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An ABCA4 loss-of-function mutation causes a canine form of Stargardt disease
Swedish Univ Agr Sci, Dept Anim Breeding & Genet, Uppsala, Sweden.
Swedish Univ Agr Sci, Dept Anim Breeding & Genet, Uppsala, Sweden;UB, Dept Anim Genom, CRAG, CSIC,IRTA,UAB, Campus UAB, Bellaterra, Spain.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.ORCID iD: 0000-0002-1459-0377
Swedish Univ Agr Sci, Dept Anim Breeding & Genet, Uppsala, Sweden.
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2019 (English)In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 15, no 3, article id e1007873Article in journal (Refereed) Published
Abstract [en]

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. Author summary Stargardt disease (STGD) is the most common inherited retinal disease causing visual impairment and blindness in children and young adults, affecting 1 in 8-10 thousand people. For other inherited retinal diseases, the dog has become an established comparative animal model, both for identifying the underlying genetic causes and for developing new treatment methods. To date, there is no standard treatment for STGD and the only available animal model to study the disease is the mouse. As a nocturnal animal, the morphology of the mouse eye differs from humans and therefore the mouse model is not ideal for developing methods for treatment. We have studied a novel form of retinal degeneration in Labrador retriever dogs showing clinical signs similar to human STGD. To investigate the genetic cause of the disease, we used whole-genome sequencing of a family quartet including two affected offspring and their unaffected parents. This led to the identification of a loss-of-function mutation in the ABCA4 gene. The findings of this study may enable the development of a canine model for human STGD.

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PUBLIC LIBRARY SCIENCE , 2019. Vol. 15, no 3, article id e1007873
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Genetics
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URN: urn:nbn:se:uu:diva-382473DOI: 10.1371/journal.pgen.1007873ISI: 000462994900009PubMedID: 30889179OAI: oai:DiVA.org:uu-382473DiVA, id: diva2:1313201
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Swedish Research Council Formas, 221-2014-1005Available from: 2019-05-02 Created: 2019-05-02 Last updated: 2019-05-02Bibliographically approved

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