The author would like to thank Dr. Cathryn Mellersh, of the Animal Health Trust, for reviewing this article prior to publication.

Cataracts are one of the Australian Shepherd's most common hereditary problems and easily the breed's most common inherited eye disease. In March of this year, at the world-famous Crufts Dog Show in Birmingham, England, Britain's Animal Health Trust (AHT,) a century-old charitable foundation dedicated to improving diagnosis and treatment of disease for dogs, cats and horses, announced a new DNA test for hereditary cataract (HC) in the Australian Shepherd.

The international breed community solidly supported the study while it was in progress. Aussie owners and breeders in the UK, North America and Europe submitted samples from over 400 dogs. AHT researchers found a mutation in a gene called HSF4 which is significantly associated with cataracts in Aussies. They subsequently developed a DNA screening test for that mutation. This test is a tool that can enable breeders to drastically reduce the frequency of cataracts in the breed.

That we have the test at all was due to a stroke of good luck. Dr. Cathryn Mellersh and her team initially found the mutation that causes HC in Staffordshire Bull Terriers, a recessive mutation of a gene called HSF4. They decided to screen all the other breeds for which they had DNA samples from dogs with cataracts to see if any shared the Staffy Bull mutation. One of those breeds was the Australian Shepherd; DNA from seven Aussies with cataracts had been stored several years before. Although Aussies didn't carry the Staffy Bull mutation, to Dr. Mellersh's surprise, they did carry another mutation in the HSF4 gene. To validate this initial result, she began to collect additional Aussie samples, first from dogs in the United Kingdom and later from North America and Europe. Ultimately, she determined that her inadvertent discovery was associated with cataracts in the breed and was able to develop a DNA test for the Australian Shepherd.

The fly in the ointment

Even though we now have a DNA test, some people are questioning the test's value and others are confused about what the test results mean for their dogs and their breeding programs. These misunderstandings have arisen due to several problematic aspects of HC in Aussies:

- There are multiple genes and gene versions that cause cataracts in dogs

- The HSF4 gene has more than one cataract-causing mutation

- The mutation found in Aussies is not a simple recessive

- Not every cataract is hereditary

All this has left more than a few people scratching their heads and wondering how to react to test results or whether to bother with testing at all.

A dog might have a cataract even though it does not have a mutation of HSF4, If a dog has just one copy of the Aussie mutation can develop cataracts, and - in what must seem a perverse whim of the DNA gods - not every dog that has the mutation has or will get cataracts, nor every dog with cataracts have the mutation.

Unlike the Staffy Bull mutation, the one found is Aussies is a dominant. While both are mutations of the same gene, they are separate alleles (versions) of HSF4. The Staffy Bull mutation is not known to occur in Aussies (though it is found in Boston Terriers, a much more closely related breed) nor does the Aussie mutation occur in Staffy Bulls.

To further complicate the picture, the Aussie mutation is not a simple dominant; it is dominant with incomplete penetrance. This means that not every dog that has the mutation will have cataracts. Instead, having the mutation confers a significantly increased risk of developing cataracts. A dog with even one copy of this mutation is twelve times more likely to develop cataracts sometime in its life than a dog that has normal versions of HSF4. The mutation was associated with all types of cataracts, but the majority of dogs had bilateral posterior cataracts - the type that has long been recognized typical of HC in our breed. [See What are Hereditary Cataracts?] The exact percentage of dogs with the mutation that have cataracts cannot be released at this time because the scientific paper based on the research is pending publication, but rest assured it is very high.

The fact that some dogs who have the mutation do not have cataracts is probably the biggest conundrum for breeders. Inheritance with incomplete penetrance means that other factors - most probably other genes - are involved in the process that determines whether cataracts do or do not develop in any particular dog. As of this point in time, we know nothing about those other factors.

Cataracts can also be referred to as having variable expressivity. This means that not every case is exactly the same. They develop in different parts of the lens. Age of onset varies considerably from young adulthood to the brink of old age. Progression, or how fast the cataracts advance, also varies. This variation in phenotype also indicates the importance of other factors to cataract development. Other genes almost certainly play a role in this variation, though they are yet to be identified.

As a final complication, not every Aussie with cataracts has the HSF4 mutation. Some cataracts are not hereditary at all, arising from injury or infectious diseases. Others may or may not be hereditary, as with nuclear sclerosis - the classic "old age" cataract. Still others, like those sometimes associated with hyaloid artery remnants, appear to be hereditary but the genetic cause is not yet known. Some cataracts are secondary to other genetic diseases: Homozygous merles with severe ocular defects not infrequently develop cataracts and dogs with the most severe form of Collie Eye Anomaly have detached retinas, which can cause secondary cataracts. Finally, there are other genetic mutations in the breed that cause cataracts, though this isn't surprising given our breed's comparatively short history and broad founder base.

Of the dogs that have the mutation but did not have cataracts, some almost certainly will develop them later in life, though at this point we aren't sure how many. The study was essentially a snapshot; it used information on dogs' eye phenotype and HSF4 genotype as of a particular point in time. While the genotype won't, change, we need to wait for a longitudinal study, the movie version as it were, before we'll know how many of those normal-eye dogs go on to develop cataracts. When that information is known we'll have a better idea what percentage of the dogs with the mutation will ultimately develop HC.

Since HSF4 is not connected to every cataract that occurs in Aussies, breeders need to accept the fact that use of this test will not necessarily prevent them from producing dogs that develop cataracts. However, effective use of the test will result in a significant decrease in the frequency of the disease across the breed as a whole. [See Types and Frequency of Cataracts]

In the Trenches

With the other genetic tests currently available for Australian Shepherds, most notably MDR1, CEA and PRA, the answer to the what to do question is straightforward: Having a single copy of the CEA-CH or prcd/PRA mutations or even two of the MDR1 are not reasons to remove a dog from your breeding program. HSF4 has not provided us with such a nice tidy little package. It also presents some tough ethical questions that can prove emotionally difficult to the breeder who discovers that one or more of her dogs have the HSF4 mutation.

People wonder why HSF4 is so important when there are other types of hereditary cataracts. But the correlation between the mutation and those dogs that have cataracts is so high that we cannot afford to ignore it.

More than a few people have questioned the wisdom of removing all HSF4 positive dogs from the breeding population, fearing that it could have a negative effect on the overall gene pool. In North America, at least, this is unlikely. CERF statistics indicate that only about one dog in 130 has bilateral posterior cataracts. Even if you allow for the fact that there will be additional dogs that have the mutation but don't exhibit cataracts, the number of dogs that would have to be withdrawn from breeding would still be less than one percent of the population. That leaves not only plenty of dogs to work with, but plenty of good dogs. However, it can't be denied that some individual breeders might be heavily impacted.

Depending on the breed population structure in countries outside North America, the frequency of the mutation might be higher or lower. If it is high in a country with a tiny population or where the population has a limited founder base, the national clubs in those places may need to develop a multi-generational plan for reducing the frequency of the mutation. For example, dogs with two copies of the mutation and those which have already developed cataracts might be removed from breeding while those with one copy who continue to have normal eyes as of the age of 4 might be used on a limited basis with mates that are tested clear of the mutation. In the meantime, efforts could be made to import new breeding stock, preferably from more varied bloodlines, that has been tested clear.

Another aspect of the HSF4 test's potential affect on the breed population relates to the breed's other significant health issues. Epilepsy is at least as common as cataract and far more devastating. The Australian Shepherd Health & Genetics Institute (ASHGI) Cancer Survey, completed last fall, indicated that hemangiosarcoma and lymphoma are very common in the breed. We also have hips, elbows and a variety of other health issues to deal with. Might we, through an over-zealous effort to eradicate the HSF4 mutation, cause ourselves and our dogs greater grief through neglect of those other issues? It is unlikely.

First of all, the existence of the HSF4 test is not a reason to ignore other health issues. Exams for hips, elbows and eye diseases of all types need to continue, as does use of the other DNA-based screening tests currently available.  (For reference, ASHGI provides a suggested testing and screening protocol on their website: http://www.ashgi.org/articles/screen_protocol.htm) But, as pointed out earlier, the frequency of cataracts, and therefore HSF4 since it is dominant, is sufficiently low that we are not apt to cause a marked increase in another disease by not breeding HSF4 dogs.

To breed or not to breed

Based on the author's correspondence and conversations with Aussie breeders since the release of the test, their one biggest conundrum is the fact that not all dogs with the mutation actually have cataracts. They want to know, for a certainty, whether or not the dog will get cataracts. And if it does not, why can't it be bred? Some have even asked whether there might not be some entire families that that have the mutation but never get cataracts - in which case why not breed them?

To begin with, while an HSF4 positive/no cataracts family might be possible, there is no evidence at this point that definitively supports that conclusion. There are clearly individuals who have reached old age with the mutation but without cataracts. There are also groups of related dogs with the mutation that don't have cataracts, but some of those dogs are still young and may develop them later. In 2006, CERF received recorded on exams of 36 Aussies with bilateral posterior cataracts. The median age of those dogs was 4.5 years old and the oldest one diagnosed was over 10. Until a longitudinal study is done that follows carriers of the HSF4 mutation into old age, we can't be sure how many of them will go on to develop cataracts, but we do know that most of them will.

Breeding a dog that has the mutation is very risky. Even if it does not have cataracts and never gets them, it will pass the mutation on to its offspring, who could well develop cataracts even if their parent did not. Half of the offspring of a dog with a single copy of the mutation will inherit it and be at high risk of developing cataracts. If the dog has two copies, all of its offspring will inherit the HSF4 mutation. The risk associated with breeding an HSF4 dog isn't worth it.

The polygenic nature of the disease leaves some people wondering why HSF4 alone is so important. HSF4 is a gene of major effect for this trait. A majority of the Aussies with cataracts of any type have at least one copy of this mutation. Other genes may well affect the final phenotype, but HSF4 provides a key indicator of dogs that are at significant risk for developing cataracts at some time in their lives.

Testing

With all the ifs and buts connected to the HSF4 mutation, breeders wonder whether they might not be better off relying on eye exams as they have always done. The problem is an eye exam only tells you what the examining veterinarian saw at the time the exam was done. For diseases present in young puppies it can be very effective at identifying affected dogs early in life, but HC frequently arises much later - often after a dog may have been bred. The advantage of a DNA test is that you know the dog's genotype whether or not it exhibits signs of the disease. Since most dogs with even one copy of this mutation will develop cataracts, you can use the test to identify those dogs and, if you test early in life, long before they develop active disease.

Because of the high risk for HC and the fact dogs with the mutation will almost certainly produce affected offspring, dogs with the HSF4 mutation should be removed from breeding. Since the test is new, it is inevitable that some dogs with the mutation will already have been bred. They should be withheld from further breeding and their offspring tested to verify their HSF4 status. [See:  How To Get Your Aussie Tested for the HSF4 Mutation]

Cataracts, and therefore the HSF4 mutation, are sufficiently common that for the next several years every breeding dog not out of two tested clear individuals ought to be tested before being bred. If your dog is clear of the mutation, it has a very low risk for developing cataracts from some other cause. Dogs with normal HSF4 test results can be advertised as such, though such ads should specifically mention HSF4 and not simply say cataract free since the test will not identify other cataract-causing mutations.

Test results, like other genetic health information, should be shared. If your dog has the mutation, let the owners of its parents and other near relatives know and advise them to test their dogs. The Orthopedic Foundation for Animals will register HSF4 test results. This is an excellent way to establish a permanent record that will be accessible to breeders world-wide and for generations to come.

While it is true we do not yet know what other mutations might also cause cataracts in Australian Shepherds, cataract research is still underway at AHT.  [See The Search Continues] We should continue to support their effort by submitting samples from dogs affected with any type of cataract. Eventually they may be able to provide us with an even more detailed understanding of the genetics of cataracts in the Aussies.

In the meantime, we must make effective use of the HSF4 test. It's the best tool we have for reducing the frequency of our breed's most common blinding eye disease.

Types and Frequency of Cataracts

The American College of Veterinary Ophthalmologists (ACVO) classifies cataracts by where they form in the lens. The lens has three layers of tissue: The nucleus at its core, an outer layer called the cortex, and a skin referred to as the capsule. The front and back are termed anterior and posterior, respectively. The outer rim of the lens is called the equator. Each lens also has anterior and posterior suture lines where the tissue came together during development.

Since not every cataract is inherited, ACVO and the Canine Eye Research Foundation (CERF) classify those that are likely due to environmental causes - generally injury or other diseases - as "significance unknown". Small cataracts are referred to as "punctate". These may or may not grow and those that do not aren't considered significant. Therefore, a dog with punctate cataracts will pass a CERF exam unless the cataracts have advanced to either the intermediate or diffuse type at a subsequent exam.

Cataracts may be in one eye (unilateral) or both (bilateral) and the later are considered the most likely to be inherited. Cataracts may start in one eye before the other, so a unilateral cataract may be discovered to be bilateral on a subsequent exam. Of the types of bilateral cataracts that will not pass CERF exams, posterior cataracts are anywhere from 4 to 10 times more likely to be found in Aussies than any other bilateral cataract. The HSF4 mutation identified by AHT is significantly associated with bilateral posterior cataracts.

A review of CERF statistics for the breed from 1999 – 2006 indicated that approximately .78%, or roughly one Aussie in 130, has this type of cataract. None of the other types of bilateral cataract (anterior, equatorial cortical, capsular, or nuclear) occur even half as frequently. The second most frequent type is bilateral nuclear cataracts, which occur in only in 1 of 550 dogs. The other types all occur in fewer than 1 in 1000 dogs.

What Are Hereditary Cataracts?

The typical inherited cataract in Australian Shepherds is bilateral, involving both eyes, and on the posterior (back) side of the lens. These cataracts usually begin in the cortex, the outer layer of the lens.

Generally, cataracts are first detected during a routine eye exam on a mature adult, but they can arise in young adulthood or in early old age. Cataracts in very young Aussie puppies are extremely unusual.

Disease progression varies. Some dogs' cataracts progress so slowly the dogs retain functional vision throughout their lives; others become blind in short order. One eye may first show signs of the disease before the other, but with hereditary cataracts the other eye will most likely develop one within a few months.

Cataracts start small and grow. When first noticed they may be referred to as "punctate". Not every small cataract will advance, which is why the American College of Veterinary Ophthalmologists and the Canine Eye Research Foundation give dogs with punctate cataracts a passing exam report. Even though the dog has passed its exam, if it is a breeding animal, the owner should hold off any breeding plans for six months to a year until a subsequent exam can determine whether the punctate is developing into a more advanced cataract.

Corrective surgery is available, but it is costly and not always successful. Fortunately for the affected dog, the disease causes no pain and most dogs adjust well to diminishing eyesight; dogs are much more attuned to sound and scent than vision.

The variable - and sometimes quite late - development of cataracts has been very frustrating for breeders. A dog might have litters on the ground before the disease develops. The advent of the new DNA test for the HSF4 mutation has the potential to reduce that risk considerably if we put it to good use.

How to get your Aussie tested for the HSF4 HC Mutation

Individual Submissions
At present, there is no lab offering the test in North America. Aussie owners can get testing kits from the Animal Health Trust in England. Upon request, AHT will send you test kits consisting of instructions, an application form, three cheek swabs and a special envelope in which the swabs may be returned. It is important that you use only materials sent to you by AHT for the test. Sign up via their website:

http://www.aht.org.uk/genetics_tests.html

Once the kit is completed and returned, results are usually available within a month.

The test is also available through AHT's partner organization in Finland, HT Diagnostics:

http://www.canigen.com/english_pages/gene_tests/hc_hereditary_cataract-test/

Clinics
Clubs or other groups may hold testing clinics. Pre-arrangement with AHT is necessary before scheduling a clinic. If you sample at least 20 dogs, a price break is available. If you would like to arrange for a clinic, contact AHT’s Symone Ingram: symone.ingram@aht.org.uk

The Search Continues

The AHT research team continues to study cataracts in Australian Shepherds, hoping to better distinguish between the type caused by the HSF4 mutation and those that are not. They also would like to identify other genes that may be causing cataracts in Aussies and why dogs with the HSF4 mutation have varying ages of disease onset and rates of progression.

Toward these goals, they continue to seek samples from Australian Shepherds diagnosed with any kind of cataract. AHT will DNA test dogs with confirmed cataracts free of charge upon receipt of a copy of the dog’s CERF form, a 5-generation pedigree and a completed DNA test application form.

Contacts:

At AHT:
Symone Ingram
Symone.ingram@aht.org.uk

In North America, kits are available from ASHGI:
ASHGI
730 E. Weldon Ave.
Fresno, CA 93704-6135
559 485-2136
51ca @ ashgi.org
www.ashgi.org