Cone dystrophy 3 (
COD3) is a severe dominantly inherited
retinal degeneration caused by missense mutations in GUCA1A, the gene encoding
Guanylate Cyclase Activating Protein 1 (GCAP1). The role of GCAP1 in controlling
cyclic nucleotide levels in photoreceptors has largely been elucidated using knock-out mice, but the disease pathology in these mice cannot be extrapolated directly to
COD3 as this involves altered, rather than loss of, GCAP1 function. Therefore, in order to evaluate the pathology of this dominant disorder, we have introduced a point mutation into the murine Guca1a gene that causes an E155G amino acid substitution; this is one of the disease-causing mutations found in
COD3 patients.
Disease progression in this novel mouse model of
cone dystrophy was determined by a variety of techniques including electroretinography (ERG),
retinal histology, immunohistochemistry and measurement of cGMP levels. It was established that although
retinal development was normal up to 3 months of age, there was a subsequent progressive decline in
retinal function, with a far greater alteration in cone than rod responses, associated with a corresponding loss of photoreceptors. In addition, we have demonstrated that accumulation of
cyclic GMP precedes the observed
retinal degeneration and is likely to contribute to the disease mechanism. Importantly, this knock-in mutant mouse has many features in common with the human disease, thereby making it an excellent model to further probe disease pathogenesis and investigate therapeutic interventions.