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Bo Chang, Jieping Wang, Bernie Fitzmaurice, Patsy M Nishina; A new mouse model of cone photoreceptor function loss (cpfl10) with normal rod photoreceptor function.. Invest. Ophthalmol. Vis. Sci. 2020;61(7):768.
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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 10 (cpfl10) in a new mouse model with no cone-mediated but normal rod-mediated photoresponses.
We identified a new mouse model of cone photoreceptor function loss with no photoreceptor degeneration, named cpfl10. To ascertain that cpfl10 was not caused by Gnat2cpfl3, a common founder mutation in mouse strains, we tested cpfl10 DNA with a cpfl3 genotyping protocol that detected a single nucleotide substitution of G to A at position 598 in exon 6, and found that it was negative for cpfl3. We characterized the clinical effects of this mutation using longitudinal electroretinography (ERG), bright field retinal imaging with image-guided OCT, and histology. We also performed genetic analysis, including linkage studies, and examined candidate gene sequences to identify the causative gene and mutation.
Mice carrying the cpfl10 mutation show an early onset ERG cone b-wave abnormality. The phenotype can be easily assessed by ERG at three weeks of age. Affected mice exhibit no cone-mediated photoresponse but normal rod-mediated photoresponses from 3 weeks to 6 months of age. Mice homozygous for cpfl10 have normal retinal image (fundus) and OCT images from 3 weeks to 6 months of age. Histological results from mice at 6 months of age showed a normal retinal structure. Genetic analysis shows that this disorder is caused by an autosomal recessive mutation that maps to mouse Chromosome 3 between D3Mit40 and D3Mit78, where the mouse guanine nucleotide binding protein, alpha transducing 2 (Gnat2) gene is located. Also the allelic test between cpfl10 and cpfl3 was positive, suggesting a new mutation occurred in the Gnat2 gene. Sequence analysis shows that the cpfl10 is caused by one base change from C to T in exon 2 of Gnat2 gene. Codon changed from CAG (codon 24) to a stop codon TAG.
Mutations in the GNAT2 gene encoding the cone-specific a-subunit of transducin cause an early-onset autosomal recessive form of human achromatopsia, a key feature of which is the absence of color discrimination. The naturally arising cpfl10 mutation will provide another good model for studying the pathogenesis of autosomal recessive achromatopsia (ACHM4, OMIM 139340) in humans.
This is a 2020 ARVO Annual Meeting abstract.
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