THE WINN
FELINE FOUNDATION
PKD Progress Report
Submitted by Leslie A. Lyons, Phd. University of California
at Davis
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:
1. the families we collected through the clinics are
strong and diverse.
2. We are beginning linkage studies on human chromosomes 4
and 16.
3. We have the DNA clones for the cat counterparts of the
human genes.
4. We have normal and affected samples for sequence
comparison.
5. 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.
6. We will hold at least one additional PKD clinic that
will focus on the strongest families and also be a service to
the community.
7. Dr. David Biller will continue to be a major
contributor of the project, and we will
maintain strong relations with Dr. Stephen DiBartola.
8. Several breeds were found to be positive for PKD, while
others have not
had any positive results at our clinics.
These breeds include:
a. Persians
76/127 positive
b. Exotics
7/11 positive
c. Chartreaux
0/20 positive
d. American Shorthair 5/39
positive
e. American Wirehair
0/9 positive
f. Norwegian Forest Cat 0/11 positive
g. 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. |
