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Cone Photoreceptor Function Loss-3, a Novel Mouse Model of Achromatopsia Due to a Mutation in Gnat2

¹From the The Jackson Laboratory, Bar Harbor, Maine; the ²Departments of Ophthalmology and Visual Sciences and ³Cell and Developmental Biology, University of Michigan, Ann, Arbor, Michigan; and the ⁴Scheie Eye Institute and Kirby Center for Molecular Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania; the ⁵Jules Stein Eye Institute, University of California at Los Angeles, Los Angeles, California.

PURPOSE. To report a novel mouse model of achromatopsia with a cpfl3 mutation found in the ALS/LtJ strain.

METHODS. The effects of a cpfl3 mutation were documented using fundus photography, electroretinography (ERG), and histopathology. Genetic analysis was performed using linkage studies and PCR gene identification.

RESULTS. Homozygous cpfl3 mice had poor cone-mediated responses on ERG at 3 weeks that became undetectable by 9 months. Rod-mediated waveforms were initially normal, but declined with age. Microscopy of the retinas revealed progressive vacuolization of the photoreceptor outer segments. Immunocytochemistry with cone-specific markers showed progressive loss of labeling for -transducin, but the cone outer segments in the oldest mice examined remained intact and positive with peanut agglutinin (PNA). The cpfl3 mapped to mouse chromosome 3 at the same location as human GNAT2, known to cause achromatopsia. Sequence analysis revealed a missense mutation due to a single base pair substitution in exon 6 in cpfl3.

CONCLUSIONS. The Gnat2^cpfl3 mutation leads to cone dysfunction and the progressive loss of cone -transducin immunolabeling. Despite a poor cone ERG signal and loss of cone -transducin label, the cones survive at 14 weeks as demonstrated by PNA staining. This mouse model of achromatopsia will be useful in the study of the development, pathophysiology, and treatment of achromatopsia and other cone degenerations. The gene symbol for the cpfl3 mutation has been changed to Gnat2^cpfl3.

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