The Many Faces of PRA: Different Genes, Different Breeds

I still remember the moment in 1998 when our sequencing data first revealed that the Irish Setter PRA we had been studying was caused by an entirely different gene than the form affecting English Cocker Spaniels. We had assumed, as many researchers did at the time, that Progressive Retinal Atrophy was essentially one disease with minor variations. That assumption was spectacularly wrong.

What we now understand, after decades of collaborative research across laboratories in Uppsala, Cornell, and the University of Pennsylvania, is that PRA represents a constellation of genetically distinct diseases. Each mutation arose independently in different breed populations, often centuries ago when founders carried the variant into what would become closed breeding pools. The clinical endpoint appears similar, but the molecular pathways differ dramatically.

The PRCD Story: One Gene, Many Breeds

The PRCD gene mutation stands as perhaps the most widespread PRA variant we have identified. This single nucleotide change, a cytosine to thymine substitution at position 5 of exon 1, has been documented in at least 29 breeds. When we published our findings in 2006, breeders were astonished to learn that their Labrador Retrievers, English Cocker Spaniels, American Cocker Spaniels, and Australian Cattle Dogs all shared the identical mutation.

The explanation lies in the antiquity of this mutation. Molecular clock analysis suggests the PRCD variant arose thousands of years ago, likely before the divergence of many modern breeds from common ancestral populations. As breed clubs established closed registries in the 19th and 20th centuries, they unknowingly locked this ancient variant into their gene pools.

Breed-Specific Variants: The rcd Family

In contrast to the widespread PRCD, other PRA mutations appear in single breeds or small breed clusters. The rod-cone dysplasia mutations illustrate this pattern beautifully.

rcd1 affects Irish Setters and was the first PRA-causing mutation ever identified at the molecular level. Dr. Gustavo Aguirre and his colleagues at Cornell mapped this mutation in 1993, a landmark achievement that opened the entire field of canine retinal genetics. The mutation sits in the PDE6B gene, which encodes a critical enzyme in the phototransduction cascade.

rcd2 causes PRA in Rough and Smooth Collies through a different mutation in the same PDE6B gene. Despite affecting the same gene, the mutations are distinct, and each arose independently in its respective breed population.

rcd3 strikes Cardigan Welsh Corgis and is caused by a mutation in PDE6A, the alpha subunit gene. When I first examined affected Corgis in our clinic, the speed of progression was striking. These dogs showed clinical signs as early as 6 weeks of age and were often completely blind by 1 year.

The Gene Discovery Timeline

Why Multiple Genes Matter for Breeders

The genetic heterogeneity of PRA creates both challenges and opportunities for breeders. A Labrador Retriever breeder must test for PRCD, but that test would be useless for an Irish Setter, which needs rcd1 testing instead. Order the wrong test, and you will receive a meaningless result.

I have worked with breed clubs who initially resisted this complexity. They wanted a single PRA test that would solve their problem. But biology does not simplify for our convenience. The breeds that have made the most progress, like the Irish Setter community, embraced comprehensive testing early and drove their PRA frequency from alarming levels down to near-zero over two decades. For more on implementing effective testing strategies, see our genetic testing guide.

The Ongoing Discovery

New PRA genes continue to emerge from our research. In 2016, we identified GR-PRA2 in Golden Retrievers, caused by a mutation in TTC8. This discovery explained cases that had tested clear for both PRCD and GR-PRA1 but still developed clinical blindness.

Several breeds still harbor PRA forms without identified causative mutations. Giant Schnauzers, Tibetan Spaniels, and certain lines of Mastiffs show clinical PRA that does not map to any known variant. These represent our next research frontiers.

Each gene we identify opens new possibilities. Understanding the molecular pathway allows us to develop targeted therapies, as the remarkable gene therapy advances demonstrate. It also enables precise carrier breeding strategies that preserve genetic diversity while eliminating affected offspring.

The heterogeneity of PRA, which once seemed like a frustrating complication, has become a powerful research tool. Each gene teaches us something new about photoreceptor biology, and each breed provides a unique model for understanding retinal degeneration. The knowledge flows both ways: what we learn from dogs informs human ophthalmology, and discoveries in human genetics guide our canine research.

Implications for Population Health

From my perspective as a population geneticist, the distribution of PRA variants tells a story about breed history. Breeds with multiple PRA forms, like Golden Retrievers, often experienced complex founding events with multiple source populations. Breeds with single variants typically trace to more limited founder pools.

This historical perspective matters for future planning. Some rare PRA variants exist at such low frequencies that they could be eliminated within a generation through careful testing and breeding protocols. Others, like PRCD in popular breeds, require longer-term strategies that balance disease prevention against maintaining genetic diversity. The Herding Gene resource offers additional context on managing inherited conditions in working breeds.

Twenty-five years after that first surprising discovery about breed-specific mutations, PRA genetics remains one of the most active areas of canine research. Each variant we identify brings us closer to a future where inherited blindness becomes preventable across all breeds. The map is not yet complete, but its contours grow clearer with each passing year.