Fedor Del Nasi - his and his lines influence on the breed

Unread postby jotunheim » Fri Aug 20, 2010 6:48 pm

Ferdinand wrote:Adlercrest Hessian was diagnosed with DCM at only 18 month of age and he lived without medication up to 7 years. Hessian was out of Danzig v. Adlercrest and Kira v. Norden Stamm. He was breed 2-2 to Ebo vd Groote Maat.


Interesting - and thank's for the information, almost brother/sister combination. Do you have date of birth, and whether or not he's still alive ...

Thank You

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Unread postby Ferdinand » Fri Aug 20, 2010 7:13 pm

@ Bitten

Hessian lived from 1989 - 1996

http://www.vom-bayrischen-loewen.de/cms ... p?idart=91

here you can read about it. This is an arcticle from Dr. Haberzettl...

he died from stomach tumor + DCM in the last stage.

Such a long live with DCM is extremly unusual but i know more dogs...
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Unread postby jotunheim » Fri Aug 20, 2010 9:17 pm

Ferdinand wrote:@ Bitten

Hessian lived from 1989 - 1996

http://www.vom-bayrischen-loewen.de/cms ... p?idart=91

here you can read about it. This is an arcticle from Dr. Haberzettl...

he died from stomach tumor + DCM in the last stage.

Such a long live with DCM is extremly unusual but i know more dogs...


Thank's AGAIN ... I have read articles from Dr. Haerzettl previously, also in regard to other topic - plus at one point been in direct contact with him. Interesting - and I truly hope other readers will find the context of the article interesting.

I'm always in search of valid information, as it will give a lot better foundation for the choices we may make.
Any information you might have in regard to this topic or other, please be so kind either to share it in this forum or send it to me privately: jotunheim@post.tele.dk

I for one will appreciate the information you have.

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Unread postby Sonia Dobe » Sat Aug 21, 2010 12:52 pm

gribbon wrote:775 examination on 412 dobermanns
it is a very small number!
RESULTS: DCM prevalence in various age groups was as follows: age group 1 (1 to <2 years) 3.3%, age group 2 (2 to <4 years) 9.9%, age group 3 (4 to <6 years) 12.5%, age group 4 (6 to <8 years) 43.6%, and age group 5 (>8 years) 44.1%. The cumulative prevalence of Doberman Pinscher cardiomyopathy was 58.2%.

Cumulative prevalence is NOT average.In another words that DOESN'T mean what you claimed at another post : " Some studies I have read are sure that DCM are the cause of 57% of deaths in the Dobermann. "
I told you that the dcm is in the genes of the breed.It was also in the past.Please don't say to me about ages of death of dogs from the past in comparison to the modern dogs.There is no sense because there is a variety of reasons which lead a dog to death and mostly because for every dog which you will mention,i can mention to you another one from the modern era who lived long.But this kind of discussion makes no sense.
.....to improve the breeding.We need a genetic test and not fears and rumors.


Estimated Gribbon:

Epidemiological measures of the frequency of a disease in a population can be evaluated from studies of Prevalence or Incidence. “Prevalence” is a measurement of all individuals affected by the disease at a point of time in all population, whereas “Incidence” is a measurement of the number of new individuals who contract a disease during a particular period of time in the risk population. “Accumulate Prevalence” is a measurement of the proportion of all individuals affected by the disease during a particular period of time. Risk population only includes healthy dogs at final time of the study (dogs died are not at risk).

DCM in Dobermann is a disease with variable Prevalence and variable Incidence over time: risk period for developing the disease can be between juvenile ages to most aged dogs (8 old). Disease is mortal in all cases and average time of survival is short. With these characteristics of the Dobermann DCM, most adequate method to evaluate the frequency of the disease in the population is the study of Accumulated Prevalence over a long trial period (5 years in this study).

Most accurate evaluation of risk of the DCM disease in the Dobermann population is given when we calculate the Accumulated Prevalence dividing the” total number of all affected dogs” of all age classes during the trial period, not by the total number of dogs but by the “total number of healthy dogs”, not including those with the disease, since they are not at risk of developing it.

Is in this case Accumulated Prevalence representative of the average risk of DCM for the subpopulation of European Dobermann? Yes! If the sample is representative (and it is), accumulated prevalence (58.2%) is the average risk. A prevalence of 58.2% for DCM means that now in a random group of 1000 healthy European Dobermanns, they are a most probable distribution of 582 of dogs that will be affected by DCM at some point in their lives, and 418 dogs not affected. It's that simple!

Is it enough and representative sample to obtain an accuracy scientific conclusion?I guess so. A level of statistical significance P<0.05 does not seem a lax level of significance. It is the most used significance level in veterinary epidemiological studies. Otherwise 5 years is a long enough time to obtain an accurate measure of DCM risk. Geographical distribution of the sample including dogs from Germany, the Netherlands, Austria, Switzerland, Italy, and some eastern European countries seems representative also.

But you are right, 412 Dobermanns can be a small number; a sample of 4000 is better and a sample of 40 is worse. Obviously, the main way to reduce the random error is increase the size of the sample. The appropriate size of a sample in an epidemiological study is not chosen at random but are calculated based on statistical formulas which relate the size of the sample with trial variables as level of statistical significance requested, probability of not detecting a real error, relative size of groups compared, etc.

Your argument is very clever but biased and confuses. If I deny the representativeness of the sample size shredding the validity… I remember you that scientific protocols are strict, and expert scientific referees evaluate the validity of the results, all methods (included the statistical methods and representativeness of the sample size), consulted bibliography and adequate relation of the discussion and conclusions topics with experimental data and cited bibliography before it publication in a scientific journal. The Journal of Veterinary Internal Medicine is not a “gossip magazine” it is the official publication of the American College of Veterinary Internal Medicine, the European College of Veterinary Internal Medicine, the European College of Veterinary Neurology, and the European College of Equine Internal Medicine, with a vey prestigious Editorial Board and an impact factor of 2.168, one most higher between Veterinary Sciences Journals.

Is the data of Accumulate Prevalence for DCM of European Dobermanns 58.2% all the truth? All statistical data ere subject to a degree of uncertainty but surely it is more near the exact value that our erratic speculations. In any case there appears a Dobermann forum the most appropriate place to discuss the validity of a scientific paper between neophytes. We would have to be grateful to the authors for their contribution, although their findings are an “inconvenient truth” for many people. When numbers appear fade fables.

Data of prevalence reported in the Discussion by the same authors for dogs from the United States or Canada vary between 45 and 63% (average between extreme values =54%). Is it a coincidence? Surely not: same founders + same bottleneck + same selection method on popular sires (although different popular sires) = same result. A catastrophe! Probably causative gene(s) are ancestral genes concentrated during selection (not recent mutations) but this matter little now. I think that the appropriate response to these data is to question our methods and strategies, not the validity and meaning of a scientific data.

What about interbreed risk of DCM? Interbreed quantitative relative risk of DCM is not documented in the bibliography. There are some quantitative data not corrected for the risk population of each breed (the number of live individuals of every breed, variable according to the popularity of each). In the paper of Petric et al. (Dilated Cardiomyopathy in Doberman Pinschers: Survival, causes of death and a pedigree review in a related line. J. Vet. Cardiol. 2002; 4:17–24) there are some data restrained to a territory (Slovenia). These data can give us some perspective of how things. Selecting data in this paper only for breeds ordinarily considered as “breed at risk” for DCM in the literature (Dobermann, Boxer, Great Dane, Newfoundland and English Cocker Spaniel). Dobermann accumulate more risk (almost double) than all others breeds at risk. Newfounland is not a popular breed but all others can be considered with a similar popularity. Approximate conclusion but it indicates a disturbing tendency.
Image

What about selection of the progenitors? The DCM is an ugly disease: autosomal dominant inheritance with reduced penetrance (Meurs et al. A prospective genetic evaluation of familial dilated cardiomyopathy in the Doberman pinscher. J Vet Intern Med. 2007; 21(5): 1016-20). Incomplete penetrance means that not all genotypes content the causative gene(s) exhibit DCM phenotype. More is reduced the level of penetrance more important is the percent of “silent carriers” in the not affected population.

Incomplete penetrance diseases is most likely a result of the way of a gene interacts with other genes as well as environmental factors of endogenous origin (for example sex hormones, immune system, etc) or exogenous origin (for example stress, food, etc). For simplicity and to understand the prospective risk for DCM in the selection of the progenitors, we can think in an inheritance model of a “major dominant gene D” responsible of DCM in Doberman and analyze it as a monogenic Mendelian trait. Just some examples:

First scenario: Penetrance 1 for DD homozygote and 0.5 for Dd heterozygote genotypes. In this scenario only rest an approximate 17.6 % of free dd genotype in the population; p(D)=0.58; q(d)=0.42.

Image

Image

Second scenario: Penetrance 0.75 for DD homozygote and 0.5 for Dd heterozygote genotypes. In this scenario only rest an approximate 8.8 % of free dd genotype in the population; p(D)=0.70; q(d)=0.30.

Image

Image

Another time approximate but disturbing. Even when a test is available we will certainly have to use heterozygous silent carriers Dd*, otherwise breeding population (dd) would be very small.

Paper of Petric et al. (Dilated cardiomyopathy in Doberman Pinschers: Survival, causes of death and a pedigree review in a related line. J Vet Cardiol 2002; 4:17–24) show that occult DCM cases (sudden death) are half that previously diagnosed DCM cases (congestive heart failure). Also diagnosed DCM cases (congestive heart failure) are more frequent in the more aged dogs (average =7.1 years old) and sudden death DCM cases are more frequent in dogs that have died younger. In this case, sample is restricted to a group of 21 affected Slovenian Dobermanns, but data may be indicative: half of all cases are occult to the ECHO-EKG Holter scanning diagnostic.

Image

A most detailed analysis of data of accumulate prevalence from West et al. show two age peaks for the Incidence (new cases in age groups) at 2-4 years (minor) and 6-8 years (major). This distribution is worrying for the progenitor’s selection because age class 6-8 shows an incidence of 31.1%, almost 1/3 of new cases of DCM in this age group, too late.

Image

Risk perception is subjective and everyone can see the glass half full or half empty as it seems. It is discussed in this section about Fedor. Can be him an affected DD or Dd? Probably no, because he has almost surpassed the age at risk (8 years). Can be him a silent carrier DD* or Dd*? Maybe yes, maybe not (his mother is probably affected DD or Dd). The time and the incidence of DCM in their progeny (the sample is very large) will reveal its likely condition. Otherwise if he is a silent carrier, most probably Dd*, no problem. In fact I have proposed before the use of heterozygous silent carriers Dd* when a genetic test can be available.

However, is a safe practice that a male as Fedor breed 150 or 200 bitches? No. If he is a free genotype dd for DCM this practice is bad (popular sire effect), if he is a silent carrier Dd* worse because he would contribute to spread the risk allele D in the population and increasing the DCM prevalence.

We could continue discussing on many other suspect dogs and the discussion would be endless with the same results among the sceptics and the cautious. I do not think starting a “witch hunt” as convenient and would not lead anywhere. Only objective and scientific data is that prevalence of the disease in Europe is 58.2%. A shame! This number has a reasonable explication only when a strong popular sire effect has disseminated the disease in the population. Retrospective origin of DCM in the North American Dobermanns is documented by the DCM status of famous Seven Sires (for example see Rod Humphries in Doberman Pinchers Magazine: The Cardiomyopathy Chronicles 1), in Europe data are scattered on different dogs but not in a synthetic article.

In absence of a genetic diagnostic, only reasonable way to prevent the increasing of the DCM prevalence in the population it is risk diversification. Risk diversification only works when you reduce the genetic quote of each individual in the Dobermann population. Limitation of litters by sire is necessary. Is limitation possible? It seems that no with the actual state of opinion of influential people and hierarchies. DCM is not Von Willebrand disease (rarely mortal and recessive), DCM is dominant although with incomplete penetrance but mortal in all affected dogs. What do you ameliorate without selection on health if a 58% of born dogs will die of DCM before 8 old? Is it coherent that the average longevity of the breed (7-8 years) is closely approximates with the limit risk age (8 old) for DCM and with data of pravalence (58%) in this study? Another coincidence? Unless we act now the percentage of affected dogs will continue to grow. What priority in this catastrophic situation, multi Ch & ZTP criteria of selection? If you add a criterion of clean DCM bloodline, how many dogs rest in this group? Sufficient number to make an amelioration job without going into a population bottleneck?

Your proposal that everything will remain as always, it is a proposal for risk. It's like if you recommended to a lung cancer patient continue smoking. Well, there is a subtle difference: the lung cancer patient can choose but the dog does not, the choice is dictated by the breeder. No, unless we act now, things that go wrong likely will get worse. I repeat, only reasonable way it is risk diversification and to limit sire utilisation.

I am aware that the reality, although inconvenient, it is stronger than any scientific or ethical argument. Perhaps the happiness of the innocent is least annoying, except for the affected dogs and for the breed survival. Even the Devil has advocates, usually much because he is very powerful, but not dogs.

Amicably:
Last edited by Sonia Dobe on Sat Aug 21, 2010 5:13 pm, edited 2 times in total.
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Unread postby Ferdinand » Sat Aug 21, 2010 4:02 pm

@ Bitten

Dr. Haberzettl died last year :-(
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Unread postby jotunheim » Sat Aug 21, 2010 5:21 pm

Ferdinand wrote:@ Bitten

Dr. Haberzettl died last year :-(


I'm truly sorry to hear this.
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Unread postby Ronindobe » Sat Aug 21, 2010 8:27 pm

As it is unnecesary...to agree with reality... I thank Sonia Dobe for a well constructed and pointed post. My one question is the validity of a "autosomal dominant" pathway. Sonia can you discuss this for me. Agreed that aspects of some studies suggest mathematics in that direct, but what about theories of polygenetic or a X related pathway? Can you focus breifly for me on your viewpoint or confidence based on your obvious familarity with the literature on the autosomal dom direction being the only or main pathway to DCM in the Dobermann?

Regardless, to me it seems a practical, progressive approach it to react to the best guess scenario. A reaction being required! A simiplified explanation helping to define a generally smart direction of breeding is a very useful tool. If there are other specific models that are also contributing, examining and reacting to such stats will still improve the status quo will it not?

Personally I prefer this explanation as the less difficult scenario. One gene or linkage being easier to ID than many. Easier to dilute [ or at least possible ] from lines that otherwise possess desireable traits. We need this gene test. How do we influence getting this done?

So the first reaction is one of pedigree analysis. Trying to get factual longevivity and cause of death data and apply it to our personal programs and hopefully to a group interprogram. Is there some value to a formation of some independent certifying body whose endorsement may be used by buyers and breeders to indicate risk levels of combinations? This is a very raw thought. Such agencies exist in other areas of commerce, and economics is the driving force of this problem. I have some people whose opinions I value on this subject, who could at least provide informed counsel to others on this topic for some compensation for time.

On a personal note. My comments about Fedor and stud use are echoed in Sonia's remarks. Myself I have a favorite male who is a linebred Gino GGrandson and a beautiful litter on the ground 12 weeks from him. Therefore I and hundreds of others who admire this great well used stud have great interest in the truth of the continual argument of his longevivity. I did my diligence in my research of his background, based on the information available to me at the time and could not find reported "abnormal" incidence in progeny of cardio problems. Problems sure, but not able to say very different than "baseline". But the data is not nearly complete or credible and that is THE problem. In this specific case, I have talked to Doug Matson and believe his report. But I feel it incumbent on Dr. Pezzano, because of the impact of Gino, the importance to the breed, to clearly put his status to rest with a public appearance and/or clear public announcement of status. He has been, after all, the president of the IDC for a very long time and worked for the breed a lifetime. The work is not done. I need to know how to use my fine boy the best or at all. The community that supports this breed with it time, energy, and money deserve to know any fact to support its proper direction. For such a huge contributor to the breed to support the effort to gather factual information neccessary for healthy breeding decisions, would greatly helpful.

Recently we also lost a great and prolific stud, Pimms Number One. My condolences to the Gorbachevs. I had been in contact with them several times about the potential breedings involving Pimms. I was interested in him as a Jivago son with some visible production. To that end later I imported a Pimms daughter out of an Urbano half sister. So I also ask directly for any information to be published clearly and in a timely manner on the cause of death of this influential champion. Again my intelligent use of this young girl in my program is based on the quality of this information.

As it stands the Euro Dobe in it's show and work forms I find to be generally a beautiful animal. I purposely moved to get representative genetics of some main "best" lines of current Euro dobe. Continue to improve my ability to determine what the hell that is with a little help from my friends. However I will be very thoughtful in the further addition or lining on any popular kennel whatever. There are aspects of almost all lines that need to be diluted away. Diversity is becoming a problem. To make qualified decisions neccessary for improvement I absolutely need the above information and credible data in general.

Thanks again Sonia!!

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Unread postby bmgillespie » Sun Aug 22, 2010 12:19 am

Ronnindobe,
I hope you get that information. I have similar dogs and would like to know same information as i am sure would a lot of other people. So good luck with that.
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Unread postby Ronindobe » Sun Aug 22, 2010 1:13 am

I just want the data to do my job at the highest level possible. I believe the expressed mission of all these owner/breeders is always the same. Not interested in blame or the past decisions in programs, just in facts about dogs and lines. Help me or get out of the way.

It may be suprising how quickly the situation can be improved with concerted effort and information. The hope I found in the remarks of Sonia was that 42% of stock may be unaffected and useable for establishing clean lines and dilute others. Of course which are they?

Good to see ya Bryant.
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Unread postby Gestur » Sun Aug 22, 2010 5:40 pm

hi,

Does anybody know the height and weight of Fedor ?
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Unread postby ROBIN » Tue Aug 24, 2010 9:28 am

Sonia , what you have posted is of great importance.

Please try to evaluate the death and the pedigree of Volvo Betelges with your "model". I am sure that many interesting things will be derived from.
Robin of Clyde ,you will always live in my heart

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Unread postby Sonia Dobe » Tue Aug 24, 2010 10:03 pm

Ronindobe wrote:I just want the data to do my job at the highest level possible. I believe the expressed mission of all these owner/breeders is always the same. Not interested in blame or the past decisions in programs, just in facts about dogs and lines. Help me or get out of the way.

It may be suprising how quickly the situation can be improved with concerted effort and information. The hope I found in the remarks of Sonia was that 42% of stock may be unaffected and useable for establishing clean lines and dilute others. Of course which are they?


Hi Ronindobe:

Thank you very much for your kind words. I take this very seriously because I am very concerned about the situation of the breed about genetic diseases. One of my dogs died from a genetic disease (hepatic) very young (2.5 years old) and their suffering left me a deep mark. I will try to respond you as clearly (my English is not my best) as possible and I added a final review of Dobermann DCM state of the art in my knowledge. To some it may be excessive but I think it's always good to have a synthesis of most relevant aspects for the breeders.

About your breeding plan.

I agree with you that most probably scenario is the first (penetrance 1 for DD genotype and 0.5 for Dd genotype). Segregation analysis of some groups in the pedigree of DCM affected dogs (paper of Meurs et all, [1] fig.1, p.1017) makes me think that this is the most likely scenario.

In this scenario Fedor can be a silent carrier Dd*, but in my opinion Gino (linebreed in your dogs), can be a most probably silent carrier Dd* for his pedigree antecedents and collaterals. In this scenario:
Image
But if you change the Dd affected by a Dd* silent carrier you will obtain the same result.
Image
This illustrates the possible case which a test mating of full siblings for eliminates in a bloodline one autosomal dominant disease with reduced penetrance, as DCM, not accomplish its goal. We can apply the same corollary than for Fedor. In you concerns, obviously the risk of a dog in your program decrease as his position goes back in the pedigree, but only if this risk has been diluted in the matings. It’s a crossword puzzle or rather a minesweeper (DD mines double explosives than Dd or Dd* mines).

In absence of a genetic diagnostic it is also clear that as important as the clinical ECHO-EKG Holter diagnostic (late diagnosis in many cases, half occult cases and short average time of survival) is the knowledge of the circumstances of death (age and possible cause) of dogs and relatives to get an estimated view of the likely condition: DD, Dd, Dd* or dd. It should be clear also that no genetic test is uncertain in our speculations, but every one can move in a space of probability based on available data on each dog in the pedigree and the use of common sense and a major gene model. Although we are blind never hurts to have a cane…

Otherwise, if we combined analysis of average longevity, mortality distribution by diseases in Dutch Dobermanns [2](table2), and accumulate prevalence of DCM in European Dobermanns [3], reasonably we can conclude that many dogs that die by natural causes and not cancer before 8 old are most likely to die of DCM. I say this only as a guide. You must not forget either that usually only children or drunks tell the whole truth on the issues drawbacks and this is another variable that must be contemplated in your crossword puzzle.

Assume that the penetrance of the heterozygote is 0.5 is a working reasonable hypothesis, but it remains only as hypothesis. If the penetrance is more reduced for heterozygote genotype Dd:
Image
I do not think that is very far from 0.5. We sometimes forget that genes are inherited, not genotypes and the silent carriers Dd* disseminate the disease well as those Dd affected but without prior notice.

About DCM mode of inheritance

Usually in Sciences a complex issue like this one is solved by successive approximations over time and the contradictions are resolved on the basis of new researchs. Normally most recent papers include most reliable conclusions. In my opinion Dr. Meurs’s group (Washington State University) is the most prestigious on canine and Dobermann DCM. His work [1] about mode of inheritance includes the monitoring of 41 dogs in four generations but specially with few dogs without diagnosis or knows phenotypic status compared with other studies [4]. Their conclusion (autosomal dominant with reduced penetrance) I think is more reliable. Most recent paper of Wess et al. [3] reported this mode of inheritance from this bibliographic source, but there is notice of this mode of inheritance since 1996 (fourteen years ago) in a paper of Hammer et al. [17].

As I related in my last note for reduced penetrance diseases is most likely a result of the way of a gene interacts with other genes as well as environmental factors of endogenous origin (for example sex hormones, immune system, etc) or exogenous origin (for example stress, food, etc).
Image

For example, in the paper of Petric et all.[4] is reported a major incidence between males than females in a sample of 21 dogs of a determinate Dobermann Slovenian line with high incidence of DCM and with a high level of inbreeding. Why this difference? For example a line may exhibit a higher incidence in males because a particular combination of environmental factors of endogenous (most probably) origin or exogenous origin represent a plus to attain the threshold value more readily in males, but not necessary by interaction with genes of the X chromosome. Neither this work is oriented to population genetics, but it is the Chapter 2 of a work oriented to Molecular genetics on searching gene polymorphisms linked to DCM phenotypes [5]. Although the results (males biased), in this work (preceding the paper of Meurs et al.[1]), the authors indicate in their introduction the same mode of inheritance (autosomal dominant with reduced penetrance) from Hammer et al. [17], so authors understand perfectly the limitations of their study.

Anyway, paper of Wess et al.[3] there is little difference between the sexes, although not significant. If in this paper we present the results of Table 1 (p.3) in a most synthetic form than Figure 2, grouping the data of all age classes:
Image
We can observe that there is a little difference in the clinical signs for diagnosed females and males. Females show more probably EKG Holter signs, whereas males show a most probably signs of EKG+ ECHO and signs of congestive heart failure. Also the sum of all cases shows a little difference (11.4%) between females and males (44.6 and 55.4% respectively). These differences are not significant, as they say the authors, in relation with an X linked mode of inheritance. Do they mean anything? I think so, 412 dogs are not 21 dogs, they are many dogs. In any case nothing in relation with genes of the X chromosome. Something in relation with sexual hormones (environmental endogenous factor) that reduced a little the penetrance level in females? Perhaps but I don’t know. This is not a “discovery” and surely now these authors and others are studying the different possibilities to explain this difference.

We can not forget also that genetic structure of the autosomes (no sexual chromosomes) varies between males and females, particularly the so-called chromosomes hotspots. Genes linkage is higher in males near telomeres and in females near centromeres of chromosomes. In fact average recombination rates during meiosis are higher in canine females than males (1.2 times higher). See bellow for canine chromosome 2 these differences.
Image

Is the DD or Dd affected status related with the variable expressivity of DCM in relationship with age of death (0-8 years), mode of presentation (sudden death or congestive heart failure) and clinical signs (ECHO-EKG Holter)? Another time is possible but I don’t know (but I sniff...). There must be a reasonable explanation for variable expressivity of DCM.

What about genes involved in DCM?

Although there is increasing data on the genetic origin of DCM in Dobermann, by moment there are no conclusive results about causative gene(s). The causative gene(s) responsible for this disease remain unresolved. In Dobermann the searching of mutations on many genes coding cytoskeletal proteins that have important structural functions in the cardiomyocytes (heart muscle cells), and in the proteins associated with the connective tissues of intracellular and extracellular matrix, they have been negatives: actin [6], desmin [7], delta sarcoglycan [8], phospholamban [9], alfa tropomyosin [5, Ch.4], troponin C, lamin A/C, cysteine and glycine-rich protein 3, troponin T, β-myosin [10] and calstabin2 [11].

Image

Another possibility is that Dobermann DCM can be an autoimmune disease. Neither any success in finding genes or markers in DLA-Class II (DQA1, DQB1 and DRB1) related with an autoimmune response [5, Ch.7]. However metallothioneins (proteolytic enzymes) have been implicated in the degradation and remodelling of collagen (component of connective tissue) in the diseased ventricle; it has been shown an increase in the expression of matrix metalloproteinase-9 (MMP-9) and neutrophil elastase in the left ventricles of Dobermanns with DCM correlated with an inflammatory cell response [12]. But changes in the collagenous matrix are also present in normal Dobermans [13]. MMP-9 has a protective antioxidant role and it overexpressed (high level) in unaffected Dobermanns. This can be related with the low diversity in DLA-II genes observed in the breed [14, 15] and the Dobermann predisposition for some autoimmune diseases. These background changes in the collagenous matrix could be involved in the rapid progression -not causal gene(s)- of the disease in Dobermann and the short time survival [13].

Dr. Meurs (Washington State University) in cooperation with others US universities research groups has discovered that a gene which encodes the sarcoplasmic reticulum protein calstabin2 (control release of calcium) it is involved in the development of Boxer's Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) [11] and an indicative genetic test for Boxer is currently available in Washington State University. Also Great Dane dogs with DCM demonstrate abnormal calstabin2 expression but in a contrary sense [16]. Mode of inheritance of ARVC in Boxer is similar to DCM in Dobermann but unfortunately, the DCM phenotype in the Dobermann is not related by the same protein calstabin2 [11].

Groups of Ljubljana & Utrech Universities found statistically significant correlations between DCM phenotypes and a polymorphic microsatellite marker REN252E18 in the gene encoding the giant myofilament protein Titin [5, Chp.7]. Briefly Titin's role in sarcomere structure provides a structural framework through association with other proteins as Actin, Myosin and others, and they keeps the thick filament centered during muscular activation.

Image


The difference in haplotype frequencies between the DCM and the DCM-free group and the frequency of dogs homozygous for a protector haplotype 1 and allele 260 were statistically significant. “Protector allele” 260 is majority in DCM free phenotypes and a most frequent “risk allele” 256 in the DCM phenotypes. Other haplotypes different that 256 exhibit the same tendency:

Image

I don’t know why, but after this Thesis there isn’t other publication of this research group about the Titin gene in relation with DCM in Dobermann.

Bellow table shows a resume of DCM mode of inheritance and possible genes involved for different breeds at risk:

Image

Obviously DCM is a complex disease with many variables among breeds, especially different founders so different background gene alleles involved. Complex problems rarely have simple solutions, and then we should not believe in miracles too.

Bibliography:
[1] Meurs KM, Fox PR, Norgard M, Spier AW, Lamb A, Koplitz SL, Baumwart RD.: A prospective genetic evaluation of familial dilated cardiomyopathy in the Doberman pinscher. J Vet Intern Med. 2007; 21(5): 1016-20.
[2] Mandigers P.J.J., Senders T., Rothuizen J. Morbidity and mortality in 928 Dobermanns born in the Netherlands between 1993 and 1999. Veterinary Record 2006: 158: 226-229.
[3] Wess G, Schulze A, Butz V, Simak J, Killich M, Keller LJ, Maeurer J, Hartmann K: Prevalence of dilated cardiomyopathy in doberman pinschers in various age groups.
J Vet Intern Med. 2010; 24(3):533-538.
[4] Petric AD, Stabej P, Zemva A. Dilated cardiomyopathy in Doberman Pinschers: Survival, causes of death and a pedigree review in a related line. J Vet Cardiol 2002; 4:17–24.
[5] Stabej P. Molecular genetics of dilated cardiomyopathy in the Dobermann dog. Doctoral Thesis, Utrech University, 2005.
[6] Meurs, K.M., Magnon, A.L., Spier, A.W., Miller, M.W., Lehmkuhl, L.B., Towbin, J.A: Evaluation of the cardiac actin gene in Dobermanns with dilated
cardiomyopathy. Am J Vet Res. 2001; 62: 33-36.
[7] Stabej P., Imholz S., Versteeg S.A., Zijlstra C., Stokhof A.A., Domanjko-Petric A., Leegwater P.A., van Oost B.A.: Characterization of the canine desmin (DES) gene and evaluation as a candidate gene for dilated cardiomyopathy in the Dobermann. Gene 2004, 340, 241-249.
[8] Stabej P, Leegwater PA, Imholz S, Versteeg SA, Zijlstra C, Stokhof AA, Domanjko-Petric A, Van Oost BA: The canine sarcoglycan delta gene: BAC clone contig assembly, chromosome assignment and interrogation as a candidate gene for dilated cardiomyopathy in Dobermann dogs. Cytogenet Genome Res 2005 , 111(2):140-146.
[9] Stabej P, Leegwater PA, Stokhof AA, Domanjko-Petric A, Van Oost BA: Evaluation of the phospholamban gene in purebred large-breed dogs with dilated cardiomyopathy. Am J Vet Res. 2005, 66:432-436.
[10] Meurs KM, Hendrix KP, Norgard MM.: Molecular evaluation of five cardiac genes in Doberman Pinschers with dilated cardiomyopathy. Am J Vet Res. 2008; 69-8; 1050-1053.
[11] Oyama MA, Reiken S, Lehnart SE, Chittur SV, Meurs KM, Stern J, Marks AR.: Arrhythmogenic right ventricular cardiomyopathy in Boxer dogs is associated with calstabin2 deficiency. J. Vet. Cardiol. 2008; 10(1):1-10.
[12] Gilbert S. J., Wotton P.R., Tarlton J.S., Duance V.C., Bailey A.J.: Increased expression of promatrix metalloproteinase-9 and neutrophil elastase in canine dilated cardiomyopathy. Cardiovasc Res (1997) 34 (2): 377-383.
[13] Gilbert S. J., Wotton P.R., Sims T.J., Bailey A.J, Duance V.C.: Alterations in the organisation, ultrastructure and biochemistry of the myocardial collagen matrix in Doberman pinschers with dilated cardiomyopathy. Research in Veterinary Science. 2000; 69 (3), 267-274.
[14] Angles JM, Kennedy LJ, Pedersen NC.: Frequency and distribution of alleles of canine MHC-II DLA-DQB1, DLA-DQA1 and DLA-DRB1 in 25 representative American Kennel Club breeds. Tissue Antigens 2005: 66: 173–184
[15] Mandinguers 2005, Insights in the pathogenesis of Dobermann hepatitis, Thesis Univ. Utrech, p.188.
[16] Oyama MA, Chittur SV, Reynolds CA.: Decreased triadin and increased calstabin2 expression in Great Danes with dilated cardiomyopathy. J Vet Intern Med. 2009; 23(5) :1014-1019.
[17] Hammer, T.A., Venta P.J., Eyster G.E. 1996. The genetic basis of dilated cardiomyopathy in Dobermanns. Anim. Genet; 27:101–119.
Last edited by Sonia Dobe on Wed Aug 25, 2010 10:59 am, edited 3 times in total.
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Unread postby bmgillespie » Wed Aug 25, 2010 10:41 am

Obviously DCM is a complex disease with many variables among breeds, especially different founders so different background genes involved. Complex problems rarely have simple solutions, and then we should not believe in miracles too.

AMEN! :D
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Unread postby Ronindobe » Wed Aug 25, 2010 8:02 pm

Great post and response! I am rereading to digest.... It is so refreshing to have a discussion that relies more on information than sheer passion. Please PM me with contact info for some side conversation. Are you currently involved in this or similar work?

Thank you for your thought provoking input!

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Unread postby Ronindobe » Wed Sep 08, 2010 3:49 am

Hello Sonia!
Was just reading your post again. So can some assumptions be made based on 256/260 haplotype ratio in a prototypical DNA analysis as to DCM risk?
Also the concept of endogenously triggered autoimmune response or genetic reaction to the same is intriguing. At one time I was interested in estrogenic mimickry and I have often pointed out the deterioration of the quality of the water supply as a potential issue in increases in cancer issues, but I could see the possibility of external insults helping the variability of the penetrance.
Still the idea of a more limited gene set than the 167 Oyama possibilities would be some comfort. If the model works "most" of the time, I am willing to utlilize it.

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