A LINE-1 insertion situated in the promoter of IMPG2 is associated with autosomal recessive progressive retinal atrophy in Lhasa Apso dogs

Abstract

Background Canine progressive retinal atrophies are a group of hereditary retinal degenerations in dogs characterised by depletion of photoreceptor cells in the retina, which ultimately leads to blindness. PRA in the Lhasa Apso (LA) dog has not previously been clinically characterised or described in the literature, but owners in the UK are advised to have their dog examined through the British Veterinary Association/ Kennel Club/ International Sheep Dog Society (BVA/KC/ISDS) eye scheme annually, and similar schemes that are in operation in other countries. After the exclusion of 25 previously reported canine retinal mutations in LA PRA-affected dogs, we sought to identify the genetic cause of PRA in this breed. Results Analysis of whole-exome sequencing data of three PRA-affected LA and three LA without signs of PRA did not identify any exonic or splice site variants, suggesting the causal variant was non-exonic. We subsequently undertook a genome-wide association study (GWAS), which identified a 1.3 Mb disease-associated region on canine chromosome 33, followed by whole-genome sequencing analysis that revealed a long interspersed element-1 (LINE-1) insertion upstream of the IMPG2 gene. IMPG2 has previously been implicated in human retinal disease; however, until now no canine PRAs have been associated with this gene. The identification of this PRA-associated variant has enabled the development of a DNA test for this form of PRA in the breed, here termed PRA4 to distinguish it from other forms of PRA described in other breeds. This test has been used to determine the genotypes of over 900 LA dogs. A large cohort of genotyped dogs was used to estimate the allele frequency as between 0.07–0.1 in the UK LA population. Conclusions Through the use of GWAS and subsequent sequencing of a PRA case, we have identified a LINE-1 insertion in the retinal candidate gene IMPG2 that is associated with a form of PRA in the LA dog. Validation of this variant in 447 dogs of 123 breeds determined it was private to LA dogs. We envisage that, over time, the developed DNA test will offer breeders the opportunity to avoid producing dogs affected with this form of PRA.

Next-Generation Sequencing Applications for Inherited Retinal Diseases

“…This is applicable to translocations and inversions, as unlike CNVs, the read depth is not expected to be altered in these scenarios. Given the significant presence of retrotransposon sequence in the human genome, it is not surprising that several retrotransposons insertions have been reported to disrupt the functionality of IRD genes [125][126][127]. The BBS1 gene in particular, has been recently reported to harbour retrotransposons causative of disease [128,129].…”

A missense variant in IFT122 associated with a canine model of retinitis pigmentosa

“…Findings in ophthalmoscopic examinations of PRA affected dogs typically include diffuse tapetal hyperreflectivity resulting from retinal thinning, attenuation of the retinal blood vessels, and at later stages, atrophy of the optic nerve head (Parry 1953). Over 20 genes have been implicated to date, with the most recent reported from the Lhasa Apso dogs with a LINE-1 insertion variant in the IMPG2 gene (Miyadera et al 2012;Hitti-Malin et al 2020). Another PRA affected breed is the Lapponian Herder (LH), in which the autosomal recessive PRCD variant explains a subset of cases (Zangerl et al 2006).…”

A missense Variant in IFT122 Associated with a Canine Model of Retinitis Pigmentosa

“…Over 20 genes have been implicated to date, with the most recent reported from the Lhasa Apso dogs with a LINE-1 insertion variant in the IMPG2 gene (Miyadera et al 2012;Hitti-Malin et al 2020). Another PRA-affected breed is the Lapponian Herder (LH), in which the autosomal recessive PRCD variant explains a subset of cases (Zangerl et al 2006).…”