DACHSHUNDUpdate - ANCIENT MUTATION DISCOVERED - Purina Pro Club
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DACHSHUND Update
A NESTLÉ PURINA PUBLICATION DEDICATED TO DACHSHUND ENTHUSIASTS VOLUME 16 | SUMMER 2018
ANCIENT
MUTATION
DISCOVERED
Dogs’ Short Legs & Abnormal
Intervertebral Discs
Are Linked
SUMMER 2018
GENETIC DISCOVERY FINDS DACHSHUNDS’
SHORT-LEG PHENOTYPE
LINKED TO IVDD
Dachshund breeder MaryAnne Teal Although the cause of IVDD has
of Williamsburg, Virginia, has been been a mystery, a common theory
around the block more times than has blamed the Dachshund’s long
she would like dealing with dogs back. A recent breakthrough discovery
diagnosed with intervertebral disc at the University of California-Davis
disease (IVDD). Despite her efforts identified a functional fibroblast
to study bloodlines and breed away growth factor 4 (FGF4) retrogene
from the debilitating disease known insertion on canine chromosome 12.
for its high mortality rate and high The finding is key in helping to explain
cost of surgical and veterinary care, the causative variant attributed to
Teal has not been successful. the chondrodystrophy (CDDY)
An owner of Smooth Standard phenotype in Dachshunds, as well
Dachshunds for 30 years, Teal as many other breeds.
“Bonnie” (Tealdachs Sailor’s Delight) adores the breed’s big personality, “Their backs are not so much
was diagnosed with intervertebral disc its long-backed body and short legs. long as their legs are short,” says
disease (IVDD) at age 4 and recovered
partially with treatment. Her dam was Her love for her Dachshunds is seen Danika Bannasch, DVM, PhD, the
diagnosed with IVDD after producing in the top-quality care she has given Maxine Adler Endowed Chair of
the litter.
her dogs with IVDD. Decompression Genetics at UC Davis, whose labo-
surgery and rehabilitation did not ratory made the gene discovery.
always help her dogs regain walking Type I IVDD is most common in
ability. When these efforts did not Dachshunds. It is an an inherited
restore mobility, she outfitted her disorder caused by CDDY, a condi-
“Caring for a paralyzed dog dogs with carts and her home with tion of shorter legs and abnormal
ramps and gates to keep them safe. intervertebral discs in which the
is emotionally, financially “IVDD has pretty much affected discs degenerate prematurely in
and physically draining.” our lives in every possible way,” young dogs, occurring in some
Teal says. “We have stressed our dogs as young as 1 year of age. In
Tealdachs breeder MaryAnne Teal own backs and knees lifting and contrast, Type II IVDD occurs in
carrying our dogs. It is absolutely older dogs and is usually limited
heartbreaking when a dog never to a single intervertebral disc.
walks again. Caring for a paralyzed Having a gelatin-like core surround-
dog is emotionally, financially and ed by a fibrous coating, the inter-
physically draining.” vertebral discs, located between the
Teal is not alone. Dachshunds have vertebrae, protect and cushion the
the highest occurrence of IVDD than spinal column. In dogs predisposed
any other breed, with an estimated to Type I IVDD, the discs calcify and
disease incidence of 19 to 24 percent,1 harden, which can cause them to
thus many breeders and owners can herniate into the spinal canal. As the
relate to what it’s like to care for a discs press on the nerves of the
dog affected by IVDD. spinal cord, a dog may experience
2
DACHCHUND Update
“Both the FGF4-12 and
FGF4-18 mutations occur
concurrently in unrelated
dog breeds from diverse
breed groups and geo-
graphical locations.”
“Hildie” was breeder MaryAnne Teal’s first Dachshund to have IVDD. Only 2 1/2 years
old when she developed the disease, Hildie was paralyzed for the rest of life despite
Emily Brown, PhD, DVM, genetics graduate
surgery and rehabilitation.
student at the University of California-Davis
pain, nerve damage, loss of bladder phenotype known as chondrodys-
and bowel control, and/or paralysis. plasia (CDPA) that also occurs in
In Teal’s experiences, her first dog several breeds, including Dachshund,
with IVDD was partially paralyzed Basset Hound, Pembroke Welsh
after being diagnosed at 2 1/2 years Corgi, Pekingese, Scottish Terrier,
old. Her second dog, a show cham- West Highland White Terrier, and
pion and Hound Group winner, was Cairn Terrier. The identification of
bred before being affected with IVDD. the FGF4-18 insertion was made in
Although the dog recovered, she pro- 2009 by a research team at the
duced a daughter that developed National Institutes of Health study-
IVDD at 4 years old and recovered ing breed sizes and morphology.
partially with treatment though she “The chondrodystrophy-associated
struggled for the rest of her life with mutation occurred a long time ago,”
ataxia, or muscle incoordination. says Emily Brown, PhD, DVM, a
“The FGF4-12 retrogene insertion genetics graduate student in Dr.
in the dog genome that is respon- Bannasch’s laboratory who con-
sible for CDDY is characterized by tributed to the UC Davis research.
short legs due to dysplastic, short- “There are descriptions of short-
ened long bones and susceptibility legged dogs dating over 4,000
to Type I IVDD across several dog years ago. Both the FGF4-12 and
breeds,” Dr. Bannasch says. FGF4-18 mutations occur con-
An earlier FGF4-retrogene inser- currently in unrelated dog breeds
tion discovery on canine chromo- from diverse breed groups and
some 18 explains a short-legged geographical locations.”
3
SUMMER 2018
WHAT IS A RETROGENE? DWARFISM & ABNORMAL chondral ossification, the process
INTERVERTEBRAL DISCS whereby cartilage is replaced by
The mutation that causes dogs’ A fascinating aspect of the domesti- bone in the developing limb.
short legs and susceptibility to cation of the dog from the wolf is “Dwarfism caused by chondro-
IVDD is a functional fibroblast the subsequent variation in size and dystrophy has long been known
growth factor (FGF4) retrogene shape of purebred dog breeds that to be associated with abnormal
insertion on canine chromosome has transpired from dog breeding intervertebral discs,” Dr. Bannasch
12. A retrogene results from the and selection. One of the most says. “A reduction of long bone
retrotransposition of processed extreme examples of dog breed growth occurs due to defects in
mRNA (messenger RNA). All differences is in limb length, with endochondral ossification. These
cells have an mRNA molecule extremely short limbs defining early changes in the structure of
that transcribes the DNA from many breeds. growth plates cause shorter legs
the cell’s nucleus to the cyto- Extensive examination of growth and can also impact dogs through
plasm, or ribosomes, where it plates has been performed on many premature degeneration of the
is synthesized into protein. Only short-legged breeds, such as Dachs- intervertebral discs.”
a small percent of retrogenes hund, Pekingese, French Bulldog, The FGF4-12 insertion mutation
encode functional proteins, such American Cocker Spaniel, and Beagle, causing CDDY affects height phe-
as FGF4-12. as these breeds also are prone to notype in a semi-dominant inheri-
IVDD. Histopathological analysis of tance, whereby dogs with two
the bones of puppies from these copies of the mutation are smaller
breeds has shown that their short than those with one copy. The muta-
stature is due to defects in endo- tion impacts the IVDD phenotype
4
DACHCHUND Update
with a dominant inheritance, thus
dogs only require one copy of the GENETIC TESTING FOR IVDD RISK & SUBMITTING
retrogene insertion to be predisposed. SAMPLES FOR FURTHER STUDY
Interestingly, some, but not all,
CDPA-affected breeds are at increased A DNA test is available for chondrodystrophy (CDDY) and chondro-
risk for IVDD. For example, neither the dysplasia (CDPA) at the University of California-Davis Veterinary
Cairn Terrier nor the West High- Genetics Laboratory (VGL). The test can be ordered online.
land White Terrier has IVDD. The The VGL reports test results and their interpretations as follows:
autosomal dominant inheritance of CHONDRODYSTROPHY (CDDY & IVDD RISK)
the FGF4-18 insertion means dogs N/N No copies of CDDY mutation
need only one gene copy from a
N/CDDY One copy of CDDY mutation. Dog is at risk for IVDD.
sire or dam to inherit CDPA. Notably,
Mutation causes leg shortening compared to N/N dogs.
some dogs have both FGF4-12 and
When bred to an N/N dog, this will produce 50 percent
FGF4-18 mutations, which result in
of normal-sized puppies and 50 percent of puppies at
a more drastic reduction of leg length.
risk for IVDD.
Similarly, in humans, mutations in
the FGF family of genes (FGFR3) CDDY/CDDY Two copies of CDDY mutation. Dog is at risk for IVDD.
cause achondrodysplasia, the most Mutation causes leg shortening compared to N/N dogs.
common dwarfism in people and Will produce 100 percent of puppies with shorter legs
a type of chondrodystrophy that at risk for IVDD.
prevents bones from growing as
long as they should. The disorder CHONDRODYSPLASIA (CDPA)
is linked to shortened limbs and N/N No copies of CDPA mutation
abnormal vertebrae associated with N/CDPA One copy of CDPA. Mutation causes leg shortening
intervertebral disc disease. FGF genes compared to N/N dogs.
are involved in several embryological
CDPA/CDPA Two copies of CDPA. Mutation causes leg shortening
development processes in humans
compared to N/N dogs.
and are key for appropriate growth
and development.
Thus far, 44 Dachshunds have been tested, says Cecilia Penedo,
Odd though it may seem, a
PhD, VGL associate director. “Genotype homozygosity is about 93
medium-legged breed, the Nova
percent for CDDY and 98 percent for CDPA in these tested Dachs-
Scotia Duck Tolling Retriever, helped
hunds, though this is an area in which we need to learn more and
the researchers discover the FGF4-12
collect a broader sample size.”
mutation that predisposes Dachs-
Danika Bannasch, DVM, PhD, the Maxine Adler Endowed Chair of
hunds, as well as many other breeds,
Genetics at UC Davis, whose laboratory made the FGF4-12 gene dis-
to short legs and IVDD. The idea of
covery, says, “We would love to get research samples from Standard
using Tollers, the smallest of the
Dachshunds and in particular senior and geriatric dogs without disc
retriever breeds, was because they
disease. Most of our samples have some from hospital cases, which
are commonly affected by a form of
possibly biases the CDDY frequency.”
skeletal dysplasia that causes short-
If you are interested in submitting a research sample, please con-
legged individuals and abnormalities
tact Dr. Bannasch at BannaschLab@ucdavis.edu using “IVDD” in the
such as long-bone bowing, physeal
email subject line.
(growth plate) widening and joint
incongruity.
“Using a genome-wide association chromosome 12 similar to the one
study (GWAS), we compared 13 found previously on chromosome
Tollers with severe skeletal dyspla- 18 in some short-legged breeds.
sia and 15 Toller controls without “Since the skeletal dysplasia phe-
severe skeletal dysplasia,” says Dr. notype is not uncommon among
Bannasch. “To our surprise, we found dog breeds, we investigated hap-
the short-legged Tollers had an FGF4 lotype sharing across breeds and
retrogene insertion on canine saw that a portion of this haplotype,
5
SUMMER 2018
skeletal dysplasia-affected Toller,
one IVDD-affected Dachshund and
83 unaffected controls.
“We found that this second FGF4
retrogene insertion in the canine
genome is not only responsible for
skeletal dysplasia in Tollers but also
for chondrodystrophy, including the
predisposition to Type I IVDD across
all dog breeds,” Dr. Bannasch continues.
The research team looked at other
breeds that are considered chon-
drodysplastic and found the same
mutation on chromosome 12 in the
Dachshund, Beagle, American Cocker
Spaniel, a short-legged Coton de
Tulear, French Bulldog, Maltese,
Pekingese, Pembroke Welsh Corgi,
and a short-legged Miniature Poodle.
Some of the breeds, such as Dachs-
hund, had mutations on both chro-
mosome 12 and chromosome 18.
The chromosome 12 mutation
that causes CDDY is found in more
breeds than the chromosome 18
mutation that causes CDPA. Other
breeds with the FGF4-12 retrogene
insertion are: Basset Hound, Bichon
Frise, Cardigan Welsh Corgi, Cavalier
King Charles Spaniel, Chesapeake
Bay Retriever, Chihuahua, Dandie
Dinmont Terrier, English Springer
Spaniel, Jack Russell Terrier, Nova
Scotia Duck Tolling Retriever, Toy
Poodle, Portuguese Water Dog,
Scottish Terrier, and Shih Tzu.
“We realized that the long-held
belief that all short-legged ‘dwarf’
Dr. Danika Bannasch of the University or genetic variance, was shared with dogs result from the same chon-
of California-Davis is shown with her Beagles and American Cocker drodysplasia condition is wrong,”
2-year-old Nova Scotia Duck Tolling
Retriever, “Genes” (Aqueus Wild Type Spaniels, two breeds considered says Dr. Bannasch. “There are two
JH). A Toller enthusiast, Dr. Bannasch classically chondrodystrophic.” independent genetic mutations
recognized the breed’s short-legged
phenotype and growth plate abnormalities, In order to determine if the same caused by separate mutations of
which helped her team discover the region was associated with IVDD, the same retrogene that cause
FGF4-12 retrogene that affects Dachs-
hunds and many other breeds. the researchers performed a second slightly different types of dwarfism.
GWAS for Type I disc disease across It may have to do with the surround-
breeds including mixed breeds and ing chromosomal region that drives
found, indeed, the same region expression in the developing disc.
was associated. Chondrodysplasia is due to the
To pinpoint the causative variant FGF4-18 insertion mutation, and
for skeletal dysplasia and IVDD, they chondrodystrophy is caused by
sequenced the genomes of one the FGF4-12 insertion.”
6
DACHCHUND Update
IMPACT ON BREEDING is across Dachshund sizes, so selec-
Dachshund breeders may wonder tion against it should be done very
whether it is possible to select slowly and may not even be possible
against the CDDY mutation that if CDDY is homozygous.”
predisposes dogs to IVDD, while Given the high mortality rate of
LOOKING TO REPRINT?
keeping the CDPA mutation and IVDD combined with the high cost
the breed’s desirable short legs. of care and surgery, the FGF4-12
Dachshund Update articles may
“The most important factor is how retrogene insertion discovery pro-
be reprinted provided the article
widespread the FGF4-12 mutation vides important insights, though
is used in its entirety and in a
is in the gene pool, as there must more research is needed to better
positive manner. To request
be sufficient variation at that locus understand its impact on a breed-
permission to reprint an article,
in order to breed away from IVDD,” specific level. Dr. Bannasch and her
please contact the editor at:
explains Dr. Bannasch. “I think it is team are eager to collect more genet-
barbara.fawver@purina.nestle.
important for breeders to under- ic samples and continue the work.
com. Reprints should include the
stand that the FGF4-12 mutation “We are optimistic that someday
following attribution: Used with
is very common in most of the there will be more hope for Dachs-
permission from the Dachshund
predisposed breeds.” hunds and an ability to breed away
Update, Nestlé Purina PetCare.
In the Dachshund, the FGF4-18 from IVDD,” Teal says. “This has been
retrogene insertion is fixed, which a difficult, heartbreaking journey
means all Dachshunds have this for us, but our love for our dogs
mutation, she says. However, only has carried us through.” n
those that also have the FGF4-12
1
Ball MU, McGuire JA. Swaim SF, et al.
mutation are affected with IVDD
Patterns of Occurrence of Disk Disese
or at increased risk for IVDD. Thus, Among Registered Dachshunds. Journal
some dogs can have short legs and of the American Veterinary Association.
normal discs, while others may have 1982;180:519-522.
short legs and abnormal discs.
“Although this finding is exciting, Purina appreciates the support of
it is premature to think it will quickly the Dachshund Club of America
solve the problem of IVDD in and particularly Charlotte Borghardt,
chair of the DCA Health Commit-
Dachshunds,” Dr. Bannasch says.
tee, in helping to identify topics
“We are not sure how common or
for the Dachshund Update.
genetically set chondrodystrophy
7
SUMMER 2018
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