Purpose.: This work investigates a novel, naturally occurring mouse model of achromatopsia. The specific missense mutation within the Gnat2 gene was identified and the subsequent retinal phenotype characterized.

Methods.: The Gnat2 sequence was amplified using PCR from BALB/c and Gnat2 c. 518A> G retinae and the product sequenced. Retinal function was assessed at 3, 6, 9, and 12 months using the electroretinogram. Transducin and opsin expression were assessed at 3 and 12 months using immunohistochemistry and quantitative PCR. Retinal remodeling and Müller cell gliosis were investigated using immunocytochemistry.

Results.: An A to G missense mutation at position 518 of the Gnat2 gene was identified that resulted in an aspartic acid to glycine substitution. Gnat2 c. 518A> G animals showed no cone response, while the rod response was normal except for a decrease in the photoreceptor response at 12 months (a-wave,− 14%). Gnat2 c. 518A> G retinal sections showed no transducin immunolabeling; however, protein was detected via Western blot. Gnat2 gene expression was only decreased at 12 months of age (− 27%). There was reduced cone number at 12 months (− 27%) and M-opsin showed evidence of mislocalization. Displaced photoreceptor terminals and altered horizontal cell, cone/rod bipolar cell morphology were evident at 3 months, becoming more extensive at 12 months with the emergence of Müller cell gliosis.

Conclusions.: The Gnat2 c. 518A> G mouse contains a missense mutation that results in no cone function due to a misfolding of transducin. Cone photoreceptors also show signs of opsin mislocalization, retinal remodeling and degeneration. This naturally occurring model shows all the hallmark signs of achromatopsia.