RENAL DYSPLASIA INFORMATION PAGE


**NEW** ----RD Quick Reference

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COMPREHENSIVE INFORMATION ARTICLE

What is RD? More...

Renal dysplasia (RD) is an important category of kidney diseases in canines. Dysplasia is defined as abnormal growth or development of cells or organs. In the case of RD the kidney fails to develop properly during embryogenesis in the womb. At birth immature structures consisting of undifferentiated fetal cells or tissue types are found in the kidney, and are persistent throughout the life of the animal.

Renal dysplasia can present itself with a wide range of symptoms and pathological findings. Definitive diagnosis of RD is done by a wedge biopsy which reveals dysplastic lesions, including abnormal ducts, and glomeruli.
Individuals with an abnormal biopsy can be asymptomatic, showing no signs of the disease. On the other hand, they may present with classic signs of chronic end stage renal failure, or somewhere between these two extremes. Given this broad spectrum of symptoms affected individuals often go unnoticed, and remain in the breeding population. This is why development of a genetic test was necessary for the management and elimination of this disease.

RD- a Closer Look More...

What you see is not always what you get. For those breeders that deny that RD is a problem in their kennel, you would see it if you had done biospies on you dogs.

Below is a summary of an article by
Dr. Kenneth C. Bovee (click on link for actual reference)

In October of 2003, Dr. Kenneth C. Bovee from the University of Pennsylvania published his findings in the Shih tzu from a 10 year study involving 143 dogs and 52 matings. His findings clearly show that the majority of breeding stock had some level of fetal glomeruli, and estimates from this study indicated that the prevalence of this defect (meaning biopsy positive fetal glomeruli) was probably about 85% in the breed, however the actual clinical cases that manifested severe renal dysfunction was low.

Other critical conclusion from this 10 year study was that animals with a low perentage of fetal glomeruli could produce those with renal disease and even the breeding of 0% fetal glomeruli (biopsy negative) adults resulted in offspring with 1-3% fetal glomeruli. The apparent low incidence of disease was a danger to the breeding population as seemingly normal adults could go undetected in the breeding population, and produce clinically affected offspring. Further, while using biopsy data to try and control this disease in the breeding population limited to some degree the production of severely affected progeny, this was not entirely successful in eliminating the transmission of biopsy positive offspring from the parents.

Further Dr. Bovee speculated, based on these findings that the mode of inheritance was not a simple recessive, and could follow a pattern of dominant with incomplete penetrance.

Thus the development of a genetic test was imperative to control this disease in this breed as well as others.


Truer words were never spoken! More...

The following is a quote from an article by Susan L Fleisher. While Susan was a lay person, her personal tragedy with the death of her Standard poodle puppy with RD led her on a quest to discover everything that she could about the disease. She wrote several of the most comprehensive and probably the most cited articles on RD on the internet. Her article is not only well referenced from the scientific literature, but her quote below best summarizes the main problem with RD that exists to this day. Even though this was written over a decade ago, the frustration with this disease and the failure of recognition of this disease as genetic remains today. Susan passed away in 2007, but her legacy remains in her articles on RD. Everyone needs to read her article(s) that are available on the internet on many sites (see for example http://www.vetprof.com/clientinfo/juvenilerenal.html ).

"The information I have gathered since then leads me to believe that most individual cases of RD are treated by owners and veterinarians as isolated occurrences rather than as the manifestation of a genetic disease. If the breeder is informed about a medical problem in a puppy she has sold, and often she is not, or, if just the owner of the dam is informed, and it is only one puppy in a litter about whom she is informed, it is again treated as an isolated incident. Unless there are multiples in a litter it goes largely unrecognized, and no recognition is made nor thought given to those littermates who are carriers."

Which Breeds Have RD? More...
Many
breeds of dogs are afflicted with RD, and this has been documented in
veterinary text books, as well as case reports and articles in the scientific
literature. Of note is that RD in these breeds share a common phenotype,
characterized by immature glomeruli, and/or tubules and persistent
mesenchyme.

RD is largely thought of as a health problem in Lhasa apsos, and Shih Tzus.

This is not true!



The hybrid dog dilemma. More...
"Hybrid dog" is a term applied to offspring from parents with purebred ancestry rd is inherited as an autosomal dominant trait (see below for specifics). Therefore, any hybrid dog with a parent from our group of breeds that we offer DNA testing for can carry the rd mutation and can pass it on to it's progeny. The danger is that RD will spread amongst these breeds if left unchecked. Making a hybrid from two breeds known to have an RD mutation further increases the likelihood of spread of the disease. rd, a dominant mutation, is found in such high frequency in so many breeds that are used to generate hybrids that as a practical matter, spread of rd to progeny from hybrid crosses is unpreventable unless breeders start to test now. So far, the frequency of the rd mutation is high in every breed that we have studied with the exception of the German Shepherd dog.



How is RD inherited? More...

The mode of inheritance of rd has been widely debated, as this disease can
present itself with a wide range of symptoms and pathological findings.
Definitive diagnosis of rd is done by a wedge biopsy which reveals dysplastic
lesions, including abnormal ducts, and glomeruli. Individuals with an abnormal
biopsy can be asymptomatic, showing no signs of the disease, On the other
hand, they may present with classic signs of chronic end stage renal failure, or
somewhere between these two extremes. Given this broad spectrum of
symptoms affected individuals often go unnoticed, and remain in the breeding
population. This is why development of a genetic test is critical to the
management and elimination of this disease. Further a genetic test can be used
to show the mode of inheritance .

Through pedigree studies, the mode of inheritance was finally revealed as
Dominant with Incomplete Penetrance.

What does Dominant with Incomplete Penetrance mean? More...

Dominant with incomplete penetrance refers to a situation where an inherited mutation may or may not be expressed in an individual.



The traits that we see in an individual are collectively known as the "phenotype", while the "genotype" refers to genetic constitution or makeup of
an individual.


Penetrance refers to the frequency that the phenotype (or some characteristics of the disease) is observed. If, for example, the penetrance. is 75%, then the chances of offspring to develop a disease are 3 out of 4. In the case of rd, the penetrance is low with a penetrance. estimated to be about 2-5%. Therefore only a small number of individuals with the mutation will show signs of the disease. However, they can pass the disease on to their offspring. This is why a genetic test is critical to manage rd; this is the only way to
eliminate this disorder. There may be risk factors or triggers that are yet undiscovered that may increase the chances of an individual to develop rd
.

A mutation is a permanent change in the DNA sequence of a gene, whether itis good, bad or neutral. Mutations that cause a genetic disease can be inherited as dominant where one bad copy of the gene is sufficient to cause disease or a phenotypic trait to be observed, or recessive where two bad or mutated copies of the gene are needed to cause disease or phenotypic trait to be observed.


All chromosomes exist in pairs in the nucleus of cells. Each pair is comprised of one chromosome from the sire and one from the dam. Therefore, every animal has two copies of every gene. In dogs there are 78 chromosomes, or 39 pairs.


Development of a Genetic for RD test at DOGenes More...

During the development of the fetus, certain genes act in a pathway or cascade to direct the development of the various organs and structures that make up the body (think of it as dominos: if one domino is missing the other ones wont perform their task in the array). Since every cell contains two copies of every gene, one non-mutated copy may be sufficient to complete to cascade (recessive inheritance). The human genome contains about 20,000 to 25,000 genes, and the canine genome is likely to contain about the same number. Of these several hundred or more may be dedicated to the maturation of specific organs. Not all of these tissue specific genes are absolutely essential to the development of specific cell types, as has been shown in knockout mice, where genes have been completely eliminated with no observable effect on the animal. In the case of renal dysplasia in model organisms such as the mouse, mutated transcription factors (genes that code for proteins that turn on other genes) or growth factors (genes that code for proteins that promote the growth of cells), have been implicated in causing the disease.


One approach to discover genes that are cause genetic diseases is to use candidate genes known to cause specific diseases in model organisms, like the mouse, rats, zebra fish or even the lowly fruit fly.


This was the approach used in the quest to find a mutation for RD in dogs. After DNA sequencing six candidate genes, a possible set of mutations was finally uncovered in a gene in Lhasa apsos and Shih Tzus. These allelic variants (mutations) were located in the same region of the canine Cox-2 gene. Four variants have been found in breeds that are known to be afflicted with RD. Consequently a genetic test is now available for many of these breeds. If an animal has one or two copies of these mutations they are at risk for developing the disease or passing it on to their offspring.


Through pedigree studies, the mode of inheritance was finally revealed as
Dominant with Incomplete Penetrance.
How can the new test be used to eliminate this disorder from a breed
without compromising the gene pool?
More...

Genetic tests are designed to manage and eventually eliminate disorders without compromising the diversity in a gene pool. If you have just found out that your dog carries a mutation for renal dysplasia, do not panic. Now you have the opportunity to manage and eliminate this disease. The frequency of this mutation is extremely high in many breeds. This mutation has been elusive and impossible to eliminate prior to the development of a genetic test, as the disease appears sporadically because it is inherited with incomplete penetrance, meaning that an animal that carries this mutation may or may not show clinical signs of the disease, but can still pass it on to the next generation.

As in any breeding you must consider the positive and negative traits of each partner, and how the parents traits can best balance and compliment each
other.


All dogs (and living organisms) are carriers of multiple mutations.

If a genetic disease is produced in an animal, it is not necessarily the result of poor breeding practices, but is the nature of inheritance as a random event. Although the exact mutation rate for canines is difficult to determine, by extrapolation from other species, there is a good chance that every individual produced has a new mutation in some gene. Therefore, with every generation of breeding, new mutations arise, but since they are present at a low frequency, they are generally lost in subsequent breeding. There is no such
thing as a perfect animal!


Chromosomes exist in cells in pairs, one from the sire and one from the dam. Dogs have 39 sets of chromosomes. Each set or pair is composed of two chromosomes, one from the sire, and one from the dam. In the case of a simple recessive mutation, one of the chromosomes, either from the sire or the dam, makes enough protein from for the animal to survive. Therefore, the wild type chromosome of the pair provides enough protein (gene product) to compensate for the chromosome that carries a mutation. In the case of a
dominant mutation, only one copy of the chromosome carrying the mutation is necessary to produce disease.


With the identification of one of the many mutations that your animal carries, you can now proceed to at least eliminate this identified mutation, and not inadvertently select for another deleterious mutation that your animal carries.
Wholesale elimination of carriers is the worst decision that you can make as this would deplete the gene pool.


As in any breeding you must consider the positive and negative traits of each partner, and how the parents traits can best balance and complement each other.


What information does this DNA test actually tell the breeder? More...
The DNA test results are reported as follows:

a) Carrier - (one copy of the rd mutation)

b) Homozygous mutant allele = Homozygote (two copies of the rd mutation)

c) Clear - No copies o f the rd mutation are present.

With a & b results above Đ the animal is potentially affected by rd or
could pass it on to its progeny.


How do I submit my dogs DNA for testing? More...

DOGenes uses cheek swabs for DNA testing.
We ask for three samples per dog. When you order a test we send you the cheeks swabs.

You take the samples and return them to us for testing.

Breeding Decisions More...

For breeds with a high frequency of the rd mutation:

1. My dog is a clear. Examine this dogs good and bad traits. Can he/she be bred to a carrier in your kennel that can complement their traits? Yes. At this time, many breeds with rd have an very high frequency of the mutation, and in order to protect the gene pool, this type of breeding is necessary.

You keep the clear puppy from this cross that has the traits from both parents that you were hoping to get.

2. My dog is a carrier. Ideally, this animal should be bred to a clear with traits that would complement this animal. - Clear progeny from this cross can be kept for future breeding. There is a 50% chance in this case of producing a clear in the first generation. If no other options exist, this animal can be bred to another carrier. In this case, your chances of producing a clear for your next generation are 25%. There is a 25% chance that a animal that is homozygous for the mutant allele will be produced from this breeding.

3. My dog is homozygous for mutant alleles, but otherwise is sound in body and temperament, and brings positive traits to the breed. This is a two step breeding to get a clear. This dog should be bred to a clear, if possible. All of the puppies in the first generation will be carriers. No need to DNA test at this point. A carrier puppy from the first generation of breeding can now be used in the second generation to produce clears as in example 2.


DOWN THE ROAD, your ultimate goal is to breed clear to clear so that you have eliminated rd from your kennel without having compromised the gene pool.


Click Here to view to outcomes of various breedings



RD stories from owners and Breeders: SHARING IS BELEIVING! More...
SUBMIT YOUR STORY: Click Here

READ STORIES : Click here


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