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Dominant Cone-Rod Dystrophy: A Mouse Model Generated by Gene Targeting of the GCAP1/Guca1a Gene

Buch, PK; Mihelec, M; Cottrill, P; Wilkie, SE; Pearson, RA; Duran, Y; West, EL; ... Hunt, DM; + view all (2011) Dominant Cone-Rod Dystrophy: A Mouse Model Generated by Gene Targeting of the GCAP1/Guca1a Gene. PLOS ONE , 6 (3) , Article e18089. 10.1371/journal.pone.0018089. Green open access

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Abstract

Cone dystrophy 3 (COD3) is a severe dominantly inherited retinal degeneration caused by missense mutations in GUCA1A, the gene encoding Guanylate Cyclase Activating Protein 1 (GCAP1). The role of GCAP1 in controlling cyclic nucleotide levels in photoreceptors has largely been elucidated using knock-out mice, but the disease pathology in these mice cannot be extrapolated directly to COD3 as this involves altered, rather than loss of, GCAP1 function. Therefore, in order to evaluate the pathology of this dominant disorder, we have introduced a point mutation into the murine Guca1a gene that causes an E155G amino acid substitution; this is one of the disease-causing mutations found in COD3 patients. Disease progression in this novel mouse model of cone dystrophy was determined by a variety of techniques including electroretinography (ERG), retinal histology, immunohistochemistry and measurement of cGMP levels. It was established that although retinal development was normal up to 3 months of age, there was a subsequent progressive decline in retinal function, with a far greater alteration in cone than rod responses, associated with a corresponding loss of photoreceptors. In addition, we have demonstrated that accumulation of cyclic GMP precedes the observed retinal degeneration and is likely to contribute to the disease mechanism. Importantly, this knock-in mutant mouse has many features in common with the human disease, thereby making it an excellent model to further probe disease pathogenesis and investigate therapeutic interventions.

Type: Article
Title: Dominant Cone-Rod Dystrophy: A Mouse Model Generated by Gene Targeting of the GCAP1/Guca1a Gene
Open access status: An open access version is available from UCL Discovery
DOI: 10.1371/journal.pone.0018089
Publisher version: http://dx.doi.org/10.1371/journal.pone.0018089
Language: English
Additional information: © 2011 Buch et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This study was supported by grants from the UK Medical Research Council (Hunt and Ali), the Wellcome Trust (Hunt), Fight for Sight UK (Ali), Foundation Fighting Blindness USA (Hunt), the Royal Society (Pearson) and the National Institute for Health Research USA (Ali and Michaelides). The authors also acknowledge support from the Biomedical Research Centre for Ophthalmology at Moorfields Eye Hospital, Moorfields Special Trustees and UCL Institute of Ophthalmology. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Keywords: CYCLASE-ACTIVATING PROTEIN-1, PAIRED-FLASH ELECTRORETINOGRAMS, DRIVEN RETINAL RESPONSES, CALCIUM-CHANNEL BLOCKER, D-CIS-DILTIAZEM, GUANYLATE-CYCLASE, RETINITIS-PIGMENTOSA, IN-VIVO, PHOTORECEPTOR DEGENERATION, CGMP PHOSPHODIESTERASE
UCL classification: UCL > School of Life and Medical Sciences
UCL > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology
UCL > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology > Institute of Ophthalmology - Genetics
UCL > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology > Institute of Ophthalmology - Ocular Biology
UCL > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology > Institute of Ophthalmology - Visual Neuroscience
UCL > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > School of Life and Medical Sciences > Faculty of Life Sciences > The Sainsbury Wellcome Centre
URI: http://discovery.ucl.ac.uk/id/eprint/1302504
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