Abstract
The domestic dog segregates a significant number of inherited progressive retinal diseases, several of which mirror human retinal diseases and which are collectively termed progressive retinal atrophy (PRA). In 2014, a novel form of PRA was reported in the Swedish Vallhund breed, and the disease was mapped to canine chromosome 17. The causal mutation was not identified, but expression analyses of the retinas of affected Vallhunds demonstrated a 6-fold increased expression of the MERTK gene compared to unaffected dogs. Using 24 retinopathy cases and 97 controls with no clinical signs of retinopathy, we replicated the chromosome 17 association in Swedish Vallhunds from the UK and aimed to elucidate the causal variant underlying this association using whole genome sequencing (WGS) of an affected dog. This revealed a 6–8 kb insertion in intron 1 of MERTK that was not present in WGS of 49 dogs of other breeds. Sequencing and BLASTN analysis of the inserted segment was consistent with the insertion comprising a full-length intact LINE-1 retroelement. Testing of the LINE-1 insertion for association with retinopathy in the UK set of 24 cases and 97 controls revealed a strong statistical association (P-value 6.0 x 10−11) that was subsequently replicated in the original Finnish study set (49 cases and 89 controls (P-value 4.3 x 10−19). In a pooled analysis of both studies (73 cases and 186 controls), the LINE-1 insertion was associated with a ~20-fold increased risk of retinopathy (odds ratio 23.41, 95% confidence intervals 10.99–49.86, P-value 1.3 x 10−27). Our study adds further support for regulatory disruption of MERTK in Swedish Vallhund retinopathy; however, further work is required to establish a functional overexpression model. Future work to characterise the mechanism by which this intronic mutation disrupts gene regulation will further improve the understanding of MERTK biology and its role in retinal function.
Highlights
In the domestic dog, there are a large number of inherited and progressive retinal diseases, which are collectively termed progressive retinal atrophy (PRA)
We utilised PCR-free Whole genome sequencing (WGS) to generate complete sequence spanning the genomic interval defined by the previous genome-wide association study (GWAS) data [25] (CanFam 3.1 chr17:34,421,056–40,576,539) using a UK case that possessed two copies of the risk allele (C) at SNP BICF2G630207991
Given previous evidence for involvement of the MERTK gene, we initially focused on the region directly encompassing MERTK by visually scanning sequence reads in IGV (Integrative Genomics Viewer) [29]
Summary
There are a large number of inherited and progressive retinal diseases, which are collectively termed progressive retinal atrophy (PRA). Identification of each specific genetic mutation responsible provides a greater understanding of each disease and in dogs allows identification of affected individuals and carriers before breeding, which can lead to the reduction of incidence or eradication of the disease from the population. In humans this knowledge raises the possibility of treatment of affected individuals using gene replacement therapy [21,22]
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