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Bo Chang, Jieping Wang, Bernard FitzMaurice; A new mouse model of cone photoreceptor function loss (cpfl9) with cone photoreceptor degeneration.. Invest. Ophthalmol. Vis. Sci. 2016;57(12):3150. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
To report the clinical characterization, genetic analysis and gene identification of a spontaneous mutation named cone photoreceptor function loss 9 (cpfl9) in a mouse model with a significantly reduced cone electroretinography (ERG) response.
While screening mouse strains and stocks at The Jackson Laboratory for genetic mouse models of human ocular disorders, we identified a new mouse model of cone photoreceptor function loss with cone photoreceptor degeneration. We characterized the clinical effects of this mutation using serial electroretinography (ERG), fundus photography, and histology studies. Genetic analysis including linkage studies and comparison of whole exome sequences of mutant and wild-type (WT) controls identified the causative gene and mutation.
Mice carrying the cpfl9 mutation show an early onset phenotype that can easily be recognized by ERG at three weeks of age with an abnormal cone-mediated photoresponse and at six weeks to 11 months by a reduction in rod-mediated photoresponses. Mice homozygous for cpfl9 have small, evenly spaced white dots throughout their retinas and these small white dots become apparent by indirect ophthalmoscopic examination by 3 months of age. Histological results from mice at parallel ages show an overall normal retinal structure with cone photoreceptor degeneration. Genetic analysis shows that this disorder is caused by an autosomal recessive mutation that maps to mouse Chromosome 11 between D11Mit349 and D11Mit41, suggesting that the human homolog may be on Chromosome 17p13.1. By high throughput sequencing of a whole exome capture library of a cpfl9/cpfl9 mutant and subsequent sequence analysis, a 25 bp deletion within exon 11 in the Gucy2e [guanylate cyclase 2e] gene, was identified, that is predicted to lead to a frame shift and premature termination.
The cpfl9 is a new spontaneous cone photoreceptor function loss mutation not previously described in mouse. Retinal guanylate cyclase-1 (GC1) encoded by Gucy2e (GUCY2D in human) plays a very important role in cone photoreceptor cell survival and function in cpfl9 mice. The loss-of-function mutations in human GUCY2D cause LCA1 and are one of the most common causes of LCA. The cpfl9 mutant will serve as an important model to test therapeutic methods for human LCA1.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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