Dominant cone-rod dystrophy: a mouse model generated by gene targeting of the GCAP1/Guca1a gene

• Published in: PloS one 2011-03, Vol.6 (3), p.e18089
• Main Authors: Buch, Prateek K, Mihelec, Marija, Cottrill, Phillippa, Wilkie, Susan E, Pearson, Rachael A, Duran, Yanai, West, Emma L, Michaelides, Michel, Ali, Robin R, Hunt, David M
• Format: Article
• Language: English
• Subjects: Amino acid substitution; Analysis; Animals; Apoptosis; Asymptomatic Diseases; Biology; Congenital diseases; Cyclic GMP; Cyclic GMP - metabolism; Cyclic guanosine monophosphate; Defects; Degeneration; Disease Models, Animal; Dystrophy; Electroretinograms; Electroretinography; Gene expression; Gene Knock-In Techniques; Gene mutation; Gene Targeting; Genes; Genes, Dominant - genetics; Genetic aspects; Guanylate cyclase; Guanylate Cyclase-Activating Proteins - genetics; Guanylate Cyclase-Activating Proteins - metabolism; Hereditary diseases; Histology; House mouse; Humans; Immunohistochemistry; Intracellular Space - metabolism; Kinetics; Medicine; Mice; Missense mutation; Mutant Proteins - genetics; Mutant Proteins - metabolism; Mutation; Mutation - genetics; Pathogenesis; Pathology; Permeability; Photoreception; Photoreceptors; Point mutation; Proteins; Retina; Retinal Cone Photoreceptor Cells - metabolism; Retinal Cone Photoreceptor Cells - pathology; Retinal degeneration; Retinal Rod Photoreceptor Cells - metabolism; Retinal Rod Photoreceptor Cells - pathology; Retinitis Pigmentosa - genetics; Retinitis Pigmentosa - physiopathology; Rodents; Therapeutic applications; University colleges
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0018089

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.