Identifying Mutations Associated with HC in the Dog
Tufts' Canine and Feline Breeding and Genetics Conference, 2009
Cathryn Mellersh
Animal Health Trust, Newmarket, Suffolk, UK

Objectives of the Presentation

 An overview of the lens and an understanding of the different forms of canine cataract.

 A summary of what is currently known about the genetics of canine hereditary cataract.

 A brief overview of current ongoing investigations into hereditary cataract in other breeds.

Overview of the Issue

Cataract, which is simply defined as opacity of the lens of the eye, is recognized as one of the most frequent intraocular diseases and a leading cause of blindness in the dog.(1,4)

The lens of the eye is an intriguing part of the body. It needs to remain transparent throughout an organism's life, which is of course necessary for its function as an optical instrument, but highly unusual for a cellular tissue. The lens consists of a central nucleus of primary lens fibres surrounded by a cortex of secondary lens fibres, both of which are surrounded by a proteinaceous capsule. Lens fibres are organized in densely packed lamellae, and during development they lose their nuclei to become metabolically inert. The lens fibres are specialized for the production of crystallins, a specialised group of proteins that are optimised for the task of remaining intact and solubilized. In addition to the crystallins the lens is also composed of cytoskeletal proteins, such as vimentin, membrane proteins which are responsible for the communication between lens fibres and extracellular matrix proteins, such as type IV collagen.


In humans inherited forms of cataracts have now been mapped to around 30 different genetic loci and approximately 20 genes have been identified at these loci.

Not all canine cataracts are inherited. Hereditary (primary) cataracts (HC) have no obvious or apparent cause and usually exhibit marked breed specificity in their ophthalmoscopic appearance, age of onset, rate of progression, degree of bilateral symmetry and their position within the lens. The position of the cataract within the lens is a key characteristic that ophthalmologists use to judge whether a cataract is hereditary and will routinely differentiate between anterior, posterior, nuclear, cortical and subcapsular cataracts. In contrast, non-hereditary (or secondary) cataracts are those that follow some other hereditary eye disease, e.g. generalized progressive retinal atrophy, retinal dysplasia, glaucoma and do not generally exhibit any breed specificity. Primary HC has been described in as many as 97 different breeds (1,2) and some breeds are unfortunate enough to show more than one form, e.g. the Boston Terrier, Cavalier King Charles Spaniel.

Hereditary cataract would seem to have a recessive mode of inheritance in the majority of breeds.(5,7) Recessive conditions are difficult to control within canine populations because asymptomatic carriers can only be identified retrospectively, once they have reproduced and affected offspring have been diagnosed. An additional factor that makes HC difficult to eradicate by selective breeding alone is the fact that the condition is a middle- to late-onset condition in many breeds, meaning affected dogs may be innocently bred from prior to diagnosis. Despite the large number of breeds affected with hereditary cataracts (HC) surprisingly little is known about the genetics of the condition. Understanding the genetics basis of HC in different breeds will enable the development of breed-specific DNA tests that breeders can use such tests to determine the genotype of their dogs and make sensible breeding choices that minimize the risk of producing offspring affected with cataracts in the future.

Previous and current investigations aimed at understanding the genetic basis of inherited canine cataracts are summarized below.

Hereditary Cataract in the Staffordshire Bull Terrier

Primary HC in the Staffordshire Bull Terrier (SBT) was first reported in the United Kingdom in 1976.(8) This cataract is bilateral, symmetrical in the two eyes, and progressive until total with resultant blindness.(9) It is not congenital (present at birth) but appears at a few weeks to months in age, progressing to total cataract by 2 to 3 years of age. Pedigree perusal and the examination of closely related animals, in particular parents and littermates, strongly indicated a simple, autosomal, recessive mode of inheritance.(9) At the Animal Health Trust in 2006 we undertook a candidate gene approach to investigate 20 genes, known to be associated with inherited cataracts in humans, for their potential role in the development of HC in the SBT. One of the genes we investigated, called HSF4, belongs to a family of heat shock transcription factors and has been reported to cause both autosomal dominant and recessive cataracts in both humans and mice. We identified a single C nucleotide insertion in exon 9 of HSF4 that that alters the reading frame of the gene, introduces a premature stop codon that leads to the premature truncation of the HSF4 protein and is the cause HC in the SBT.(10)

A DNA test is now available that breeders are making extensive use of to eradicate this serious and blinding form of cataract from their breed.

The figure below illustrates the DNA test results from Clear, Carrier and Affected SBTs.


Hereditary Cataract in the Boston Terrier

Boston Terriers (BST) suffers from two clinically distinct forms of hereditary cataract which occur at different ages and which are different in their appearance and progression. Early-onset hereditary cataract (EHC) affects dogs within the first few months of life, is always progressive and bilateral and results in total blindness whereas late-onset hereditary cataract (LHC) in general affects dogs over the age of three and is more variable in its clinical phenotype, age of onset, progression and the degree to which vision is impaired. EHC in the Boston Terrier is very similar in clinical appearance to HC in the SBT, and is in fact caused by the identical HSF4 insertion described above. In contrast, LHC in the Boston Terrier is caused by a different, as yet unidentified, mutation and is thus genetically, as well as clinically, distinct from EHC in this breed.(11)

Hereditary Cataract in the French Bulldog

The HSF4 mutation that causes HC in the SBT and the BST has also been identified in French Bulldogs (FBD) affected with early-onset, progressive cataracts and a DNA test is also available for this breed. However, a small number of FBDs have recently been identified that have clinically distinct cataracts and which lack the HSF4 insertion, suggesting HC may be genetically heterogeneous in this breed also (unpublished).

Hereditary Cataract in the Australian Shepherd

At the same time as the HSF4 insertion was identified in the SBT, BST and FBD we also discovered another, very similar, mutation in a small number of Australian Shepherds (AS) with cataracts. The mutation in the AS is a single nucleotide deletion, also in exon 9 of HSF4. With the support and co-operation of the international AS community we have since thoroughly investigated the relationship between the HSF4 deletion and the development of cataracts in the AS and have been able to conclude the mutation is in fact associated with HC in this breed. The situation is, however, more complex than in the other 'bull type' breeds investigated to date. Both the age of onset and the clinical appearance of HC in the AS are more variable than in other breeds, and there is some evidence for a co-dominant mode of inheritance. Heterozygous dogs (that carry a single copy of the mutation) are at increased risk of developing posterior polar subcapsular cataracts (PPSC) that usually do not progress to cause visual impairment, whereas homozygous dogs (that carry 2 copies of the mutation) tend to develop more progressive cataracts. The variability observed within this breed may indicate additional, cataract-associated mutations are segregating within the AS population.

Current Studies in Additional Breeds

As described above HSF4 has now been implicated in the development of HC in four different breeds; it has also been excluded from involvement in an even greater number of breeds, including the Alaskan malamute, Bichon Havanais, Belgian Shepherd Tervueren and Groenendael, English Miniature Terrier, Finnish Lapphund, Griffon Bruxellois, Jack Russell Terrier, Kromfohrlander, Lapponian Herder, Miniature Schnauzer, Miniature Pinscher, Nova Scotia Duck Tolling Retriever, Rottweiler, Samoyed, Schnauzer and Tibetan Mastiff.

These findings illustrate that HC is a heterogeneous condition and further studies are necessary to fully understand this complex condition. At the AHT we are currently investigating the genetic basis of HC in many different breeds, including the Golden Retriever, the American Cocker Spaniel, the Siberian Husky, the Large Munsterlander, the German Pinscher and the Icelandic Sheepdog.

DNA has been collected from dogs of all these breeds that are affected with cataracts (cases) and also from healthy dogs (controls). Both cases and controls can originate from any country but all need to have had their eyes examined by veterinary ophthalmologists and to have been issued with Canine Eye Registration Foundation (CERF) forms from American College of Veterinary Ophthalmologists Diplomates (dogs from the United States) or their international equivalents. Dogs from the UK are usually examined by one of a team of 31 appointed Eye Panelists under the British Veterinary Association/Kennel Club/International Sheepdog Society Eye Scheme ( We collaborate very closely with veterinary ophthalmologists to try to ensure the cases all have cataracts that are typical of HC in their particular breed, and do not have non-hereditary cataracts that are secondary to other primary ocular conditions, for example. The controls are selected to be dogs that have received clear examination reports well into later life.

Once we have collected sufficient numbers of cases and controls of the same breed we undertake a 'Whole Genome Scan' (WGS) whereby we analyze each of the cases and controls of a given breed with over 22,000 different genetic markers from all around the genome and look for those that are shared between all the cases and different in the controls. These markers indicate the region(s) of the genome where the cataract mutation(s) is located. Once a cataract-causing mutation has been 'mapped' in this way, hopefully to a relatively small region of the genome, additional markers from within the region are genotyped on samples from additional dogs in a process known as 'fine-mapping'. Fine mapping allows the region containing the mutation to be narrowed as much as possible, hopefully until it is reduced to a region (known as the critical region) that contains only a very small number of genes. Once the critical region has been reduced as far as possible, all genes within the region will be examined, and any that are reasonable candidates for cataracts will be sequenced, nucleotide by nucleotide, in affected and unaffected dogs, to finally identify the mutation that is responsible for HC in that breed. It should be noted that it is normal for a critical region to still contain hundreds of thousands of nucleotides of DNA, and the sequencing of candidate genes may involve reading many thousands of nucleotides of DNA, a process that can take the average laboratory several months to complete.

Whole Genome Scans are currently being undertaken in the additional breeds listed above, and it is hoped analysis of the genotyping data will reveal new mutations that will enhance our knowledge and understanding of HC in the dog and also enable the development of DNA tests that over time will provide breeders with the tools to eradicate these conditions.


Inherited forms of cataract affect a very large number of breeds although surprisingly little is known about the genetics of the condition in different breeds. As mutations start to be identified that are associated with hereditary cataract in different breeds it is quickly becoming apparent that the condition is genetically heterogeneous and although some related breeds do share cataract mutations many more breeds have mutations that remain to be identified.

References/Suggested Reading

1.  Davidson MG, Nelms SR. Diseases of the lens and cataract formation. In: Veterinary Ophthalmology. (ed. Gelatt KN). 3rd ed. Lippincott/Williams & Wilkins, Philadelphia, 1999; 797-825.

2.  Rubin LF. Eye Diseases in Purebred Dogs Williams & Wilkins, Baltimore, 1989.

3.  Slatter D. Fundamentals of Veterinary Ophthalmology. 3rd ed. W.B. Saunders, Philadelphia, 2001.

4.  Helper LC. Magrane's Canine Ophthalmology. 4th ed. Lea & Febiger, Philadelphia, 1989.

5.  Gelatt KN, Samuelson DA, Bauer JE, Das ND, Wolf ED, Barrie KP, Andresen TL. Inheritance of congenital cataracts and microphthalmia in the Miniature Schnauzer. American Journal of Veterinary Research 1983; 44: 1130-1132.

6.  Wallace MR, MacKay EO, Gelatt KN, Andrew SE. Inheritance of cataract in the Bichon Frise. Veterinary Ophthalmology 2005; 8: 203-205.

7.  Spiess BM. [Inherited eye diseases in the Entlebucher mountain dog]. Schweiz Arch Tierheilkd 1994; 136: 105-110.

8.  Barnett KC. Comparative aspects of canine hereditary eye disease. Advances in Veterinary Science and Comparative Medicine 1976; 20: 39-67.

9.  Barnett KC. Hereditary cataract in the dog. Journal of Small Animal Practice 1978; 19: 109-120.

10. 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: 369-378.

11. Mellersh CS, Graves KT, McLaughlin B, Ennis RB, Pettitt L, Vaudin M, Barnett KC. Mutation in HSF4 Associated with Early but Not Late-Onset Hereditary Cataract in the Boston Terrier. Journal of Heredity 2007; 98: 531-533.


Speaker Information
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Cathryn Mellersh
Animal Health Trust
Newmarket, Suffolk, UK

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