"DCM Research"
- A = affected and C = clear, we have the following possible combinations and results:
AA x AA, we get 100% AA, all homozygote positives.
AA x AC, we get 50% AA, homozygote positives and 50% AC, heterozygote positives.
AA x CC, we get 100% AC, all heterozygote positives.
AC x AC, we get 25% AA, homozygote positives, 50% AC, heterozygote positives and 25% CC, clear
(negative).
AC x CC, we get 50% AC, heterozygote positives, 50% CC, clear (negative).
CC x CC, we get 100% clear (negative).
The main points are:
1. Two heterozygote positive parents can get clear offsprings.
2. A positive homozygot parent can't get clear (negative) offsprings, no matter what status has the other
parent.
3. A clear (negative) parent can't get homozygote positive offsprings, no matter what status has the other
parent.
The study found several (5) variations of the TTN gene, a gene encoding the giant myofilament protein
titin (TTN), which was one of the candidate genes that evaluated as part of a study of the genetic
aetiology of DCM in Dobermanns. The diagnosis of DCM of the dogs included to the study was based on
clinical and/or radiographic symptoms of congestive heart failure (CHF) and was confirmed in each case
by two-dimensional echocardiography. Almost every dog carrying one of them, (type 260, or haplotype 1),
was asymptomatic for DCM (except 2 ). The other variations were present in the group of sick dogs:
.............................................................
Typing of TTN microsatellite marker REN252E18 in the Dobermanns
showed a sharp partition of genotypes between the DCM and DCM non-affected Dobermanns.
The difference is enrichment of the 260 allele in the DCM-free group and enrichment of all other alleles
(especially allele 256) in the DCM group. The haplotype analysis of two small deletions and one
nucleotide substitution showed a similar partition between DCM and DCM-free dogs. The most striking
finding of the haplotype analysis was the variance of
haplotypes in the group of DCM Dobermanns as opposed to the relative uniformity of the DCM-free
group. While individual TTN marker alleles showed association with the DCM phenotype, they did not
combine to a single haplotype that was predominant in the DCM group. Next to haplotype 2, which was
shared between 12 out of 26 DCM dogs, we defined a total of four different haplotypes in the DCM group.
Thedivergent haplotypes in the DCM group and the high frequency of haplotype 1 in the non-affected
group and the random group form the basis for the hypotheses that will be discussed. In statistical terms,
the two alternative explanations are:
1. All titin alleles other than 260 (or haplotype 1) cause DCM, OR
2. The 260 allele (haplotype 1) confers protection against DCM.
For the first explanation it has to be assumed that the DCM-causing mutation is either very old, so the
linkage phase has been lost, even for intragenic markers, or that a DCM-causing mutation has occurred
multiple times in the Doberman breed. For the second possibility, it has to be assumed that there is a
DCM causing gene elsewhere in the genome.
In favour of the second possibility is the condition that it requires the least number of mutational events.
Our data do not allow us to conclude as yet whether the DCM-causing mutation is in a gene different from
the titin gene or that the first and the second explanation are not mutually exclusive.
There were 2 dogs in the DCM group that were homozygous for the 260 allele and 3 dogs homozygous
for haplotype 1. In the DCM-free group, there were five dogs that were not homozygous for the 260 allele
or haplotype 1. There are several explanations possible for these exceptions. In the DCM group, it is
possible that dogs had developed DCM due to a secondary cause. Conversely, dogs that were classified
as healthy may still develop DCM at an age older than 9 years. Another explanation (under the protective
allele hypothesis) for the five non-affected dogs that are not 260 (haplotype 1) homozygous is that they
are DCM non-affected due to the absence of the pathological mutation. (ELSEWERE in the genome). In
the DCM and DCM non-affected dogs described in this study, several
markers for DCM candidate genes and the DLA markers (mentioned below) have previously been typed
(Stabej et al. 2004; Stabej et al. 2005a; Stabej et al. 2005b) and showed no association with one or the
other phenotype, making it unlikely that the partition of the REN252E18 is due to a selection bias different
from the DCM status.
......................................................
So, maybe dr Meuers found the mutated gene primarily responsible for DCM, and the TTN status of a
dog -in another part of the genome- is what desides if the dog will get sick or not.
(quoted from DR)