Abstract
Purpose: :
Mutations in the RP1 gene cause 5-7% of dominant RP. The pathogenesis of the RP1 form of RP is not completely understood. To help elucidate the function of the RP1 protein and the mechanism by which mutations in RP1 lead to photoreceptor cell death, we previously generated a mutant Rp1 allele which mimics the most commonly observed mutation in human RP1. Mice homozygous for this mutant allele, designated Rp1-myc, undergo a rapid-onset retinal degeneration. In contrast, photoreceptors of heterozygous Rp1-myc mice on a mixed 129 - C57B6/J background remain healthy over a period of 18 months. In order to investigate the influence of genetic background on the course of the retinal degeneration in the Rp1-myc mice, we generated three strains of congenic Rp1-myc mice on different genetic backgrounds.
Methods: :
To generate the congenic Rp1-myc strains of mice, we crossed the Rp1-myc allele onto the pigmented C57BL/6J, DBA/1J backgrounds and the albino A/J background for 7-9 generations. The retinal function of heterozygous congenic mice and littermate controls in all three backgrounds was characterized by ERG analysis. Retinal morphology and ultrastructure were assessed by light and electron microscopy.
Results: :
In the N9 C57BL/6J and DBA/1J congenic Rp1-myc mice, retinal function and morphology were identical to wild-type littermate controls up to 18 months of age. In the A/J albino Rp1-myc mice, retinas of the N7 heterozygous mice showed significant degenerative changes by 14 months of age. The thickness of outer nuclear layer and the outer-segment length were reduced by approximately 50% compared to wild-type littermate controls. The rod ERG response was also reduced by approximately 40%. Evaluation of retinal function in N8 and N9 A/J-Rp1-myc mice is in progress.
Conclusions: :
Albino Rp1-myc mice have significant degeneration of photoreceptors compared to pigmented Rp1-myc mice on C57BL/6J and DBA/1J backgrounds. These results are consistent with the hypothesis that phenotypic expression of RP1 disease is dependent, at least in part, on sequence alterations in other genes. The congenic mice generated for these analyses provide a valuable resource to identify the genes which modify the severity of RP1 disease.
Keywords: photoreceptors • retinal degenerations: hereditary • genetics