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

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 degen...

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Autores principales: Mäkeläinen, Suvi, Gòdia, Marta, Hellsand, Minas, Viluma, Agnese, Hahn, Daniela, Makdoumi, Karim, Zeiss, Caroline J., Mellersh, Cathryn, Ricketts, Sally L., Narfström, Kristina, Hallböök, Finn, Ekesten, Björn, Andersson, Göran, Bergström, Tomas F.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6424408/
https://www.ncbi.nlm.nih.gov/pubmed/30889179
http://dx.doi.org/10.1371/journal.pgen.1007873
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author Mäkeläinen, Suvi
Gòdia, Marta
Hellsand, Minas
Viluma, Agnese
Hahn, Daniela
Makdoumi, Karim
Zeiss, Caroline J.
Mellersh, Cathryn
Ricketts, Sally L.
Narfström, Kristina
Hallböök, Finn
Ekesten, Björn
Andersson, Göran
Bergström, Tomas F.
author_facet Mäkeläinen, Suvi
Gòdia, Marta
Hellsand, Minas
Viluma, Agnese
Hahn, Daniela
Makdoumi, Karim
Zeiss, Caroline J.
Mellersh, Cathryn
Ricketts, Sally L.
Narfström, Kristina
Hallböök, Finn
Ekesten, Björn
Andersson, Göran
Bergström, Tomas F.
author_sort Mäkeläinen, Suvi
collection PubMed
description 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.
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spelling pubmed-64244082019-04-02 An ABCA4 loss-of-function mutation causes a canine form of Stargardt disease Mäkeläinen, Suvi Gòdia, Marta Hellsand, Minas Viluma, Agnese Hahn, Daniela Makdoumi, Karim Zeiss, Caroline J. Mellersh, Cathryn Ricketts, Sally L. Narfström, Kristina Hallböök, Finn Ekesten, Björn Andersson, Göran Bergström, Tomas F. PLoS Genet Research Article 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. Public Library of Science 2019-03-19 /pmc/articles/PMC6424408/ /pubmed/30889179 http://dx.doi.org/10.1371/journal.pgen.1007873 Text en © 2019 Mäkeläinen et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Mäkeläinen, Suvi
Gòdia, Marta
Hellsand, Minas
Viluma, Agnese
Hahn, Daniela
Makdoumi, Karim
Zeiss, Caroline J.
Mellersh, Cathryn
Ricketts, Sally L.
Narfström, Kristina
Hallböök, Finn
Ekesten, Björn
Andersson, Göran
Bergström, Tomas F.
An ABCA4 loss-of-function mutation causes a canine form of Stargardt disease
title An ABCA4 loss-of-function mutation causes a canine form of Stargardt disease
title_full An ABCA4 loss-of-function mutation causes a canine form of Stargardt disease
title_fullStr An ABCA4 loss-of-function mutation causes a canine form of Stargardt disease
title_full_unstemmed An ABCA4 loss-of-function mutation causes a canine form of Stargardt disease
title_short An ABCA4 loss-of-function mutation causes a canine form of Stargardt disease
title_sort abca4 loss-of-function mutation causes a canine form of stargardt disease
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6424408/
https://www.ncbi.nlm.nih.gov/pubmed/30889179
http://dx.doi.org/10.1371/journal.pgen.1007873
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