Manchester Terrier Association


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Von Willebrand's disease (vWD) 


Von Willebrand’s disease in the Manchester Terrier.


Dr Jeff Sampson


The Disease


A viable circulatory system is fundamental to mammalian life because it provides the millions of millions of cells that make up an animal with essential supplies, like oxygen and glucose, to maintain cellular health.  It is therefore not surprising that mammals have evolved mechanisms that maximise the integrity of the circulatory system.  One of these is the ability to clot blood at the site of an injury to prevent excessive blood loss that would compromise the effectiveness of the circulatory system.  


Blood clotting relies on a complex array of proteins, collectively known as clotting factors, that are floating around the blood system in a quiescent, biologically inactive form.  Blood loss activates a cascade of events that result in the biological activation of these clotting factors and the formation of a blood clot at the site of injury, thereby stemming what could otherwise be a disastrous loss of blood.  One of the very first clotting factors involved in the initiation of the clotting process is a protein known as von Willebrand’s factor.  Failure of any one of these clotting factors can lead to a bleeding disorder and the cause of von Willebrand disease in the Manchester Terrier is the result of not being able to make sufficient amounts of von Willebrand factor.


The Genetics


Like all proteins, von Willebrand’s factor is made from information that is stored in a gene, in this case the von Willebrand gene.  Dogs have two copies (alleles) of each an every gene, one allele inherited from the dam and the other from the sire, so dogs have two alleles of the von Willebrand gene.  Some time ago a mutant von Willebrand gene was introduced into the Manchester Terrier breed gene pool.  This could have been as a result of a brand new mutation in just one particular dog, or it could have arrived following the introduction a dog from another breed into the Manchester Terrier breeding population which carried the von  Willebrand mutant gene.  No-one really knows when this event first happened, but today the consequence is that there are now two different alleles of the von Willebrand gene in the Manchester Terrier gene pool:  the normal allele, sometimes referred to as the wild type allele, and the mutant allele.  We now know that the mutation is a recessive mutation.


So, this means that every Manchester Terrier will have one of the following genotypes, genetic makeup, with respect to the von Willebrand gene:




Normal

This is a dog that has inherited two normal, wild type alleles of the von Willebrand gene.   This dog is genetically normal and will also be clinically normal because both wild type alleles will be able to be used to produce the normal complement of circulating von Willebrand factor.  Such a dog is homozygous for the wild type allele.


Carrier

This is a dog that has inherited one normal allele and one mutant allele of the von Willebrand gene.  This dog will still be clinically normal and have no problem with blood clotting.  This is because the normal allele will be able to provide sufficient von Willebrand factor.  However, if a carrier is bred from then its offspring will have a 50% chance of inheriting its wild types allele and 50% chance of inheriting its mutant allele.  Such a dog is said to be heterozygous for the mutant allele.


Affected

This dog has inherited a mutant allele from both of its parents and is therefore homozygous for the mutant allele.  This dog will be clinically affected because it cannot make sufficient quantities of the von Willebrand factor to sustain efficient blood clotting.  If a clinically affected dog is born from two clinically normal parents, then both must be carriers of the von Willebrand mutant gene.  Obviously, if an affected dog is bred from it can only pass mutant alleles on to its offspring; whether they then become clinically affected will depend on the allele inherited from the other parent.


The Mutation


The mutation responsible for von Willebrand disease in the Manchester Terrier has been identified and it turns out to be a rather unusual type of mutation which means that the mutant allele can still be used to produce small amounts of biologically active von Willebrand factor.  So, even the dog that is homozygous for the mutant allele, the clinically affected dog, will produce around 10-20% of the normal levels of circulating von Willebrand factor.  These low levels of Willebrand factor, even in the affected dog, means that the disease is a relatively mild bleeding disorder, and is known as Type I von Willebrand disease.  It is believed that all Manchester Terriers that suffer from Type I von Willebrand disease are homozygous for the mutant allele.


Other breeds of dog suffer from other forms of von Willebrand disease, there are both Type II and Type III diseases, which have a much greater clinical severity.  Type II and Type III disease result from totally different mutations of the von Willebrand disease, and have not been identified in the Manchester Terrier.




The DNA Test


Some years ago now a group of American research workers identified the mutation responsible for Type I von Willebrand disease and developed a simple DNA test that would identify its presence in a dog’s DNA sample.  This test was first offered by a company called VetGen in the States, who still are one of the major providers of von Willebrand DNA testing.  Latterly, a German company with a UK base, called Laboklin, have also started offering the test.  The test is also available form other companies in Europe, for example Finnzymes, which is the company that the Kennel Club uses for von Willebrand testing in the Dobermann, another breed that suffers from Type I von Willebrand disease.


Nowadays, these DNA tests are extremely straightforward, easily accessible and relatively inexpensive, of the order of £60-£80.  Most companies now simply require a mouth swab to be taken and submitted, which means that the testing is non-invasive and therefore does not require veterinary intervention and sampling can be easily performed by the dog’s owner.  The swab is usually a small nylon brush which is gently rubbed against the inside of the dog’s cheek.  This removes some of the cells that line the cheek, which then stick to the brush.  The dried brush is then returned to the testing laboratory where the DNA is released from the cells that have adhered to the brush and tested to see which alleles of the von Willebrand gene are present.


So, the outcome is that the test gives the dog’s true genotype with respect to von Willebrand disease and there are three possible results.  A tested dog could be one of the following:


  • Normal/Clear, which means that its DNA sample has two normal alleles of the von Willebrand gene

  • A carrier, having one normal allele and one mutant allele

  • An affected, with two mutant alleles


The use of DNA testing as part of a responsible breeding programme


Obviously, breeders of Manchester Terriers want to remove the mutant allele from the breed’s gene pool so that the clinical disease will cease to be a problem for future generations of Manchester Terriers.  This they can do by carefully selecting parental pairs that will slowly reduce the population frequency of the mutant allele in the breed.  Great care has to be taken in this selection process to avoid removing too many dogs from the breeding population, simply because they might carry one or two mutant alleles of the von Willebrand gene.  Removing too many dogs because of their von Willebrand genotype might well set the breed up for even greater genetic problems in the future because the subset of dogs chosen to breed from to reduce von Willebrand disease may well be carrying other mutations capable of establishing even worse inherited problems in the future.


The beauty of having a DNA test for an inherited disease like von Willebrand disease is that breeders can set up breeding programmes to reduce the frequency of the disease without resorting, necessarily, to removing a single dog from the breeding population.  This means that they can select away from the disease without compromising the breed’s genetic diversity, which is already low for other reasons.


The basic requirement is that breeders DNA test all of their potential breeding stock before they are used for mating.  This way they will know the dogs’ genotypes and can take account of them when selecting mating pairs.  So, if a dog is normal, then there are no mating restrictions because we know that such a dog can only pass normal, wild type alleles to its offspring.  What about if a dog is a carrier?  I know of some breeders who see carriers as ‘tainted stock’ and will never contemplate using such a dog in a breeding programme.  Well they are entitled to this view, but I don’t believe that this is a responsible attitude for the breed as a whole.  Removing a dog from a breeding programme simply because it is a carrier of von Willebrand disease means future generations will be denied any positive genetic features that the dog in question might pass on and, if too many carriers are removed, this will severely compromise the breed’s genetic diversity.


DNA testing now means that carriers can be bred with confidence, however, knowing a dog is a carrier imposes certain restrictions on the choice of mate.  So, if a breeder is contemplating mating a carrier, then (s)he should not mate it to an untested dog, because there is no clue as to the alleles it is carrying.  Nor should it be mated to another DNA tested carrier or an affected dog because progeny will have far too high a risk of developing von Willebrand disease; if a carrier is mated to a carrier then every puppy will have a one in four chance of being affected, if a carrier is mated to an affected each puppy will have a one in two chance of being affected.  However, breeders will be able to mate a carrier to a DNA-tested normal/clear dog with absolute confidence that none of the progeny will become clinically affected.  A carrier mated to a normal dog will give puppies that have a 50% chance of being either a carrier or a normal dog, and DNA testing the puppies will tell the breeder which puppies are normal and which are carriers.


This approach allows breeders to impose strong genetic selection to reduce the frequency of the mutant allele in the population.  The programme described above will allow a breeder to go from a carrier bitch to a normal bitch in just one generation.  However, DNA testing should not be the sole selective criterion.  Breeders still need to concentrate on other traits like breed type and temperament, so if you are choosing a DNA tested normal male for your carrier female, then choose a male that you would have considered anyway that is DNA-tested normal.  Likewise, when selecting a puppy bitch to breed on from in a carrier/normal mating, make sure the normal puppy is one you would have chosen to breed from anyway.  If there isn’t a normal puppy to your liking in the litter, keep going with carrier/clear matings until you find a good, DNA-tested normal puppy.  I hope this explanation is sufficient to show how the use of DNA testing can help breeders reduce the frequency of a mutant allele without the need to remove huge numbers of dogs from the breeding pool, thereby limiting the impact that genetic selection might have on breed genetic diversity.


What about affected dogs identified as a result of DNA testing?  As a general rule I think it fair to say that affected dogs should not really be bred from.  However, if a breeder can find compelling reasons why an affected should have a litter, then there is a route using DNA testing.  A DNA-tested affected dog can be mated to a DNA-tested normal dog; in this case all of the litter will be clinically normal carrier dogs, there will be no need to DNA test them.  If one of these first generation progeny is eventually mated to another DNA-tested normal mate, then the progeny of this second generation will almost certainly contain genetically normal puppies.  So, in just two generations you can, with care, go from an affected dog to a normal dog.  Of course a major consideration here has to be the nature of the inherited disease.  Although von Willebrand disease in the Manchester Terrier is a mild form of bleeding disorder, it doesn’t seem wise to breed from an affected bitch, because her clinical state could well complicate the pregnancy and birth, but if you had an affected male that you can convince yourself is worthy of breeding, then the above approach might be adopted.


An Official DNA Testing Scheme for von Willebrand Disease in the Mancheser Terrier


So, I hope that the essence of a responsible breeding scheme is clearly outlined above.  Any scheme should insist on DNA testing all potential breeding stock before they are mated and then take account of the result when selecting mating pairs.  Then any progeny should be DNA tested to discover their genotype with respect to the disease.  


The Kennel Club now has considerable experience working with breed clubs to maximise the effectiveness of DNA testing for single gene disorders.  The device that has been developed is something called an Official DNA Testing Scheme.  This involves establishing a programme with the DNA testing facility to release all of the test results that they produce, normal, carrier or affected, directly to the KC.  The application process normally has a declaration, signed by the owner/agent of the dog, giving the company permission to release the result to the KC on the understanding that the result may be published by the KC.  Upon receipt of results from the testing laboratory, the KC places the DNA test result on the tested dog’s data in the KC registration database, which triggers publication of the result via a number of different routes:


  • As a one-off publication in the next available Breed Records Supplement (BRS)

  • On any new registration certificate issued for the dog after the date that the result was placed on the registration database

  • On the registration certificates of all of the dog’s future progeny


In addition, lists of tested dogs with their results are maintained on the Kennel Club’s web site.  Finally, the result of any tested dog that exists on our database can be accessed by anyone using the newly-developed ‘Health Test Result Finder’.


One further facility that is available via an Official Testing Scheme is that if a litter of puppies is registered from two DNA-tested normal dogs, then the registration of each puppy will be annotated with the term ‘hereditarily clear’.