PRA CORD 1 MUTATION
This page contains four separate articles that appertain to PRA Cord 1 Mutation. The articles are as follows:
- Worldwide Announcement of DNA Test
- Important Announcement to the English Springer Spaniel Worldwide Community concerning Progressive Retinal Atrophy Research - April 2007
- The Procedure for Requesting a DNA test for PRA Cord 1 Mutation
- Cone-Rod Dystrophy in Dachshunds and English Springer Spaniels - A new name for an old disease
WORLDWIDE ANNOUNCEMENT OF DNA TEST
A worldwide statement was issued on 20th April 2007 by Dr. Cathryn Mellersh from the Animal Health Trust (AHT) and Dr. Gary Johnson from the University of Missouri USA, stating that a mutation (known as the Cord1 mutation) has been identified that is a major risk factor for the development of one specific form of PRA in English Springer Spaniels. They also announced that a DNA test for this mutation has been developed and is now available in both the USA and UK. Other forms of PRA that may also exist in the Breed have not yet been genetically identified and can only therefore be detected by clinical eye testing.
Following that announcement, a number of breeders, who had donated samples from clinically affected dogs and their close relatives to the original PRA research project at the AHT, were invited to request from them the genetic results for these dogs.
These breeders had, naturally, expected that their clinically affected dogs would be confirmed as genetically affected, but when some results showed this not to be the case (i.e. their dogs tested as either genetically clear or carriers), considerable confusion and alarm ensued concerning the validity of the DNA test.
It is the opinion of both Dr. Mellersh and Dr. Johnson, that, barring any errors in the testing procedures, these unexpected genetic results can be explained by either of the following:
1) In some rare instances, a dog can develop PRA as a result of carrying a single copy of the mutation (i.e. a genetic carrier), rather than two mutant copies as would be expected in affected dogs. This would be unusual, based on what is known, but cannot formally be excluded at this stage.
2) There is another form of PRA in the English Springer Spaniel caused by a different mutation in a different gene that, as yet, has not been identified. Different genetic forms of the same eye disease occurring in the same breed are not unheard of, and it is entirely possible that some dogs can carry either or both mutations.
The original announcement (see below) made by Dr. Mellersh and Dr. Johnson, may, unintentionally, have given the impression that the new test was the whole answer with regard to PRA in the Breed. Whilst it certainly mentioned that a second form of PRA was a possibility, the figures quoted (which were based on statistics from the USA studies) suggested that a second form was probably rare. Dr. Mellersh was and still is unable to give any estimates or make any predictions as to which form of PRA is the most prevalent form in the UK. This is because she only has a very limited number of clinically ‘affected' samples to work with, and these samples do not represent a random subset of the UK population.
The DNA test for PRA that has been made available is for one specific mutation in one specific gene (known as the ‘PRA Cord 1 Mutation', which is a mutation in the RPGRIP1 gene), and the test cannot, therefore, detect any other mutation that may be responsible for any other form of PRA. It does not, however, diminish its validity for this particular mutation, which is undoubtedly associated with PRA in English Springer Spaniels.
To find a list of PRA Cord1 DNA test results, click on List of PRA Cord1 DNA test results
To find test results for individual dogs, click on KC Health Test Results Finder
Statistics from the AHT show that between 20 - 30% of dogs tested are genetic carriers for the Cord 1 (RPGRIP1) mutation, with approximately 3% being genetically affected. It should be noted that these figures were obtained using dogs NOT collected specifically for PRA research and thus represent a random cross section of the breed. Irrespective of whether a second form of PRA exists in the Breed, the prevalence of this mutation alone in the UK population is very significant.
The DNA test allows breeders to identify those dogs either carrying or affected by this mutation, and, through careful and sensible breeding over several generations, to eliminate it from their breeding. The fact that it is not the whole of the answer to PRA is, of course, disappointing, but the fact that a DNA test is available for any form of PRA has to be a step forward.
This new test, as with any other, is simply another tool that breeders now have at their disposal should they wish to make the most of the information available to them. When making decisions on breeding, the results of any test should be taken in the overall context of the merits or weaknesses of each dog and the severity or consequences of the disease to which the test relates.
With regard to PRA, it is the intention to carry out further research into both of the following areas:
a) The identification of the mutation that causes a second form of PRA in the Breed. This will require samples from dogs that are diagnosed as clinically affected but their DNA test shows that they are not genetically affected for the Cord 1 (RPGRIP1) mutation.
b) The identification of dogs that have been tested as genetically affected for the Cord 1 (RPGRIP1) mutation, but are not yet clinically affected. From a breeding point of view, it is the genetic status that counts, but Dr. Mellersh and Dr. Johnson have advised that other genes may influence the age of onset and rate of progression in dogs genetically affected for the Cord 1 (RPGRIP1) mutation, and further studies are required to explain this.
Individual owners and breeders whose dogs fall into either of the above categories, and who wish to donate a DNA sample to the research, are invited to contact Dr Cathryn Mellersh at the AHT to request a swab kit or more information.
ESS owners and breeders, who wish to do so, are encouraged to use the new DNA test for PRA Cord 1 in addition to continuing with clinical eye testing for all breeding stock.
ESS Breed Clubs Health Coordinators:
Lesley Bloomfield Tel: 01923 823579 Email
Louise Scott Tel: 020 8427 3396 Email
IMPORTANT ANNOUNCEMENT TO THE ENGLISH SPRINGER SPANIEL WORLD WIDE COMMUNITY CONCERNING PROGRESSIVE RETINAL ATROPHY RESEARCH (APRIL 2007)
- Dr Gary Johnson from the University of Missouri in the USA (UMO) and Dr Cathryn Mellersh from the Animal Health Trust in the UK (AHT) have identified a specific DNA mutation (known as the Cord1 mutation) that is a major risk factor for development of Progressive Retinal Atrophy (PRA) in English Springer Spaniels. Other forms of PRA caused by a different mutation (or mutations) may also exist within the Breed, but have not yet been genetically identified.
- A DNA test has been developed for the Cord1 mutation and is now available in both the USA and the UK, along with information about what the test can and cannot tell them. In the UK, the test is available from the AHT - further details concerning the procedure and costs are given below under the section headed "Testing Your English Springer Spaniels". PRA caused by other genetic mutations, as yet unidentified, can at the present time only be detected by clinical eye testing.
- The percentage of English Springer Spaniels testing as affected or carrier for this mutation is very high. (80% of the dogs tested in the USA during the research tested as affected or carrier for this mutation).
- It is likely to take several generations to reduce the frequency of this mutation in the ESS population.
- Additional research in the USA, funded by the ESSFTA Foundation and the AKC Canine Health Foundation, has been initiated to help answer the questions that remain unexplained by the discovery of this mutation.
Dr Mellersh recently published information on a mutation found to cause a recessive cone-rod form of PRA in Miniature Longhaired Dachshunds. In a limited survey, Dr. Mellersh also found the mutation to be present in ESS. Because of this, Masters student Xuhua Chen from Dr Johnson's USA laboratory tested over 1100 ESS DNA samples and found that dogs that inherited the mutation from both their sire and dam were approximately 20 times more likely to develop PRA compared to other ESS. Preliminary ERG clinical studies by Dr Kristina Narfstrom, Laboratory for Comparative Ophthalmology, University of Missouri-Columbia, suggest that ESS have a cone-rod form of PRA similar to that found in the Dachshunds.
It is important to note that there are a large number of dogs that have tested as genetically affected, but are reported as clinically normal by their owners. This is also similar to the situation in Miniature Longhaired Dachshunds. With the wide range of age of onset observed for PRA in ESS, it may be that many of these dogs will develop symptoms eventually. It is also possible that these dogs have some loss of visual function that has not yet been detected by the owner.
Good News - Bad News:
The good news - a DNA test is now available that clearly identifies dogs that are clear (have 2 normal copies of the gene), those who are carriers (have one normal copy of the gene and one mutated copy of the gene), and those who are at much higher risk for developing PRA (have 2 mutated copies of the gene). Wise use of this test can reduce the incidence of dogs at risk for PRA in future generations.
The bad news - In the USA only 20% of the 1100-plus ESS's genotyped during the research tested as clear or normal. 38% tested as carriers, and 42% tested as genetically affected. Should the same statistics follow in the UK/Europe, eliminating all dogs testing as affected from breeding programmes would have a major impact on the Breed, and would have the potential to devastate successful breeding programmes. Reducing the incidence of dogs at risk for PRA, while maintaining genetic diversity and positive qualities present in the Breed, is likely to be a slow process and will take several generations.
The DNA test is accurate and valid in being able to determine the genetic status of each dog. However, it is not able to predict at what age a genetically affected dog may become clinically affected.
We are aware that the age at which dogs develop PRA can vary dramatically. Additional research is being carried out to help us understand why some genetically affected dogs develop PRA early and others later. This research is likely to take some time, and in the meantime, therefore, it is felt that it is in the Breed's best interests to make the DNA test available now rather than wait 2 or 3 years until we understand the story completely. From experience with the Miniature Longhaired Dachshunds PRA, there is a wide range of variation, both in terms of clinical presentation and the degree of visual impairment that is associated with this mutation. Dogs that are DNA tested as being affected may themselves not develop the disease until relatively late in life, but it may well be possible for offspring of those dogs to display an earlier, more progressive form of PRA, depending on other genetic variants that they do or do not inherit.
Considerations for English Springer Spaniel Breeders:
The mutation is a risk factor for the development of PRA in English Springer Spaniels: Most of the dogs that were tested in the USA as "affected" are considered to have normal eyesight by their owners. Some of these dogs may develop PRA as they get older; however, there are many examples of old English Springer Spaniels that DNA test "affected" but, have subtle, if any, visual impairment.
On the other hand, 95% of the English Springer Spaniels with clinically recognized PRA test "affected." Erroneous diagnoses or a second rare form of PRA may account for the 5% of English Springer Spaniels with PRA that do not test "affected."
The USA study implies that the likelihood of developing PRA is approximately 20 times higher for English Springer Spaniels testing "affected" than it is for other English Springer Spaniels. This is strong evidence that testing "affected" is a major risk factor for PRA in English Springer Spaniels and indicates that the prevalence of English Springer Spaniel PRA can be reduced by breeding programmes that select away from the mutant gene. This can be accomplished by giving highest preference to breeding stock that test "normal," intermediate preference to dogs that test "carrier" and lowest preference to dogs that test "affected."
Recommendations to English Springer Spaniel Breeders:
Although we believe that English Springer Spaniel breeders should make efforts to reduce PRA in future generations of their line, we also believe that if the mutation is so common in the Breed, overly aggressive elimination of dogs testing affected or carrier from breeding consideration could have an overall detrimental effect on the Breed and could devastate successful breeding programmes.
A realistic approach when considering which English Springer Spaniels to select for breeding would be to consider dogs with the mutation to have a fault just as lack of working ability, poor top line, or imperfect gait would be considered faults.
Dogs that test "affected" with two mutant copies of the PRA gene should be considered to have a worse fault than "carriers" with only one mutant copy. English Springer Spaniel breeders could then continue to do what conscientious breeders have always done: make their selections for breeding stock in light of all of the dogs' good points and all of the dogs' faults. Using this approach over several generations should substantially reduce the prevalence of PRA while continuing to maintain or improve those qualities that have made English Springer Spaniels so popular.
One problem with the above approach is that the clinical consequences of testing "affected" are, as yet, poorly defined. Thus, it is hard for breeders of English Springer Spaniels to determine how much priority should be given to selecting away from the mutation. To better understand the clinical consequences, we will continue to assess clinical eye examinations (BVA/ECVO & AHT) and other relevant medical records of the dogs that are tested.
When the results of these studies become available, they will be posted on this Website.
THE PROCEDURE FOR REQUESTING A DNA TEST FOR PRA CORD 1 MUTATION IS AS FOLLOWS:
- The Animal Heath Trust requires cheek swabs for the DNA test.
- The Animal Health Trust currently charges £47.00 (inclusive of VAT) for each sample to be DNA PRA Cord 1 mutation tested. This includes the cost of the cheek swab sampling kit.
- You should make application to the AHT for the PRA Cord 1 mutation test to be carried out on the AHT specified form. The .pdf form ‘Request for DNA Testing' can be downloaded from the Animal Health Trust website at www.aht.org.uk/genetics_tests.html
- A separate form should be completed for each cheek swab sample to be tested.
- Kits for taking cheek swabs are available by phoning 08700 509144 or via email to email@example.com
- Further information can be obtained by emailing firstname.lastname@example.org
- Samples should be sent together with the completed DNA Testing Form and payment for each sample to:
Genetic Services, Animal Health Trust,
Suffolk CB7 7UU.
- The AHT will usually post the results to you within 4 - 6 weeks of receipt of sample.
If you wish to have the PRA Cord 1 mutation and Fucosidosis DNA tests done together, the joint cost is £82 (including VAT).
CONE-ROD DYSTROPHY IN DACHSHUNDS AND ENGLISH SPRINGER SPANIELS - A NEW NAME FOR AN OLD DISEASE
The aim of this document is to clarify current nomenclature (classification) for the retinal degeneration that affects miniature longhaired (MLHDs), miniature smooth haired (MSHDs) Dachshunds and English Springer Spaniels (ESSs).
It was first documented in the MLHD, and was called Progressive Retinal Atrophy (PRA). PRA is the collective term for a group of inherited eye diseases, of which there are several different, breed-specific forms that are due to mutations in different genes. In most forms of PRA the rod photoreceptors in the retina (which are responsible for vision in low light conditions) degenerate before the cone photoreceptors (which work best in mid to high levels of light and have the ability to detect colour). Hence poor night vision, or night blindness, is often the first indication that a dog has PRA. All forms of PRA studied to date result in blindness, but at different ages from a few months to several years.
Work undertaken at the Animal Health Trust identified the genetic mutation described in the MLHD and a DNA test was made available to MLHDs in February 2005. The identical mutation has since been found to be present in the MSHD population, and also in the English Springer Spaniel (ESS) and now the same test is offered to those breeds also.
In parallel to the genetic studies, work carried out by scientists at the Institute of Ophthalmology, London, in collaboration with the AHT and published in September 2007, revealed the disease the MLHDs suffer from is in fact a cone-rod dystrophy. In other words the cones degenerate before the rods. The disease has been termed cord1, for cone-rod degeneration. The MSHDs and ESSs share the identical mutation to the MLHDs and therefore also suffer from this cone-rod dystrophy.
To date, few canine cone-rod dystrophies have been studied in depth, although a very similar condition in the Wire-Haired Dachshund has been described in Norway. However, work with human cone-rod dystrophy patients has indicated that the condition can have a very late age of onset, and the levels of visual impairment can be variable between patients - similar to our findings for the progression of cone-rod dystrophy in miniature dachshunds.
We do know that the cord1 mutation can lead to blindness in MLHDs, MSHDs and ESSs. It is also eminently possible that dogs that are genetically affected, but that retain vision into later life, can produce offspring that develop clinical signs and go blind at an early age. We must stress that the testing of breeding stock for this cord1 mutation should be a priority and also that matings between two carriers should be avoided.
In summary, MLHDs, MSHDs and ESSs are affected by a cone-rod dystrophy, known as cord1, which was originally referred to as PRA. The DNA test offered by the Animal Health Trust tests for the mutation that causes this disease; the mutation is identical in MLHDs, MSHDs and ESSs. If your dog's DNA has been tested for PRA at the AHT it would have been for the cord1 mutation.
Dr Cathryn Mellersh
Animal Health Trust