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Inherited retinal degeneration (RD) leads to the impairment or loss of vision in millions of individuals worldwide, most frequently due to the loss of photoreceptor (PR) cells. Animal models, particularly the laboratory mouse, have been used to understand the pathogenic mechanisms that underlie PR cell loss and to explore therapies that may prevent, delay, or reverse RD. Here, we reviewed entries in the Mouse Genome Informatics and PubMed databases to compile a comprehensive list of monogenic mouse models in which PR cell loss is demonstrated. The progression of PR cell loss with postnatal age was documented in mutant alleles of genes grouped by biological function. As anticipated, a wide range in the onset and rate of cell loss was observed among the reported models. The analysis underscored relationships between RD genes and ciliary function, transcription-coupled DNA damage repair, and cellular chloride homeostasis. Comparing the mouse gene list to human RD genes identified in the RetNet database revealed that mouse models are available for 40% of the known human diseases, suggesting opportunities for future research. This work may provide insight into the molecular players and pathways through which PR degenerative disease occurs and may be useful for planning translational studies.

Mouse models provide a valuable tool for exploring pathogenic mechanisms underlying inherited human disease. Here, we describe seven mouse models identified through the Translational Vision Research Models (TVRM) program, each carrying a new allele of a gene previously linked to retinal developmental and/or degenerative disease. The mutations include four alleles of three genes linked to human nonsyndromic ocular diseases (Aipl1tvrm119, Aipl1tvrm127, Rpgrip1tvrm111, RhoTvrm334) and three alleles of genes associated with human syndromic diseases that exhibit ocular phentoypes (Alms1tvrm102, Clcn2nmf289, Fkrptvrm53). Phenotypic characterization of each model is provided in the context of existing literature, in some cases refining our current understanding of specific disease attributes. These murine models, on fixed genetic backgrounds, are available for distribution upon request and may be useful for understanding the function of the gene in the retina, the pathological mechanisms induced by its disruption, and for testing experimental approaches to treat the corresponding human ocular diseases.

Purpose: We directly corrected the mouse Crb1(rd8) gene mutation, which is present in many inbred laboratory strains derived from C57BL/6N and complicates genetic studies of retinal disease in mice., Methods: Fertilized C57BL/6NJ oocytes were coinjected with mRNAs encoding a transcription activator-like effector nuclease (TALEN) targeting the Crb1(rd8) allele plus single-stranded oligonucleotides to correct the allele. The oligonucleotides included additional nucleotide changes to distinguish the corrected allele (Crb1(em1Mvw)) from wild-type Crb1 and to minimize TALEN recutting. Oligonucleotide length, concentration of injected oligonucleotides and TALEN mRNAs were varied to optimize homology-directed repair of the locus. Following microinjection, embryos were carried to term in pseudopregnant females. Correction efficiency was assessed by PCR analysis of the Crb1(em1Mvw) allele. Phenotypic correction was demonstrated by fundus imaging and optical coherence tomography of live mice, and by confocal fluorescence microscopy of retinal flat mounts., Results: Under optimal conditions, homology-directed repair was observed in 27% (8/30) of live-born animals and showed minimal illegitimate recombination of donor DNA. However, extensive founder mosaicism was evident, emphasizing the need to analyze offspring of founder animals. Unlike C57BL/6NJ mice, which exhibited external limiting membrane fragmentation and regional retinal dysplasia, heterozygous Crb1(em1Mvw)/Crb1(rd8) mice showed a normal retinal phenotype., Conclusions: The C57BL/6NJ-Crb1(rd8) mutation and its associated retinal phenotypes were corrected efficiently by TALEN-mediated homology-directed repair. The C57BL/6NJ-Crb1(em1Mvw) mice generated by this strategy will enhance ocular phenotyping efforts based on the C57BL/6N background, such as those implemented by the International Mouse Phenotyping Consortium (IMPC) project.

The identification of genes that modify pathological ocular phenotypes in mouse models may improve our understanding of disease mechanisms and lead to new treatment strategies. Here, we identify modifier loci affecting photoreceptor cell loss in homozygous Mfrp(rd6) mice, which exhibit a slowly progressive photoreceptor degeneration. A cohort of 63 F2 homozygous Mfrp(rd6) mice from a (B6.C3Ga-Mfrp(rd6)/J × CAST/EiJ) F1 intercross exhibited a variable number of cell bodies in the retinal outer nuclear layer at 20 weeks of age. Mice were genotyped with a panel of single nucleotide polymorphism markers, and genotypes were correlated with phenotype by quantitative trait locus (QTL) analysis to map modifier loci. A genome-wide scan revealed a statistically significant, protective candidate locus on CAST/EiJ Chromosome 1 and suggestive modifier loci on Chromosomes 6 and 11. Multiple regression analysis of a three-QTL model indicated that the modifier loci on Chromosomes 1 and 6 together account for 26% of the observed phenotypic variation, while the modifier locus on Chromosome 11 explains only an additional 4%. Our findings indicate that the severity of the Mfrp(rd6) retinal degenerative phenotype in mice depends on the strain genetic background and that a significant modifier locus on CAST/EiJ Chromosome 1 protects against Mfrp(rd6)-associated photoreceptor loss., (Copyright © 2013. Published by Elsevier Ltd.)

Purpose: To identify genes that modify photoreceptor cell loss in the retinas of homozygous Tulp1(tm1Pjn) and Tub(tub) mice, which exhibit juvenile retinitis pigmentosa., Methods: Modifier loci were identified by genetic quantitative trait locus analysis. F2 Tulp1(tm1Pjn/tm1Pjn) mutant mice from a B6-Tulp1(tm1Pjn/tm1Pjn) × AKR/J intercross were genotyped with a panel of single nucleotide polymorphism markers and phenotyped by histology for photoreceptor nuclei remaining at 9 weeks of age. Genotype and phenotype data were correlated and examined with Pseudomarker 2.02 using 128 imputations to map modifier loci. Thresholds for the 63%, 10%, 5%, and 1% significance levels were obtained from 100 permutations. A significant, protective candidate modifier was identified by bioinformatic analysis and confirmed by crossing transgenic mice bearing a protective allele of this gene with Tulp1- and Tub-deficient mice., Results: A significant, protective modifier locus on chromosome 2 and a suggestive locus on chromosome 13 that increases photoreceptor loss were identified in a B6-Tulp1(tm1Pjn/tm1Pjn) × AKR/J intercross. The chromosome 2 locus mapped near Mtap1a, which encodes a protein associated with microtubule-based intracellular transport and synapse function. The protective Mtap1a(129P2/OlaHsd) allele was shown to reduce photoreceptor loss in both Tulp1(tm1Pjn/tm1Pjn) and Tub(tub/tub) mice., Conclusions: It was demonstrated that the gene Mtap1a, which modifies hearing loss in Tub(tub/tub) mice, also modifies retinal degeneration in Tub(tub/tub) and Tulp1(tm1Pjn/tm1Pjn) mice. These results suggest that functionally nonredundant members of the TULP family (TUB and TULP1) share a common functional interaction with MTAP1A.

Purpose: To evaluate light-induced retinal damage in transgenic T17M rhodopsin mice as a novel model for bystander cone damage during retinal degeneration., Methods: Mouse eyes were exposed to bright white light (15,000 lux, 2.5 minutes). After exposure, electroretinography was performed on mice dark adapted for 12 or more hours at 0 to 5 days to test photoreceptor response or for 0 to 12 hours to test response recovery. Retinal cryosections were examined by TUNEL staining and outer nuclear layer thickness measurements. Cone morphology was assessed by peanut agglutinin staining in retinal flatmounts and cryosections., Results: T17M retinal function and morphology changed rapidly after exposure to light. Scotopic and photopic electroretinogram responses declined progressively from 0.5 to 3 days. Scotopic response recovery peaked at 50% to 60% of the unilluminated response in 3 hours, indicating an early, rapid decline in scotopic signaling. Photopic responses were near normal or supernormal from 0 to 6 hours. Cell death peaked at 1 day, and outer nuclear layer thickness declined from 1 to 5 days. Disorganized cones were observed at 6 hours, intact and damaged cones were observed at 12 hours and 1 day, but only cone remnants were observed at 3 and 5 days. Light exposure had little to no effect on ERG responses in nontransgenic littermates and other retinal degeneration models., Conclusions: The time course of light-induced T17M retinal damage is biphasic, with an initial decline in rod function within hours followed by bystander cone and rod deterioration within days. The rapid and synchronous induction of damage in this model is attractive for characterizing bystander effects in retinal degeneration.