PKD Progress Report 2001

by Leslie A. Lyons, Phd
University of California at Davis


Published November 2001

In early February 2001, Heather Roberts, PhD joined our laboratory and she will be the team leader for PKD research. Other members of the laboratory will also be assisting with this project.

The funds from The Winn Feline Foundation will be matched by the Center for Companion Animal Health (CCAH) at Davis for $10,000 and our laboratory to cover our supplies and half of Dr. Roberts' salary. Heather has become comfortable with the laboratory and her skills required for the project have been validated. [Note: all new members of the laboratory have a three-month training period prior to long-term commitments].

Heather joined us prior to defending her thesis and we are proud to announce that on June 4th she received her doctorate. She is also a breeder and her Singapura won top honors in TICA for Best Shorthair of the Year. Hence, Heather will understand breeder concerns and issues.We have hosted two PKD clinics, the first of which was held in June 2000 and tested over 200 cats. A second PKD clinic in Davis was held this past December, with Dr. Biller, Kansas State University, performing the ultrasound evaluations. Breeders provided $10.00 to help pay the student assistants.

All other cost were charged to the Winn Grant. With the two clinics, we have scanned approximately 322 cats.The clinics focused on breeders who had large groups and cats from their programs that could be obtained from the area. Hence, large families were established. Together with samples acquired while at the NCI, nine large families are now available for analysis, comprised of 210 individuals. One of the difficulties with the large pedigree from Dr. Stephen DiBartola, Ohio State University, was that it had limited variation. Furthermore, significant associations between the genetic markers and the disease could not be established.

Since there are now nine independent families, they have a greater potential for having genetic variation and will provide significant power to the study. We have performed a simulation study with the families, and we expect up to 95% probability of detecting an association with a genetic marker that is fairly close to the disease (5 centimorgans, a genetic distance term).

At ten centimorgans, we have a 70% probability. Hence, as marker are farther from the disease, the power to detect a association drops. Thus, we will continue to build the pedigrees, but now we know which pedigrees are the most useful and powerful. As a result, our collection strategies can be very focused. These families are a 20% improvement over those that were available. If we find an association, we will approach Dr. DiBartola to see if he would like to confirm our findings and become a formal collaborator. We are also aware of a strong group in England, by Dr. Matthews Binns at the Animal Health Trust, that is making progress on PKD studies. We also anticipate providing our results to this group for confirmation.With all of the available information and nine large families to focus on, we are beginning the analysis immediately.

The DNA will be isolated from all the individual. We will be testing all the DNA markers on human chromosomes 4 and 16, where the known human genes side. We have also used the large DNA library that we developed to isolate the cat specific PKD genes, and we are now testing our clones to verify that they contain the correct gene. These clones will help us directly analyze the normal sequence of these genes for the cat. If one of the association studies shows that PKD1 or PKD2 is involved, then we are now prepared to directly sequence those genes in the cat.Recent observations in humans have shown the the evidence for a third gene for PKD is an error. The family that did not have an association with PKD1 or PKD2 has been shown to contain some affected members with PKD 1 mutations, and some with PKD 2 mutations. Hence, the association studies were confused by the presence of both mutations.

This is good news because we are now back to analyzing only two human genes. These are termed "candidates" and have very strong potential, but we must remind the community that a totally different gene may be the cause of the disease in humans. However, at least we have strong starting points.

In summary:

  • the families we collected through the clinics are strong and diverse.
  • We are beginning linkage studies on human chromosomes 4 and 16.
  • We have the DNA clones for the cat counterparts of the human genes.
  • We have normal and affected samples for sequence comparison.
  • The large DNA clones will also allow us to develop a genetic marker that is nearly on top of the gene; therefore, greatly extending families may not be necessary.
  • We will hold at least one additional PKD clinic that will focus on the strongest families and also be a service to the community.
  • Dr. David Biller will continue to be a major contributor of the project, and we will maintain strong relations with Dr. Stephen DiBartola.
  • Several breeds were found to be positive for PKD, while others have not had any positive results at our clinics.
  • These breeds include:

    • Persians 76/127 positive
    • Exotics 7/11 positive
    • Chartreaux 0/20 positive
    • American Shorthair 5/39 positive
    • American Wirehair 0/9 positive
    • Norwegian Forest Cat 0/11 positive
    • Scottish Fold 3/14 positive

BACKGROUND:

Some Persian cats have been shown to have a disease of the kidneys (PKD), that is inherited in a dominant fashion. Only one copy of the mutations is required to cause disease, which causes cysts to develop in the kidneys that impair normal function.

The cysts start to occur very early and can generally be detected by 6 to 8 months of age using ultrasound detection.

Cats can be considered free of the disease if no cysts form by 12 to 18 months of age. Although kidney cysts can be found in many types of cats, the cysts found in Persians occur very early, are found in both kidneys, and usually more than one cyst is present.

Since only Persians and cats that originated from Persians and Exotics have been shown to have this inherited form, most likely only one mutation is causing disease. Some cats can have very mild cysts while others have very severe problems; as a result, many cats can go undiagnosed.

Treatment is limited to assisting the cat's kidney functions. Liver cysts can also occur thus some cats develop liver problems too. Secondary health problems can arise due to poor kidney or liver function. Inherited kidney diseases are well documented in humans, mice and rats.

Several types of kidney diseases are known and a causative gene has been found for two forms. Other kidney diseases are not linked to the two known genes, thus others must be in the genome.

The ongoing study by Dr. Leslie Lyons hopes to determine if the two known genes that cause kidney disease in humans are also the cause of feline PKD.


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