An ABCA4 loss-of-function mutation causes a canine form of Stargardt disease.

Suvi Mäkeläinen,Karim Makdoumi,Tomas F Bergström,Agnese Viluma,Sally L Ricketts,Björn Ekesten,Marta Gòdia,Cathryn Mellersh,Minas Hellsand,Caroline J Zeiss,Daniela Hahn,Kristina Narfström,Göran Andersson,Finn Hallböök,Gregory S Barsh

doi:10.1371/journal.pgen.1007873

Abstract

Autosomal recessive retinal degenerative diseases cause visual impairment and blindness in both humans and dogs. Currently, no standard treatment is available, but pioneering gene therapy-based canine models have been instrumental for clinical trials in humans. To study a novel form of retinal degeneration in Labrador retriever dogs with clinical signs indicating cone and rod degeneration, we used whole-genome sequencing of an affected sib-pair and their unaffected parents. A frameshift insertion in the ATP binding cassette subfamily A member 4 (ABCA4) gene (c.4176insC), leading to a premature stop codon in exon 28 (p.F1393Lfs*1395), was identified. In contrast to unaffected dogs, no full-length ABCA4 protein was detected in the retina of an affected dog. The ABCA4 gene encodes a membrane transporter protein localized in the outer segments of rod and cone photoreceptors. In humans, the ABCA4 gene is associated with Stargardt disease (STGD), an autosomal recessive retinal degeneration leading to central visual impairment. A hallmark of STGD is the accumulation of lipofuscin deposits in the retinal pigment epithelium (RPE). The discovery of a canine homozygous ABCA4 loss-of-function mutation may advance the development of dog as a large animal model for human STGD.

Highlights

Inherited retinal dystrophies are a genetically and clinically heterogeneous group of eye diseases leading to severe visual impairment in both humans and dogs [1,2,3,4,5,6]
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
We have studied a novel form of retinal degeneration in Labrador retriever dogs showing clinical signs similar to human Stargardt disease (STGD)

Summary

Introduction

Inherited retinal dystrophies are a genetically and clinically heterogeneous group of eye diseases leading to severe visual impairment in both humans and dogs [1,2,3,4,5,6]. The identification of the p.C2Y mutation (OMIM: 610598.0001) in the PRCD gene is another illustrative example of the benefits of using canine genetics to find homologous candidate genes for human retinal dystrophies; the PRCD gene was initially mapped and identified in PRA-affected dogs and subsequently in a human family with RP [17]. This mutation segregates in multiple dog breeds, including the Labrador retriever, where no other causative genetic variants for inherited retinal degenerations have been identified. To identify genetic variants associated with this novel canine retinal disease, we performed whole-genome sequencing (WGS) of the two affected individuals and their unaffected parents

Methods

Results

Conclusion