Cone Photoreceptor Function Loss–3 (Cpfl3), a New Mouse Model of Achromatopsia Due to Missense Mutation in GNAT2

Abstract

Abstract: : Purpose: To report a new mouse model of achromatopsia in mice with a cpfl3 mutation found in the ALS/LtJ strain. Methods: The effects of the cpfl3 mutation were documented using electroretinography, immunohistology, ophthalmoscopy, and fundus photography. The genetic analysis of the mutation was performed using linkage studies and PCR gene identification. Results: Homozygous cpfl3 mice have a complete lack of cone–mediated response on ERG from 3 weeks of age. Cone–mediated ERGs were non detectable at 3–weeks and remain non–detectable up to 56 weeks, the oldest age tested. Rod–mediated responses are robust and clearly within normal limits at all ages, but there is a steady decline in ERG parameters with age. Immunohistologic staining demonstrates the presence of staining to transducin in cpfl3, but at a lower level than controls, while PNA staining shows that cones are present. Genetic analysis demonstrates that cpfl3 maps to mouse chromosome 3 at the same location as the human GNAT2 gene, known to cause achromatopsia. Sequence analysis reveals that cpfl3 is due to a single base pair substitution in exon 6 of the Gnat2 gene, creating a missense mutation. Conclusions: This mouse model of achromatopsia will be useful in studying the pathophysiology of cone degeneration. The gene symbol for the cpfl3 mutation has been changed to Gnat2^cpfl3.

Keywords: retinal degenerations: hereditary • genetics • degenerations/dystrophies