Dunnford Boxers

Dr. Meurs on ARVC:

    There are several reasons it took so long to 
find this gene. First, as you know, ARVC is not an 
easy condition to diagnose definitively, and 
especially it is hard to rule it out definitively, 
as our only test so far has a very high false 
negative rate.  As you will see below, it may also 
have a fairly high false positive rate.

     Once Dr.Meurs had her population of "known affected" 
and "known clear", she still had some formidable 
obstacles.  As I mentioned when we discussed the 
DM test - while several other breeds also have heart 
problems, and arrhythmia problems, they ALL seem 
very different than Boxers.  Bulldogs do also have 
a somewhat similar problem, so she has tried to 
see if this would help her in the search for the 
gene, but in the end, it did not. With DM it appears 
that the mutation occurred very early in evolution, 
and was spread across many species, and as a side 
result, many breeds of dogs. DM may share some 
common genetics with Lou Gehrig's disease in humans, 
and this was, and is, a big help.  Conversely, ARVC 
seems similar to a human condition, but none of the 
known genes that are associated with the human ARVC 
helped Dr. Meurs either.

     She knew that chromosome 17 was an "area of 
interest", but after laborious checking none of the 
genes on that chromosome previously known to be 
involved with hearts were found to be associated 
with ARVC.  She finally had to "walk it in", with 
the help of Kirstin Lindblade-Toh at the Broad, 
checking each gene one by one in the "area of interest" 
until she found it. The gene is on chromosome 17. 
It has NEVER been known to have anything to do with 
hearts before, though it has been known to be involved 
with brain. They have not found this particular 
mutation in ANY other breed, or any other SPECIES 
so far.  It has been found ONLY in Boxers, despite 
some pretty concerted looking at this point.  So, it 
appears to have been a brand new mutation, in one of 
the foundation Boxers, and has been passed on 
accidentally as time has passed. The gene codes for 
"desmosomes" which are proteins that help tissue 
hold together:

http://en.wikipedia.org/wiki/Desmosome

 
http://en.wikipedia.org/wiki/Cardiac_muscle 

The mutation of this gene found in Boxers is 
VERY large. For those who know about DNA, it 
is a 7 base deletion, which means that the 
protein produced by the mutated gene is extremely 
dysfunctional. Boxers with one copy of the gene 
(heterozygotes) will code for at least SOME normal 
protein, but will still be affected to some extent.  
Boxers with 2 copies of the gene (homozygous abnormal) 
will be more severely affected. Discovering the gene 
and exactly how it causes ARVC helped her understand 
better why Sotalol is the drug of choice.

As for recommendations:

She believes that the gene is not as wide spread as 
the gene for DM. Therefore, she believes it may be 
possible to eliminate homozygous abnormal Boxers 
without adversely affecting our gene pool. However, 
of course, this may all change as we begin testing 
the wider population of Boxers.

ARVC

Dr. Meurs stated that there was a correlation to 
the boxers with the high VPC's and runs and the 
boxers who were homozygous, that is why they should 
be removed from the breeding program. The boxers 
who are heterozygous and show no other signs have a 
50/50 chance to pass the "good gene". If heterozygous 
dogs are bred to a dog who has both good genes (cleared), 
the percentage goes up to have unaffected puppies. 
To remove the heterozygous boxers from our program 
would limit the selection of available boxers for breeding 
and could cause other conditions, such as cancer, 
because of the excessive inbreeding.

She also stated that is important not to over react 
at this time on the heterozygous dogs because there 
is a good chance that other genes are involved in the 
making of Cardiomyopathy. The human condition contains 
7 genes that make up the disease. 

Dr. Meur's said ARVC usually appears around the age 
of 5 or older. ARVC and Dilalated Cardio are two 
different diseases and the Dilalated type does not 
show on the new testing. She said we still need to do 
holter testing at this time.

She said they do not know enough at this time to 
start eliminating a bunch of dogs from our breeding 
programs. We find it interesting that she said there 
may even be reasons for keeping some affected dogs 
such as dogs that are healthy in every other way. 
They do not yet know why some affected dogs have the 
symptoms at earlier ages than others.

In the study they have found that a chunk of DNA is 
missing. Healthy cells have a hinge between them. 
In affected dogs the hinges are weakened. There are 
3 results they found.
*Homozyous* has the most DNA 
deliction and has both copies of the ARVC

gene. These dogs will be the most affected.

*Heterozyous* has one copy of the ARVC gene. 
These dogs will likely have some symptoms of 
ARVC in their lifetime.

*Negatives* will be clear.

ARVC is not an easy condition to diagnose 
definitively, and especially it is hard to 
rule it out definitively, as our only test so 
far has a very high false negative rate. It may 
also have a fairly high false positive rate.

Bavaria Boxers has a wonderful chart. Please click 
on link below to see this and more.

 http://www.bavariasboxers.com/ARVC.pdf