# A TTPA deletion is associated with retinopathy with vitamin E deficiency in the English Cocker Spaniel dog

## TL;DR

A genetic mutation in the TTPA gene causes retinopathy with vitamin E deficiency in English Cocker Spaniels, leading to blindness and ataxia, and a DNA test can now identify affected dogs early.

## Contribution

Identification of a 102 bp deletion in the TTPA gene as the cause of retinopathy with vitamin E deficiency in English Cocker Spaniels.

## Key findings

- A 102 bp deletion in exon 1 of the TTPA gene was found in dogs with retinopathy with vitamin E deficiency.
- The TTPA mutation is associated with low plasma α-tocopherol levels and neurological signs in affected dogs.
- A DNA test based on this mutation can identify presymptomatic dogs and aid in disease eradication.

## Abstract

Retinopathy with vitamin E deficiency is a familial disease in the English Cocker Spaniel dog breed. Ophthalmic abnormalities observed in retinopathy with vitamin E deficiency-affected English Cocker Spaniel include lipofuscin granule deposition within the tapetal fundus and subsequent retinal degeneration resulting in visual deficits. Affected dogs may also exhibit neurological signs that include ataxia and hindlimb proprioceptive deficits. In all cases, circulating plasma concentrations of α-tocopherol are low. This study sought to investigate the genetic basis of retinopathy with vitamin E deficiency in the English Cocker Spaniel breed. We undertook a genome-wide association study comprising 30 English Cocker Spaniels with normal fundic examinations aged 6 years or older (controls) and 20 diagnosed with retinopathy with vitamin E deficiency (cases) and identified a statistically associated signal on chromosome 29 (Praw = 1.909 × 10−17). Whole genome sequencing of 2 cases identified a 102 bp deletion in exon 1 of the alpha-tocopherol transfer protein gene (TTPA), truncating the protein by 34 amino acids. The c.23_124del variant segregated with retinopathy with vitamin E deficiency in a total of 30 cases and 43 controls. Variants in TTPA are causal for ataxia with vitamin E deficiency in humans which is a phenotypically similar disease to retinopathy with vitamin E deficiency. The identification of the canine variant is extremely significant as the availability of a DNA test will allow for identification of presymptomatic dogs and early therapeutic intervention which may prevent development of retinopathy and improve neurological signs. Breeders can also use the DNA test to efficiently eradicate the disease from this breed.

Retinopathy with vitamin E deficiency (RVED) is an inherited disease in the English Cocker Spaniel that causes blindness and ataxia. It has many similarities to ataxia with vitamin E deficiency (AVED) in humans. This study investigated the genetic basis of RVED and reveals it to be associated with a mutation in TTPA – the same gene that causes AVED. A DNA test has now been developed which will enable eradication of the disease from this dog breed and also allow for the identification of presymptomatic individuals. The latter would allow for early therapeutic intervention and prevention of retinal (and neurological) disease.