Progressive Retinal Atrophies and Cone-Rod Degenerations

Inherited forms of retinal disease are among the best clinically and genetically characterized inherited conditions in the dog. Progressive retinal atrophy (PRA) and cone-rod dystrophy (CRD) are collective terms for two broad forms of progressive, bilateral degenerative diseases that affect the retinal photoreceptor cells. Both conditions usually cause progressive vision loss that culminates in total blindness. There is no treatment for either PRA or CRD.

There is a formal difference between these two different forms of disease, depending on which type of photoreceptor starts to deteriorate first, but CRDs have ophthalmoscopic changes that are very similar to those of PRA and detailed electroretinography (ERG) studies that measure both cone and rod specific responses are required to distinguish between the two types of condition. For this reason several disorders have been initially described as PRAs, to be later re-classified when extensive ERG investigations have been undertaken, and the term PRA continues to be routinely used to describe any form of progressive retinal degeneration unless direct evidence is available to indicate it is in fact a CRD. These proceedings discuss forms of both PRA and CRD.

Within-Breed Homogeneity Versus Between-Breed Heterogeneity

Forms of retinal degeneration are widespread between breeds and currently about 14 different mutations have been reported that are associated with forms of PRA and CRD in well over 20 different breeds of dog (Table 1). It is widely accepted as being genetically heterogeneous between breeds, but that within a breed PRA or CRD will exhibit breed-specific characteristics such as age of onset and rate of progression. Because individual breeds of dog are genetically isolated populations, often derived from small numbers of founding individuals, clinically similar conditions that affect dogs of the same breed are usually genetically uniform within that breed, with all affected cases carrying identical causal mutation(s). Until recently there was little evidence to suggest forms of PRA and CRD were likely to be genetically heterogeneous within breeds, with more or less all forms being assumed to result from a single, usually recessive, breed-specific mutation.

However, as the number of known PRA and CRD mutations increases evidence is emerging that genetically distinct forms of disease are segregating in several breeds, and veterinarians and breeders should remain very vigilant to the possibility of genetically distinct forms of the disease within a breed. In addition, not all forms of PRA and CRD are the result of a single mutation, with some forms turning out to be genetically more complex than first thought.

Examples of forms of PRA and CRD that fall into these categories will be discussed during the presentation and specific examples are given below.

Cone-Rod Degeneration in the Miniature Longhaired Dachshund

A form of retinal degeneration that has been described in the Miniature longhaired dachshund (MLHD). The disease was originally described as an early-onset, autosomal recessive PRA with all affected dogs within an inbred research colony displaying ophthalmologic abnormalities that were detectable by ERG by six weeks of age and 25 weeks by funduscopy and becoming blind by the time they were 2 years of age.¹ A subsequent ERG study identified an initial reduction of the cone photoreceptor function which led to the condition being re-classified as a cone-rod dystrophy (CRD), rather than a rod-led PRA, and the disease was termed cord1 for cone-rod degeneration 1.² Using the same colony of dogs a mutation in the gene RPGRIP1 was identified that co-segregated completely with cord1 in the research colony.³ Mutations in RPGRIP1 have been associated with Leber congenital amaurosis (LCA),⁴ retinitis pigmentosa (RP)⁵ and CRD⁶ in humans, as well as inherited retinal abnormalities in mice⁷ which suggests it plays an important role in visual function. Following identification of the RPGRIP1 mutation a DNA test was made widely available and it soon became apparent that whereas within the research colony of MLHDs there was complete correlation between the RPGRIP1 genotype and phenotype of the dogs with respect to their cord1 phenotype, in the pet MLHD population this was not the case.⁸ Outside of the colony there was considerable variation in the age of onset of retinal degeneration in dogs that were homozygous for the RPGRIP1 mutation, which has also now been identified in other breeds, including the English springer spaniel and the Beagle. However, all Beagles and MLHDs that were homozygous for the RPGRIP1 mutation showed reduced or absent ERG cone responses, even in the absence of ophthalmoscopic abnormalities, a finding that has also been corroborated by Busse and co-workers.⁹ Together these findings suggest that additional mutations are involved which modify the age of onset of ophthalmoscopic abnormalities associated with the RPGRIP1 mutation. Because the original research colony used was developed from a very small number of dogs it is a real possibility that the colony was fixed for these additional mutations which, therefore, went undetected until the more outbred pet population was investigated. A recent association study using MLHDs that had either early or late onset cord1 has indeed revealed a second locus that segregates with early-onset disease (K. Miyadera, Cambridge, 2010, personal communication), indicating early onset CRD in MLHDs is more likely to be a digenic condition, and that the RPGRIP1 mutation alone causes a late onset CRD, although ERG abnormalities may be detected early in life.

Rod-Cone Degeneration in the Gordon and Irish Setters

A mutation has recently been identified that is associated with Late-Onset PRA (LOPRA) in the Gordon Setter (Downs and Mellersh, Animal Health Trust, unpublished). Owners of Gordon Setters with LOPRA report that their affected dogs develop night blindness in the first instance, which is indicative of a rod-cone degeneration, so we have termed this mutation rcd4 (for rod-cone degeneration 4) to distinguish it from other, previously described, forms of rod-cone degeneration. Following the work with rcd4 in the Gordon Setter it was also discovered that some Irish Setters that have been diagnosed with LOPRA also carry two copies of the rcd4 mutation. As a result the AHT has now made the rcd4 DNA test available to both Gordon and Irish Setters (http://www.aht.org.uk/genetics_tests.html)

Rcd4 is distinct from the early onset form of PRA, known as rcd1, which affects Irish Setters from approximately 25 days after birth and culminates at about 1 year when the population of rods and cones is depleted. Rcd1 is caused by a mutation in the gene encoding the beta subunit of cGMP phosphodiesterase (PDE6B), an essential member of the phototransduction pathway.¹⁰ So it is now known that the Irish Setter is affected by at least two genetically distinct forms of PRA with very different ages of onset.

However, not all Irish Setters or Gordon Setters that have been diagnosed with LOPRA are homozygous for the rcd4 mutation, indicating there is at least one more, genetically distinct, form of LOPRA segregating in both breeds. Whether the additional form of LOPRA is genetically identical in both breeds is unknown at this stage. There is some evidence that the third form of PRA has, on average, an earlier age of onset than rcd4 (resulting in this form being termed 'MOPRA' for mid-onset PRA by some breed forums), but more dogs need to be investigated before this can be confirmed.

The age at which dogs with the rcd4 mutation develop PRA seems to vary and dogs as young as 4yo and as old as 10yo, that carry two copies of rcd4 mutation, have been diagnosed with LOPRA. But the age at which a dog is diagnosed with PRA can obviously vary according to circumstances, and is not necessarily the same age at which it started to develop PRA. For example, a dog whose PRA is detected at a routine eye examination will likely have an earlier age of diagnosis than a dog whose PRA was only detected once it started to lose its sight. It is also formally possible that the dogs that have developed PRA relatively early also carry the mutation for the third, unidentified, form of PRA (as well as rcd4) and it is this 'mid onset' mutation that has caused them to develop PRA at a relatively young age. More research is required to understand the variability in age of onset more fully but it is certainly clear that we should keep an open mind as to the age range over which dogs can become affected with some forms of PRA.

Advice For Breeders and Veterinarians

It is crucial that breeders do not become complacent once a DNA test becomes available for a form of PRA in their breed. It goes without saying that all dogs used for breeding should be DNA tested for all known mutations that are relevant to their breed, and sires and dams selected appropriately. But DNA tests typically assay for specific mutations only and therefore should never replace routine eye examinations, which will detect genetically distinct forms of the same disease as well as all manner of other ocular disorders. All breeding stock should have their eyes examined by a veterinary ophthalmologist prior to breeding, and also at regular intervals throughout their lives. Evidence from the Gordon and Irish Setters shows that some forms of PRA don't routinely develop until dogs are as old as 8 to 10 years old, and it is without doubt that many of these cases go undetected, or be mis-diagnosed as age-related, in the absence of routine eye examinations by a specialist.

Veterinarians should also remain aware that clinically similar, genetically different forms of disease can exist within a breed. The fact that a dog has DNA tested clear for a particular PRA mutation, for example, does not guarantee that same dog will not develop a different form of PRA during its lifetime. Both veterinarians and owners should also be prepared to inform the scientists if dogs that have tested clear of a known mutation go on to develop a clinically similar condition - such cases provide important information about newly emerging conditions in a breed.

Table 1.

References

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2.  Turney C, et al. Pathological and electrophysiological features of a canine cone-rod dystrophy in the miniature longhaired dachshund. Invest Ophthalmol Vis Sci 2007;48(9):4240–4249.

3.  Mellersh CS, et al. Canine RPGRIP1 mutation establishes cone-rod dystrophy in miniature longhaired dachshunds as a homologue of human Leber congenital amaurosis. Genomics 2006;88(3):293–301.

4.  Dryja TP, et al. Null RPGRIP1 alleles in patients with Leber congenital amaurosis. Am J Hum Genet 2001;68(5):1295–1298.

5.  Booij JC, et al. Identification of mutations in the AIPL1, CRB1, GUCY2D, RPE65, and RPGRIP1 genes in patients with juvenile retinitis pigmentosa. J Med Genet 2005;42(11):e67.

6.  Hameed A, et al. Evidence of RPGRIP1 gene mutations associated with recessive cone-rod dystrophy. J Med Genet 2003;40(8):616–619.

7.  Zhao Y, et al. The retinitis pigmentosa GTPase regulator (RPGR)-interacting protein: subserving RPGR function and participating in disk morphogenesis. Proc Natl Acad Sci USA 2003;100(7):3965–3970.

8.  Miyadera K, et al. Phenotypic variation and genotype-phenotype discordance in canine cone-rod dystrophy with an RPGRIP1 mutation. Mol Vis 2009;15:2287–2305.

9.  Busse C, et al. Ophthalmic and cone derived electrodiagnostic findings in outbred Miniature Long-haired Dachshunds homozygous for a RPGRIP1 mutation. Vet Ophthalmol 2011;14(3):146–152.

10. Suber ML, et al. Irish setter dogs affected with rod/cone dysplasia contain a nonsense mutation in the rod cGMP phosphodiesterase beta-subunit gene. Proc Natl Acad Sci USA 1993;90(9):3968–3972.

11. Kijas JW, et al. Naturally occurring rhodopsin mutation in the dog causes retinal dysfunction and degeneration mimicking human dominant retinitis pigmentosa. Proc Natl Acad Sci USA 2002;99(9):6328–6333.

12. Goldstein O, et al. An ADAM9 mutation in canine cone-rod dystrophy 3 establishes homology with human cone-rod dystrophy 9. Mol Vis 2010;16:1549–1569.

13. Kropatsch R, et al. Generalized progressive retinal atrophy in the Irish Glen of Imaal Terrier is associated with a deletion in the ADAM9 gene. Mol Cell Probe 2010;24(6):357–363.

14. Goldstein O, et al. Exonic SINE insertion in STK38L causes canine early retinal degeneration (erd). Genomics 2010;96(6):362–368.

15. Downs LM, et al. A frameshift mutation in Golden Retriever dogs with progressive retinal atrophy endorses SLC4A3 as a candidate gene for human retinal degenerations. PLoS ONE 2011;6(6):e21452.

16. Zhang Q, et al. Characterization of canine photoreceptor phosducin cDNA and identification of a sequence variant in dogs with photoreceptor dysplasia. Gene 1998;215(2):231–239.

17. Zangerl B, et al. Identical mutation in a novel retinal gene causes progressive rod-cone degeneration in dogs and retinitis pigmentosa in humans. Genomics 2006;88(5):551–563.

18. Dekomien G, et al. Generalized progressive retinal atrophy of Sloughi dogs is due to an 8-bp insertion in exon 21 of the PDE6B gene. Cytogenet Cell Genet 2000;90(3–4):261–267.

19. Kukekova AV, et al. Canine RD3 mutation establishes rod-cone dysplasia type 2 (rcd2) as ortholog of human and murine rd3. Mamm Genome, 2009;20(2):109–123.

20. Petersen-Jones SM, Entz DD, Sargan DR. cGMP phosphodiesterase-alpha mutation causes progressive retinal atrophy in the Cardigan Welsh corgi dog. Invest Ophthalmol Vis Sci 1999;40(8):1637–1644.

21. Zhang Q, et al. Different RPGR exon ORF15 mutations in canids provide insights into photoreceptor cell degeneration. Hum Mol Genet 2002;11(9):993–1003.

22. Wiik AC, et al. A deletion in nephronophthisis 4 (NPHP4) is associated with recessive cone-rod dystrophy in standard wire-haired dachshund. Genome Res 2008;18(9):1415–1421.