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An ABCA4 loss-of-function mutation causes a canine form of Stargardt disease
Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences, Uppsala, Sweden.
Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences, Uppsala, Sweden.
Department of Neuroscience, Uppsala University, Uppsala, Sweden.
Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences, 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.

Place, publisher, year, edition, pages
Public Library of Science , 2019. Vol. 15, no 3, article id e1007873
National Category
Atom and Molecular Physics and Optics Ophthalmology
Identifiers
URN: urn:nbn:se:oru:diva-73243DOI: 10.1371/journal.pgen.1007873ISI: 000462994900009PubMedID: 30889179Scopus ID: 2-s2.0-85063262127OAI: oai:DiVA.org:oru-73243DiVA, id: diva2:1298310
Funder
Swedish Research Council Formas, 221-2014-1005
Note

Funding Agency:

Agria och Svenska Kennelklubben Forskningsfond  P2012-0015  N2013-0020  P2014-0018  P2015-0012

Available from: 2019-03-22 Created: 2019-03-22 Last updated: 2019-06-19Bibliographically approved

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Makdoumi, Karim

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