From:
Sukie Crandall
Date: 2007-03-15 17:56:03 UTC
Subject: [ferrethealth] Re: Blazes and Heart Disease
To: gerinanapush@sbcglobal.net, ferrethealth@yahoogroups.com, ferret-genetics@yahoogroups.com
What you are seeking is not covered in any studies specifically for
ferrets that I have encountered so far BUT there ARE studies in other
mammals that show increased rates of cardiomyopathy (especially
hypertrophic cardiomyopathy) and several of the neural crest genetic
variants. Blazes are caused by a neural crest genetic variant.
Exactly which neural crest variations are present in ferrets is
unknown. You will notice in the FHL Archives that a member who is a
genetics professor, Dr. Brett Middleton has said that the KIT
oncogene is more likely than Waardensburg Syndrome because it is a
better match for what is seen in ferrets, but that it could be that
some might have that syndrome, others might have KIT, etc. (There
are other Neural Crest variants as well.)
You will find more in
http://tech.groups.yahoo.com/group/Ferret-Genetics/
though Yahoo has gotten rid of a number of posts from earlier times
which were there and know that info about a study Wolfy (Rebecca)
carried there long ago on just this topic was among the things
removed. Hopefully, the post(s?) Dr. Silvia Pizzi who is a research
molecular geneticist (who was working on Multiple Endocrinological
Neoplasia genetics the last time we chatted) into on the higher rates
of cardiomyopathy with neural crest variations are still there, but
Yahoo has removed some of the earlier posts. She was the one who
taught me that hypertrophic cardiomyopathy rates are more strongly
affected so I think there were multiple posts from her on that.
The last time I read on postulated causes there seemed to be two
possibilities, but that may have changed in the time since then. A
little explanation so it is more understandable: Everyone has heard
of stem cells which are the earliest undifferentiated cells that
exist when the fetus is just mere days old and looked like a soccer
ball: ball shaped and hollow. After that the fetus needs to start
making certain early sections that differ from each other. These are
called "crests". The crest that will form the nerves, the heart, and
some other things is the cardiac-neural crest. The earliest
postulations on why higher rates of cardiomyopathy are found in
mammals with some types of neural crest genetic variations
hypothesized changes to this very early crest. Later this crest
splits into the cardiac crest which will go on to form exactly what
it sounds like, and the neural crest which mostly goes on to form
nerves but is also responsible for a range of other things. A more
recent hypothesis suggests that the higher rates of cardiomyopathy
found in mammals with neural crest variations is because of damage
caused by the sympathetic nervous system not forming properly. (This
is also under study in relation to some kidney problems in mammals.)
Some neural crest variations are very ancient, and found in
amphibians or reptiles, also, but they can spontaneously develop.
More often, though, they have been present but hidden in lines
because their affect on cells which later develop into so many other
types of cells (nerves, parts of the jaw, parts of the ear
structures, pigment cells, etc.) there is a lot of variation in how
it presents.
BTW, related to this: there are "Star Gene" studies which really
don't appear to be studies of a single gene. These are studies of
domestication and the changes which occur with domestication
(sometimes very, very rapidly). Among those changes are increased
rates of neural crest variant markings compared to wild related
animals, juvenile features (neotany) in things like body proportions,
shorter faces, and behavior, and (currently under study) possible
changes to the adrenal gland so that adrenaline is not released as
quickly nor in as large amounts.
I don't really have time to go through PubMed in a picky way for you,
but suggest that route to you because I think that is where most of
the abstracts on this would have been found in the past. Off-hand, I
recall something from an NIH site, too, long ago, I think. I am
doing a few slap-dash skims for you.
See also:
http://circres.ahajournals.org/cgi/content/full/92/1/73
START QUOTE
Interestingly, in humans there have been reports about hypertrophic
cardiomyopathy in association with lentiginosis as manifested in the
leopard syndrome and other disorders of the neural crest tissue
further emphasizing the potential role of neural crest in the
development of a hyperplastic or hypertrophic heart disease.22 Because
Lbx1-deficient mice decease shortly after birth when skin pigmentation
is not yet completed, we were unable to access the distribution of
skin pigments in Lbx1 mutant mice. However, in some cases
hypopigmented spots were observed on the back or the belly of
heterozygous Lbx1 mutant mice, which might indicate a
haploinsufficiency of the Lbx1 gene in regard to migration of
melanocytes. It should be pointed out, however, that the frequency of
such observations was low (<1:500).
END QUOTE
<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?
db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=14749494&query_hl=1&i
tool=pubmed_docsum>
BEGIN QUOTE
Recent Prog Horm Res. 2004;59:1-12.
Essential roles of Her2/erbB2 in cardiac development and function.
Negro A, Brar BK, Lee KF.
Clayton Foundation Laboratories for Peptide Biology, The Salk
Institute, La Jolla, California 92037-1002, USA.
The tyrosine kinase receptor erbB2, also known in humans as Her2, is
a member of the epidermal growth factor receptor (EGFR or erbB1)
family, which also includes erbB3 and erbB4. The erbBs were
discovered in an avian erythroblastosis tumor virus and exhibited
similarities to human EGFR (Yarden and Sliwkowski, 2001). Her2/erbB2
is highly expressed in many cancer types. Its overexpression is
correlated with a poor prognosis for breast and ovarian cancer
patients. ErbB receptors bind to a family of growth factors, termed
neuregulins/heregulin (NRG/HRG), which comprise NRG-1, -2, -3, and -4
and include multiple isoforms. ErbB2/Her2 is an orphan receptor that
does not bind ligand alone but heterodimerizes with the other erbB
receptors for NRG signaling. ErbB2 is expressed in multiple neuronal
and non-neuronal tissues in embryos and adult animals, including the
heart. Genetic data demonstrated that erbB2 is required for normal
embryonic development of neural crest-derived cranial sensory
neurons. ErbB2/Her2-null mutant embryos of a trabeculation defect die
before embryonic day (E) 11. To study its role at later stages of
development, we generated a transgenic mouse line that specifically
expresses the rat erbB2 cDNA in the heart under the control of the
cardiac-specific alpha-myosin heavy chain promoter. When crossed into
the null background, the expression of the rat erbB2 cDNA rescued the
cardiac phenotype in the erbB2-null mutant mice that survive until
birth but display an absence of Schwann cells and a severe loss of
both motor and spinal sensory neurons. To study the role of erbB2 in
the adult heart, we generated conditional mutant mice carrying a
cardiac-restricted deletion of erbB2. These erbB2 conditional mutants
exhibited multiple independent parameters of dilated cardiomyopathy,
including chamber dilation, wall thinning, and decreased
contractility. Interestingly, treatment of breast cancers
overexpressing erbB2 with Herceptin (Trastuzumab), a humanized
monoclonal antibody specific to the extracellular domain of erbB2,
results in some patients developing cardiac dysfunction. The adverse
effect is increased significantly in those patients who also receive
the chemotherapeutical agent anthracycline. We found that erbB2-
deficient cardiac myocytes are more susceptible to anthracycline-
induced cytotoxicity. These results suggest that erbB2 signaling in
the heart is essential for the prevention of dilated cardiomyopathy.
These lines of mice provide models with which to elucidate the
molecular and cellular mechanisms by which erbB2 signaling regulates
cardiac functions. These mice also will provide important information
for devising strategies to mitigate the cardiotoxic effects of
Herceptin treatment, allowing for the potential expanded use of this
drug to treat all cancers overexpressing erbB2.
PMID: 14749494 [PubMed - indexed for MEDLINE]
END QUOTE
http://ferrethealth.org/archive/YG3069
This is a different neural crest variant:
http://tech.groups.yahoo.com/group/Ferret-Genetics/message/3627
http://tech.groups.yahoo.com/group/Ferret-Genetics/message/3355
http://tech.groups.yahoo.com/group/Ferret-Genetics/message/3352
http://tech.groups.yahoo.com/group/Ferret-Genetics/message/3352
http://tech.groups.yahoo.com/group/Ferret-Genetics/message/166
Possibly:
<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?
db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=12920978&query_hl=1&i
tool=pubmed_docsum>
If memory serves this might be the journal article that Wolfy had
found in the past:
<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?
db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=7911041&query_hl=1&it
ool=pubmed_docsum>
BEGIN QUOTE
Curr Opin Cardiol. 1994 Jan;9(1):78-90.
Links
Cardiovascular molecular genetics.
Anderson PA.
Duke University Medical Center, Durham, North Carolina.
This monograph reviews advances in understanding the genetic basis of
heritable disorders of the heart and vasculature, including
hypertrophic cardiomyopathy, Marfan syndrome, conotruncal
malformations, atrioventricular septal defects, supravalvular aortic
stenosis, and the field defects associated with DiGeorge and
velocardiofacial syndromes. The prognostic value and the functional
effects of beta myosin heavy chain gene mutations in familial
hypertrophic cardiomyopathy are discussed. The relation between
Marfan syndrome and fibrillin mutations and that between
supravalvular aortic stenosis and William syndromes and elastin
mutations are reviewed, as is the presence of microdeletions in 22q11
in DiGeorge syndrome, velocardiofacial syndrome, and nonsyndromic
patients with conotruncal malformations. The relation between neural
crest cells and field defects are considered in the context of the
genetic basis of Patch, a mutation that results in abnormal neural
crest cell migration and conotruncal malformations. The role of
transforming growth factor beta isoforms in cardiac morphogenesis is
considered in the light of apparently normal morphogenesis in
transforming growth factor beta 1 null mice.
PMID: 7911041 [PubMed - indexed for MEDLINE]
END QUOTE
This is another LEOPARD Syndrome one:
<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?
db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=15078383&query_hl=1&i
tool=pubmed_docsum>
(BTW, there was a breeders in northern Europe who put photos of his
minks and ferrets together on his site and showed the back (but no
more) of what was one or the other with want appeared to be LEOPARD
Syndrome from the black spots on the while coat. No mention of that
line since, so it might have died out.)
These markings were not often seen when we first began having ferrets
in our family about 26 years ago, but later there was a premium price
asked by some breeders and one mid-sized farm for them and then
ferrets with these markings began to be studied more.
I used to have a neighbor who was doing human genetic counseling at a
hospital and it turns out that since nerves are involved there can be
a lot more things changed than I had realized, at least according to
the human literature on neural crest variations.
You will want to do more searching. PLEASE, share the abstracts and
URLs of related journal articles that you find.
I'll copy this to Ferret-Genetics, too, since it replaces some
previously lost stuff.
Sukie (not a vet)
Current FHL address:
http://groups.yahoo.com/group/ferrethealth
Recommended ferret health links:
http://pets.groups.yahoo.com/group/ferrethealth/
http://ferrethealth.org/archive/
http://www.afip.org/ferrets/index.html
http://www.miamiferret.org/fhc/
http://www.ferretcongress.org/
http://www.trifl.org/index.shtml
http://homepage.mac.com/sukie/sukiesferretlinks.html
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