Leber’s Congenital Amaurosis and Retinitis Pigmentosa mutations in the domestic cat

Abstract

Purpose: Two domestic cat breeds have been identified with autosomal recessive, early onset progressive retinal atrophies (PRAs). The Persian cat has clinical evidence of disease at 7 weeks of age with end-stage blindness by 16 weeks of age. Clinical onset in Bengal cats is at 12 weeks of age; but progression to end-stage blindness is slower and variable among individuals, with some cats still partially sighted at 2 years of age. Cross-breeding studies suggest a different locus for both forms of PRA. We hypothesized that genetic studies would identify DNA variants in genes causing PRA in these two cat breeds.

Methods: Breeding colonies were established using donated cats handled according to institutional animal care and use protocols and ARVO guidelines. Vision status of all cats used in the genetic studies was established by board-certified veterinary ophthalmologists and pathologist. DNA was isolated using standard methods from whole blood collected from case and control cats, and was genotyped on the illumina Infinium 63K iSelect Cat DNA array. Association studies were performed using various methods. A trio of the Bengal and Persian cats each was whole-genome sequenced using an illumina HiSeq 100 bp paired end reads to approximately 30X genome coverage for each cat.

Results: Association studies consistently localized the Persian and Bengal PRAs to cat chromosomes E1 (human chr. 17) and A3 (human chr. 20), respectively. Candidate genes for retinal degenerations within the regions were identified; however complete genetic sequences of the selected regions could not be obtained. Whole-genome sequencing of the Persian and Bengal trios identified candidate causal DNA variants. A polymorphism causing a premature stop codon was identified for the Persian PRA and a variant that alters a highly conserved amino acid was identified for the Bengal PRA, causing null and missense mutations, respectively. Genotyping of extended pedigrees of Persian, Bengal, and other feline populations supported these specific variants as causal for each PRA.

Conclusions: Mutations causative for Persian and Bengal PRAs have been genetically identified. These diseases provide two new models for Leber’s Congenital Amaurosis and retinitis pigmentosa in a novel gene. Translational studies using these two feline models will support gene, stem cell and read-through based therapies.