak from fact not speculation regarding these three breeds. We are working on other breeds as well, but we cannot promise the date at which we will find any of the other mutations (although, of course, we hope it will be sooner rather than later).

The bottom line of what is given below is as follows: (1) vWD in Doberman pinschers is a true clinical disease in which affected animals are predisposed to have abnormally (and sometimes fatally) prolonged bleeding times. (2) The Dobe disease is recessively inherited, contrary to what some previous research had suggested in the past. (3) Carriers are unlikely to have bleeding problems but affected (that is, homozygous mutant) animals are at a significant risk of serious bleeding problems, if they undergo surgery or sustain moderate trauma. Penetrance is *far* less important than was inferred from the dominant, incompletely penetrant model. (4) If this one mutant gene was eliminated from the breed, vWD would become a very rare disease, indeed, in Dobes.

I will begin by describing the disease in two other breeds, because I believe that this will lead into the Dobe situation very well. Both the Scottie and Sheltie have the severe Type 3 form of the disease. The Sheltie may be a rare exception to the rule, that better than 99% of any simply inherited disease in a breed is caused by one mutation. In other words, while the major and most severe form of vWD in Shelties is Type 3, there is a possibility that a minor portion of the vWD problem is due to Type 1 vWD. This is according to data developed by Dr. Jean Dodds and her colleagues (Brooks et al., 1992--see below for complete references). We are working to see if this is true (it seems likely). Type 2 vWD, by the way, has only been seen in only two breeds of dogs, German shorthaired pointers and German wirehair pointers, so we will ignore it, in this letter. Both the Scottie and Sheltie Type 3 vWDs are caused by mutations that prevent *any* von Willebrand factor (vWF) from being produced. The technical term for these mutations are "single base deletions." These diseases are recessive, so that both copies of the gene that a dog possesses must be mutant before the animal has a bleeding problem. Carriers almost never have bleeding problems (Johnson et al., 1988).

The Doberman pinscher mutation, on the other hand, is Type 1 but it is *recessively* inherited! Most human Type 1 vWD is inherited in a dominant, incompletely penetrant mode. There are two things that made the Dobe vWD appear to be inherited in a fashion like the human disease. (1) The Dobe mutation is what geneticists refer to as "leaky." That is, the mutant gene makes a small amount of normal vWF protein. The amount made by each mutant gene is about 5% of the total normal amount. A normal gene would make 50% (so that two genes produce 100%). (2) The frequency of the mutant gene in the Doberman pinscher breed is greater than 60%! The parent of an affected animal can be also be affected, due to the high gene frequency (thus, the apparent dominant inheritance), but this is not always the case (thus, the apparent incomplete penetrance). This result was easily (and understandably) misinterpreted as the dominant, incompletely penetrant mode of inheritance as seen in humans. In human genetics, it is assumed that each genetic disease is rare, and one would not expect the parents of "affecteds" to also be affected if the disease was recessive. With animals, rarity of a disease gene cannot always be assumed, as illustrated by Dobe vWD. Other researchers have also presented data and arguments that Dobe vWD is actually a recessive disease (Moser et al., 1996; Johnson et al., 1988). The identification of the mutation fully explains it. Homozygotes for the disease in Dobermans do *not* die in utero. The mode of inheritance with other breeds, such as the German shepherd dog, could still be dominant, incompletely penetrant. We simply are not certain of the inheritiance pattern for other breeds at this time.

Dobe carriers should produce 55% of normal vWF, on average (5% from the mutant gene and 50% from the normal gene). However, other biological variables can affect the amount of factor found in the blood. These variables include thyroid hormone level, estrous, liver status (diseased or not), etc. Variation can also be produced by inappropriate handling of the blood sample or some variability in the protein-based tests themselves. These variations for concentration of the protein in the blood can make an animal appear to be a carrier on one day and homozygous normal (clear) on the next (which value does a breeder believe?). This is why the protein-based tests are not as useful as they might otherwise be. The DNA-based tests are completely different, because they detect the genetic change at the gene level, which does not vary. There are only three possible results from the DNA-based test. An animal is either clear, a carrier, or affected. Re-testing is pointless, because the result will always be the same for a given animal. So one test is good for the life of the animal. Incidentally, we have also set up the test so that it is noninvasive (you swab the inside of the dog's mouth with a small, soft brush), convenient (you can send the brush by regular mail--no need to refrigerate), and you can test at any age, even young puppies.

Dobe *carriers* with abnormally long bleeding times are not common. Dodds, Johnson and Stokol et al. have all reported that animals do not usually bleed excessively when they have factor levels greater than 36% of normal (Dodds, 1982; Johnson et al., 1988; Stokol et al., 1995). Carriers will occasionally go below this level, but usually not by very much. Surveys of fairly large numbers of animals have been conducted, and the data appear to show the expected trimodel distributions for number of animals vs. factor concentrations (Dodds and Covey, 1981; Moser et al., 1996; Johnson et al., 1988; Stokol et al., 1995). By extrapolating the overlapping curves it can be seen that carriers do not dip into the danger range more than occasionally. Therefore, the fear that an animal who tests as a carrier might someday suddenly become a severe bleeder because of the dominant, incompletely penetrant scenario is completely negated. Occasional carriers might have bleeding times that are prolonged, but these are the exceptions. Clear animals will never bleed abnormally, due to hereditary vWD (the removal of the disease gene should be, after all, the eventual goal).

Fortunately, even affected Dobes usually do not bleed spontaneously (unlike the case for Scotties, and perhaps Shelties). If they did, there probably would have been a stronger natural selective pressure to remove the disease gene. However, with surgery or moderate trauma, these dogs are at risk for serious bleeding problems (there are numerous reports in the scientific literature addressing this fact, and I am sure that there have been numerous anecdotal reports in this forum as well). So the disease and its causative gene are something that breeders should most certainly want to remove from their breeding programs. This will have to be done with care, however, because we do not believe that it is in the best interest of the breed to limit the gene pool by breeding only clear to clear. By following the guidelines that Kristi at VetGen posted previously (also available at http://www.vetgen.com/), it should be possible to allow the desirable genes to separate from the disease gene over a few generations, while at the same time preventing the occurrence of affected animals.

The mutation that we have found accounts for essentially all of the vWD seen in Dobermans. It is always possible that a rare mutation in combination with the common mutation would cause a bleeder. However, this should be very rare, because the rate of occurrence of *new* mutations for most genes is between one in one hundred thousand to one in a million per generation (Crow, 1993 and references contained therein). If the mutation we have found is eliminated from the breed, von Willebrand's disease will also be eliminated from the breed (ignoring those one in a million new mutations that can never be prevented). The same is true for specific lines, as well. Breed out the disease gene (which can now be detected) and the disease will be gone from the line.

If some portion of this letter needs clarification, please let me know and I will do my best to do so. The other primary investigators for this research are Vilma Yuzbasiyan-Gurkan, Ph.D. and William Schall, DVM at Michigan State University, and George Brewer, MD and Jianping Li in the Department of Human Genetics at the University of Michigan. I hope that you find this letter useful and, once again, Jim, I apologize for its length.

Sincerely,
Pat
Patrick Venta, Ph.D.
College of Veterinary Medicine
Michigan State University

References:

  • Brooks, M., W.J. Dodds, and S.L. Raymond. Epidemiological features of von Willebrand's disease in Doberman pinschers, Scottish terriers, and Shetland sheepdogs. Journal of the American Veterinary Medical Association 200:1123-1127 (1992).
  • Crow, J.F. How much do we know about spontaneous human mutation rates? Evironmental and Molecular Mutagenesis 21:122-129 (1993).
  • Dodds, W.J. Detection of genetic defects by screening programs. AKC Gazette pp. 56-60 (June 1982).
  • Dodds, W.J. and J.S. Covey. Canine von Willebrand's disease. AKC Gazette pp 53-55 (April, 1981).
  • Johnson, G.S., M.A. Turrentine, and K.H. Kraus. Canine von Willebrand's disease. A heterogeneous group of bleeding disorders. Veterinary Clinics of North America: Small Animal Practice 18:195-229 (1988).
  • Moser, J., K.M. Meyers, and R.H. Russon. Inheritance of von Willebrand factor deficiency in Doberman pinschers. Journal of the American Veterinary Medical Association 209:1103-1106 (1996).
  • Stokol, T., B.W. Parry, and P.D. Mansell. von Willebrand's disease in Dobermann dogs in Australia. Australian Veterinary Journal 72:257-262 (1995).
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