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Re: [pyrnet] GPCA -- and dwarfs
In a message dated 10/13/2000 11:52:01 AM Eastern Daylight Time,
JGentzel@aol.com writes:
> Are you implying there is a known difference between chondrodystrophy
> seen in Pyrs and Malamute's? If so, reference that information for us.
I'm implying nobody knows for certain, whether it is different or whether
it's the same genetically and/or physiologically in the phenotype across the
board, because the gene or genes responsible for the condition have not been
identified on the molecular level in either breed.
To me the bottom line to me is, we don't know if it's the same mutation and
same expression of the same gene between the two breeds, or if it's different
mutations and/or expressions of the same gene, or even if it's two totally
independent genes' mutations with different or similar expression. We only
know sometimes the general phenotype is similar and sometimes it is
different. We know nothing about the genotype at the molecular level and we
no nothing about which genetically encoded processes are mutated with either
bread, or with ANY breed that has dwarfism for that matter.
It was once believed that genes encoded only for total function or
nonfunctional, or that they were either "good" or "bad", but that is not
generally the belief these days. Mutations in genetic processes can code for
a range of function on a progressive scale, perhaps from nonfunctional, to
poorly functional, to moderately functional, to highly functional, to
optimally functional. Or, if you prefer, function on a scale of 0-100%.
Such a range of expression is often seen even with the very *same* identical
genetic mutation across a vast case history of patients. The genetic defect
two of my children were born with, an inborn error of metabolism called
Tyrosinemia which can result from at least 27 *different* identified
mutations in the FAH gene, is an excellent example. A simple autosomal
recessive that can result in a wide range of variation of expression, from
lethal to only mildly or moderately impaired.
What we *do* now know with regard to molecular studies on certain genetic
health defects in dogs is that all mutations aren't created equally. You
can't simply go by a phenotype or expression that results in similar or even
identical diagnoses and conclude the results are due to the same genetic
mutations, nor can you conclude the expression of such defects will always be
the same across the board. This has been demonstrated in particular with PRA
in dogs, for which there are as I recall at least three (maybe more) DNA
tests available, and they are all BREED SPECIFIC.
Researchers have already identified at least three different genes causing
PRA in dogs (at least some homologous to genes causing PRA in humans and
other mammals), and it is also known that some breeds have more than one PRA
causing mutation within the breeds. There is sufficient reason to believe
the same principles may well apply to all other kinds of genetic health
conditions. At least that is my opinion.
This is precisely why these DNA tests that are being developed are generally
only applicable to certain breeds, because a mutation is not a mutation is
not a mutation. Yet, interestingly enough, mutations at completely separate
and independent genes can cause similar or even identical phenotypes *in
general*, but not always similar or identical phenotypes when it comes to
diagnostics and expression of symptoms and histology presented. This is
quite possibly why some breeds with dwarfism also have accompanying eye
anomalies, and some breeds don't. Some breeds with dwarfism have
accompanying blood cell anomalies and some don't. Some breeds with dwarfism
have accompanying hearing anomalies and some don't. Some breeds with
dwarfism have accompanying reproductive anomalies and some don't. And some
breeds (or individuals in any breed) with dwarfism may well have no other
accompanying health anomalies at all, only shortened limbs and abnormal
radiographic findings. And on and on it may well go, not just with dwarfism
but with any number of genetic health conditions we like to neatly categorize
by general phenotype or expression because we don't have enough knowledge at
the molecular level to categorize them by genotype and the underlying
impaired processes that are genetically encoded, and to what degree they
impair function.
Patric certainly is more qualified than I am to effectively address some of
the above points and considerations, so I would ask you, Patric, to please
step in and correct me if I am in gross error with any my above opinions or
statements as made, because I certainly do not want to be responsible for
spreading misinformation.
My personal feeling is because of some of these comparatively new and
revealing truths (about the complexity of genes and heredity) being
discovered as molecular genetics research moves along in dogs and other
species, it is difficult for me to warmly embrace and wrap my arms around the
idea that only ONE "hierarchy of disagreeableness" as was presented from Dr.
Padgett can be applied across the board. Dr. Padgett himself has rearranged
his suggested guidelines for priorities in his book from what appears to be
his earlier lecture material, or perhaps it's the other way around, maybe the
book came first. Here is one source (which is not dated) where he lists them
in the following order or priority:
[see: http://www.workingdogs.com/doc0031.htm]
"Disagreeableness of Genetic Traits:
Severe Traits
Disorders that cause pain to the animal
(i.e. glaucoma, CMO, hip dysplasia, entropion, distichiasis,
luxated patella, Legg-Perthes)
Disorders that disfigure, maim or otherwise render an animal nonfunctional
(i.e. cataracts, retinal dysplasia and detachment, chondrodystrophy).
Disorders that require treatment for the life of the animal
(i.e. Grey collie syndrome, diabetes, inherited hypothyroidism).
Disorders that require surgical correction for the animal to survive
(i.e. esophageal achalasia, anasarca, ventricular septal defects).
Disorders that are difficult to control
(i.e. multigene traits, abiotrophic traits)."
__________
Yet in his book (1998) he lists them as follows (page 161, Table 9.1):
"1. Painful Disorders
Examples: glaucoma, craniomandibular osteopathy, hip dysplasia, entropion,
portocaval shunts, dermatomyositis, cancer
2. Disorders that disfigure, maim, or otherwise render an animal nonfunctional
Examples: English Pointer dwarfism, cataracts, retinal dysplasia and
detachment, Malamute chondrodystrophy, PRA, deafness
3. Lethal disorders
Examples: malignant histiocytosis, inherited kidney function, anasarca,
globoid cell leukodystrophy, Portuguese Water Dog storage disease
4. Disorders requiring treatment for the life of the animal
Examples: grey Collie syndrome, diabetes, epilepsy, copper toxicosis
5. Disorders requiring surgical correction for the animal to survive or live
relatively painlessly
Examples: esophageal achalasia, ventricular septal defects, elbow dysplasia,
distichiasis
6. Disorders that are difficult to control
Examples: multigene traits; late onset traits, such as subaceous adenitis,
subaortic stenosis, oseteochondritis dissecans"
_______________
If he is subject to change his opinion over time, then how can we blindly
accept these suggestions or guidelines for long-term usage in any genetic
disease control plan for an entire breed? And doesn't it make sense that
such priorities may need to be breed specific depending on what problems
occur in each breed and what their frequencies are? And why on earth does he
place entropion in the "painful disorder" category which he lists as the top
priority of categories instead of in the next to least least important
category "disorders requiring surgical correction"? And why then did he move
"distichiasis" (which is another anomaly in which the eyelashes irritate the
eye) from cateogry #1 to cateogory #5, but not entropion?
I don't mean to sound harsh nor rude nor unappreciative of his efforts, but
the guy just doesn't have the utmost credibility in my eyes, and I personally
am not going to subscribe to everything he says partly (but not wholly) for
that reason.
> <<Somehow, believe it or not, it would appear he has differentiated
> in the various expressions and types of dwarfism and the degree of
> severity and quality of life issues as such in his priority scheme.>>
>
> Does he actually say that or have you make the conclusion that that
> is what he has said when he seemed to qualify the chondrodysplasia
> to Mals and then only mentioned chondrodysplasis in Pyrs? You
> somehow see that, as him taking Pyrs out of the category thereby
> stating, in absence of saying anything, that they should not fall into
> that category. That being the case, what category does he place
> the Pyr?
He actually said precisely what I quoted directly out of the book. My
comment or conclusion if you will was why didn't he include dwarfism in Great
Pyrenees? What could be the reason for that? One reason *might* be he
doesn't consider it as serious and debilitating as he does Malamute or
Pointer dwarfism. Do I know that for certain? No, I don't. That's why I
prefaced my comment with "it appears". It certainly shows he has reworded
this section from earlier materials used, so why? Which does he believe? I
haven't called or written to ask him. Have you? Do you know which he
subscribes to at this moment in time? Is all dwarfism maiming, disfiguring,
rendering nonfunctional in his opinion, or are only some types of dwarfism?
You originally chose to quote Padgett's statement about dwarfism in general
falling into this "maiming, disfiguring, nonfunctional" category. I was
merely pointing out that in a later work, he didn't lump ALL dwarfism in
general into that category. I admittedly don't know why, I was speculating.
> Lets cut to the chase.
>
> You believe that Dwarf Pyrs are never disfigured, maimed, and
> nonfunctional Pyrs? None of the above or any combination of same.
Nope, that's not what I said. I personally believe the majority likely are
not nonfunctional, and I believe the majority likely enjoy a good quality of
life. But that is my own conclusion based on data and information from a
variety of sources. Might I be wrong? Yes! Might you be wrong? Yes!
Might Dr. Padgett be wrong? Yes!
> If you believe that, what do you say to those who think they are and
> cull?
I say that is their choice, just as I feel those who choose not to cull are
entitled to their choice, but if those who choose to cull are saying they
have done so because the animal was nonfunctional, had a poor quality of
life, and was in significant pain because of the condition, then provide some
valid case history and diagnostic evidence that supports these findings,
otherwise we are never really going to know what percentage of dwarf Great
Pyrenees might be "suffering" due to their maimed, disfigured nonfunctional
condition that severely negatively impacts on quality of life.
It's quite possibly just like hip dysplasia with regard to variation in range
of expression. Some radiographically dysplastic animals from mild to severe
never have a serious problem that impacts on quality of life while others do.
In my experience with Pyrs, the majority of radiographically dysplastic dogs
aren't nonfunctional. Doesn't mean breed them, but it does mean evaluating
the condition with regard to breeding priorities and quality of life issues
for the animal might be very subject to interpretation.
Kelley Hoffman
kshoffman@aol.com