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Siberian Husky
Vol. 10, No. 1
■
December 2011
Genetic Complexity of Cataracts Hampers Efforts to Identify Causative Mutations
W
hen his 6-month-old female
Siberian Husky, “Luna,” began
running into furniture and
stumbling down steps, owner Daniel
Meunier of Cadyville, N.Y., knew it was
unusual behavior for a young dog. When
he looked into the puppy’s eyes, he saw
a bluish-white milky film and recognized it as a sign of juvenile cataracts,
a hereditary condition that affects
about 6 percent of Siberian Huskies.
An avid outdoorsman who enjoys
skijoring and backpacking with his
Huskies, Meunier took Luna to be
examined by a veterinary ophthalmologist who confirmed that she had
bilateral juvenile hereditary cataracts
(JHC). In other words, both eyes were
affected by the early-onset type of
cataracts. The ophthalmologist recommended surgery to remove Luna’s
lenses and replace them with artificial
lenses to restore her vision. Though
Meunier considered the cataract surgery
costly, he wanted to do all he could
to prevent Luna from going blind.
A replacement prosthetic lens was
surgically implanted in Luna’s left eye,
but the right eye was not healthy
enough to have an implant. Though
the vision in the right eye was blurry,
it remained functional for many years
until Luna developed glaucoma. She
then lost her vision in the right eye.
Today, 11-year-old Luna continues to
see well out of her left eye. She adores
going on hikes and spending time outdoors with Meunier.
Juvenile cataracts are a form of
primary hereditary cataracts (HC). Two
of Luna’s littermates also developed
juvenile cataracts. Though cataract
surgery corrects blurred vision, some
owners find the cost prohibitive.
Complications, such as Luna experienced in her right eye, can diminish
the promise of vision.
Cataracts are a leading cause of
blindness in dogs and humans. Approximately 100 breeds are affected by
primary hereditary forms,1 and some
breeds may develop more than one
form.2 The Siberian Husky Club of
America (SHCA) requires Siberian
Huskies to receive CERF (Canine Eye
Registration Foundation) certification
and be registered on the Siberian
Husky Ophthalmic Registry (SHOR) in
order to receive their eye clearances
for CHIC (Canine Health Information
Center) certification.
“Fortunately, only a small percent-
age of juvenile cataracts in Siberian
Huskies progress to blindness,” says
Sheila Morrissey, D.V.M., SHCA genetics chairwoman.
Despite the large number of breeds
affected with hereditary cataracts,
little is known about the genetics of
the condition, and only a single gene,
heat shock transcription factor HSF4,
has been identified as contributing
to the development of cataracts in
certain breeds.1 Samoyeds, Siberian
Huskies, Finnish Lapphunds and Icelandic Sheepdogs are among the
Northern breeds researchers are studying to learn more about the genetics
of this condition.
“We think hereditary cataracts in
Northern breeds are genetically complex, meaning they probably result from
mutations in more than one gene or
an interaction between genes and the
environment,” says Cathryn Mellersh,
Ph.D., a researcher at the Animal Health
Trust in the U.K. who has studied cataracts in dogs since 2001. “It is not a
simple recessive or dominant condition.”
Genetic research of cataracts in
dogs benefits from knowledge about
the genetics of the disease in humans.
Continued on page 2
DNA Samples Needed for Cataract Research
esearchers at the Animal Health Trust in the U.K.
and OptiGen in Ithaca, N.Y., are requesting DNA
samples of breeds affected by cataracts. Here is infor-
R
mation about samples that are needed. Additional
information about sample types and how to submit
them is available on their websites.
Animal Health Trust
Newmarket, Suffolk (U.K.)
www.aht.org.uk/cms-display/
genetics_research.html
Samples from dogs of any breed affected with bilateral cataracts, and
dogs of any breed over 6 years of age that have been examined by
a veterinary ophthalmologist and are clear of cataracts. Note that
Australian Shepherds must be 8 years of age to receive clear status;
a free DNA test is provided to Australian Shepherds affected by
bilateral cataracts and that are over 8 years old and test clear of
cataracts. The researachers particularly are interested in samples from
Australian Shepherds and Golden Retrievers with PPSC, Miniature
Schnauzers with congenital HC, and Irish Red and White Setters
with HC.
OptiGen
Ithaca, N.Y.
www.optigen.com/opt9_research.html
Samples from dogs with PPSC between 1 ½ and 3 years of age
of these breeds: Bernese Mountain Dog, English Springer Spaniel,
Golden Retriever, Labrador Retriever and Rottweiler. Dogs with PPCO
between 1 and 3 years of age of these breeds: Alaskan Malamute,
Samoyed and Siberian Husky.
Note: PPSC are posterior subcapsular cataracts that develop under the lens capsule, the sac-like covering of the eye. PPCO are posterior cortical
cataracts in which the opacity starts in the rear center axis of the cortex. HC are hereditary cataracts.
Causative Mutations
continued from page 1
Inherited cataracts in people usually
occur in association with metabolic
diseases or as part of more complex
genetic syndromes.1 There are about
39 genetic loci that have been associated with cataracts in humans, and
mutations in specific genes have
been identified for approximately 26
of these.
Loss of Functional Vision
Early cataracts may affect only a
small part of the lens and not impair
vision. As they mature, cataracts may
cover the entire lens and cause loss of
functional vision. They may develop
rapidly over weeks or slowly over years
and may occur in one eye before the
other. The common effect of cataracts
is loss of vision due to the cloudy
opacity that develops in the normally
clear lens of the eye. The opacity
inhibits the lens from focusing light
onto the retina. As the lens gets
cloudier, the amount of light reaching
the retina is reduced until a dog
eventually becomes blind.
Primary hereditary cataracts have
breed-specific characteristics relating
to appearance, age of onset, rate of
progression and bilateral occurrence.2
The majority are presumed to have a
simple autosomal recessive mode of
inheritance, although current studies
suggest this may not be the case in
many breeds. Secondary cataracts may
develop due to other hereditary eyes
diseases, such as progressive retinal
atrophy or glaucoma, or due to conditions such as diabetes mellitus, aging
or trauma.
The location of cataracts determines
their ophthalmological classification.
Posterior polar subcapsular cataracts
(PPSC) begin developing under the
lens capsule, which is the sac-like
covering of the lens. These occur in
dogs around 1 ½ to 3 years of age.
Affected breeds include Alaskan
Malamutes, Bernese Mountain Dogs,
English Springer Spaniels, Golden
Retrievers, Labrador Retrievers,
Samoyeds, and Siberian Huskies.
The genetic mutations responsible
for hereditary cataract have been
identified in four breeds: Australian
Shepherd (HC), Boston Terrier (JHC,
HC), French Bulldog (JHC, HC), and
Staffordshire Bull Terrier (HC). Direct
DNA tests are available to breeders
and owners through the Animal Health
Trust in the U.K. and VetGen in Ann
Arbor, Mich. The Animal Health Trust
has tested about 5,000 Staffordshire
Bull Terriers since the test was introduced in 2006 and about 3,000
Australian Shepherds since 2008.
Research leading to the discovery
of these mutations initially relied on
a candidate gene approach to identify
possible mutations. Mellersh and her
team studied cataracts in Staffordshire
Bull Terriers, looking at 20 genes that
had been identified as candidates for
the development of inherited cataracts
in humans. The HSF4 gene, located on
chromosome 16 in people and chromosome 5 in dogs, provided an answer.
“We found that Staffordshire Bull
Terriers had an extra letter inserted in
their gene code,” Mellersh says. “Then,
we looked at Boston Terriers and found
that they, too, had the same mutation
in the HSF4 gene. As we studied this
more, we found that some Bostons
have a later onset form of cataracts
not related to HSF4.”
The HSF4 gene mutation relationship also did not hold up when the
researchers looked at cataracts in
other breeds, including Cocker Spaniels,
Golden Retrievers and Miniature
Schnauzers. These breeds had normal
copies of the HSF4 gene. When the
researchers looked at cataracts in
Australian Shepherds, they found a
mutation in the HSF4 gene, but instead
of an extra letter, this breed had a
deleted letter.
“A few Aussies with cataracts do
not carry the HSF4 mutation, which
led us to speculate that another yet
unidentified mutation in a different
gene simultaneously circulates in the
Aussie population and plays a role in
the development of hereditary cataracts,” Mellersh says.
A DNA test was developed for HC
in Australian Shepherds, but as the
mutation is described as a “risk factor”
rather than a “causal mutation,” the
DNA test does not give an absolute
indication whether a dog will develop
cataracts. “An Aussie with one or two
copies of the mutation has a 17 times
higher risk of developing cataracts
than one without the mutation,”
Mellersh says. “Because the mutation
is dominant, only one parent of a dog
with the mutation needs to carry the
mutation for offspring to be affected.
A dog with no copies of the mutation
will not develop hereditary cataracts
associated with HSF4, although there
is a chance it could develop cataracts
from yet an unknown mutation.”
In collaborative research, Mellersh
and Hannes Lohi, Ph.D., of the University
of Helsinki and the Folkhälsan Research
Center in Finland, are seeking the causative mutations for hereditary cataracts
in Northern breeds. “We have excluded the HSF4 gene from involvement
in the development of cataracts in
Northern breeds,” Mellersh says. “We
believe other genes are responsible.”
They screened four Northern breeds
— Finnish Lapphund, Icelandic Sheepdog, Samoyed and Siberian Husky —
using genome scanning arrays to find
regions of the genome shared among
affected dogs that are different in
unaffected dogs. “A suggested association was found on chromosome 7
in Samoyeds but not in the other
breeds,” says Mellersh.
Another researcher at the Animal
Health Trust, Sally Ricketts, Ph.D.,
discovered a region on a different
chromosome that is associated with
cataracts in Siberian Huskies and
2
possibly Alaskan Malamutes and
Samoyeds. Her work supports the
theory that more than one gene
mutation may be responsible for
cataracts in Northern breeds,
Mellersh says.
“Our initial results indicate that
several of these breeds may share
associated cataract regions,” says
Mellersh. “We are planning to follow
this work up with more studies of these
regions. DNA samples from additional
dogs with hereditary cataracts will
improve our chances of success.”
The possibility of a DNA test for
cataracts promises insightful information for breeders. “A genetic test will
provide information that will enable
breeders to continue breeding great
bloodlines without fears of puppies
inheriting cataracts,” Mellersh says.
“A genetic test will provide simple
results to use when they are making
breeding decisions. Potentially,
breeders can eliminate cataracts in
two generations.”
Sue Pearce-Kelling, president of
OptiGen, a veterinary testing laboratory, cautions that the genetics of
cataracts may not be simple in some
breeds. “My suspicion is that we will
find there are many causes of cataracts
and that the DNA tests may be able
to reduce genetic causes but not
environmental causes.
“For this reason, it will be even more
important for breeders to continue to
have their dogs’ eyes examined routinely by a veterinary ophthalmologist
and for us to keep the message strong
that a DNA test does not take the
place of a clinical eye examination.
The two tools complement each other
to help ensure the healthiest outcomes.”
Meunier, whose Siberian Husky,
Luna, developed juvenile hereditary
cataracts, says, “Though I am not a
breeder, I would love to see a DNA
test for cataracts in Siberian Huskies.
It would help determine the likelihood
of a particular breeding producing a
higher incidence of cataracts. The
economic impact of cataracts is substantial and the cumulative impact
of surgery for cataracts can affect
quality of life.” ■
Mellersh CS, McLaughlin B, Ahonen S, Pettitt
L, Lohi H, Barnett KC. Mutation in HSF4 is
associated with hereditary cataract in the
Australian Shepherd. Veterinary Ophthalmology.
2009;12(6):372-378.
2
Mellersh CS, Pettitt L, Forman OP, Vaudin M,
Barnett KC. Identification of mutations in HSF4
in dogs of three different breeds with hereditary
cataracts. Veterinary Ophthalmology. 2006;9(5):
369-378.
1
Purina appreciates the support
of the Siberian Husky Club of
America and particularly Sheila
E. (Blanker) Morrissey, D.V.M.,
SHCA genetics chairwoman, in
helping to identify topics for the
Purina Pro Club Siberian Husky
Update newsletter.