Abstract
Retinitis pigmentosa (RP) is the leading cause of blindness with nearly two million people affected worldwide. Many genes have been implicated in RP, yet in 30–80% of the RP patients the genetic cause remains unknown. A similar phenotype, progressive retinal atrophy (PRA), affects many dog breeds including the Miniature Schnauzer. We performed clinical, genetic and functional experiments to identify the genetic cause of PRA in the breed. The age of onset and pattern of disease progression suggested that at least two forms of PRA, types 1 and 2 respectively, affect the breed, which was confirmed by genome-wide association study that implicated two distinct genomic loci in chromosomes 15 and X, respectively. Whole-genome sequencing revealed a fully segregating recessive regulatory variant in type 1 PRA. The associated variant has a very recent origin based on haplotype analysis and lies within a regulatory site with the predicted binding site of HAND1::TCF3 transcription factor complex. Luciferase assays suggested that mutated regulatory sequence increases expression. Case-control retinal expression comparison of six best HAND1::TCF3 target genes were analyzed with quantitative reverse-transcriptase PCR assay and indicated overexpression of EDN2 and COL9A2 in the affected retina. Defects in both EDN2 and COL9A2 have been previously associated with retinal degeneration. In summary, our study describes two genetically different forms of PRA and identifies a fully penetrant variant in type 1 form with a possible regulatory effect. This would be among the first reports of a regulatory variant in retinal degeneration in any species, and establishes a new spontaneous dog model to improve our understanding of retinal biology and gene regulation while the affected breed will benefit from a reliable genetic testing.
Highlights
Retinitis pigmentosa (RP) is a heterogeneous group of inherited retinopathies with varying genetic background and highly variable clinical consequences
Genetic and functional analyses to find the genetic cause for progressive retinal atrophy (PRA) in Miniature Schnauzers
We discovered two forms of PRA in the breed, named type 1 and 2, and show that they are genetically distinct as they map to different chromosomes, 15 and X, respectively
Summary
Retinitis pigmentosa (RP) is a heterogeneous group of inherited retinopathies with varying genetic background and highly variable clinical consequences. RP is the leading cause of irreversible blindness in man with a worldwide prevalence of one in 4,000 people [1]. The disease first manifests as impaired vision in dim light (nyctalopia) resulting from progressive loss of the rod photoreceptor cells. Complete blindness is expected due to cone photoreceptor degeneration accompanied by changes in the retinal pigment epithelium (RPE), the retinal vasculature, the glial cells and neurons of the inner retina. Despite a large number of implicated genes and variants, 30–80% of the patients have RP of unknown genetic cause and many genes remain still to be discovered [3]
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