Whole genome sequencing identifies a homozygous nonsense mutation in the JPH2 gene in Shih Tzu dogs with progressive retinal atrophy

Abstract

Summary Progressive retinal atrophy (PRA), common autosomal recessive disorder affecting several dog breeds including Shih Tzu, is characterized by degeneration of photoreceptors leading to blindness. To identify PRA genetic variants, three affected and 15 unaffected Shih Tzu and 20 non‐Shih Tzu were recruited. Dogs underwent ophthalmologic examination and electroretinography, revealing hallmark retina pathological changes and an abnormal electroretinography in all affected dogs but not in unaffected dogs. WGS was performed. Non‐synonymous homozygous variants were searched in coding regions of genes involved in retinal diseases/development; the criterion was that variants should only be present in affected dogs and should be absent in both unaffected and 46 genomes of dogs (from an available evolutionary database). Only one out of the 109 identified variants is predicted to harbor a high‐impact consequence, a nonsense c.452A>C (p.L151X) in the JPH2 gene. The genotype of JPH2 variant in all 38 dogs was determined with Sanger sequencing. All three affected dogs, but none of the 35 unaffected, were homozygous for the nonsense variant. JPH2 has been previously found to be expressed in several excitable cells/tissues including retina photoreceptors. Hence, JPH2 is a candidate gene for PRA in Shih Tzu.

Genotypic and allelic frequencies of progressive rod‐cone degeneration and other main variants associated with progressive retinal atrophy in Italian dogs

“…This initially causes night blindness, which then progresses to severe visual dysfunction under both dim and bright light; finally, the degeneration of cones can lead to total blindness. 3 Some genetic variants responsible for PRA can lead to rod degeneration only, while others can involve cones as well; however, an earlier and more severe loss of rods represents the peculiar PRA phenotype. 1 Affected dogs show changes in the fundus in an ophthalmologic examination, such as hyperreflectivity of the tapetum, attenuation of retinal blood vessels and atrophy of the optic disk.…”

“…1 Various modes of inheritance have been described for PRA including autosomal recessive, autosomal dominant and Xlinked; the most common mode of inheritance is recessive. 2,3 Over 20 genes have been identified in PRA across different breeds with a wide range of genetic alleles reported. [9][10][11][12][13][14][15][16][17] Genetic tests are available for the detection of various forms of PRA and are able to detect affected/at-risk dogs, heterozygous carriers and clear subjects.…”

“…Progressive retinal atrophy (PRA) is a heterogeneous group of inherited retinal disorders affecting up to 100 canine breeds and has been shown to be homologous with retinitis pigmentosa in humans. [1][2][3][4][5] The disease is characterised by a primary degeneration of rod photoreceptors followed by the degeneration of cones. This initially causes night blindness, which then progresses to severe visual dysfunction under both dim and bright light; finally, the degeneration of cones can lead to total blindness.…”

“…Progressive retinal atrophy (PRA) is a heterogeneous group of inherited retinal disorders affecting up to 100 canine breeds and has been shown to be homologous with retinitis pigmentosa in humans 1–5 . The disease is characterised by a primary degeneration of rod photoreceptors followed by the degeneration of cones.…”

“…The disease is characterised by a primary degeneration of rod photoreceptors followed by the degeneration of cones. This initially causes night blindness, which then progresses to severe visual dysfunction under both dim and bright light; finally, the degeneration of cones can lead to total blindness 3 . Some genetic variants responsible for PRA can lead to rod degeneration only, while others can involve cones as well; however, an earlier and more severe loss of rods represents the peculiar PRA phenotype 1 .…”