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.

Adipor1tm1Dgen and Mfrprd6 mutant mice share similar eye disease characteristics. Previously, studies established a functional relationship of ADIPOR1 and MFRP proteins in maintaining retinal lipidome homeostasis and visual function. However, the independent and/or interactive contribution of both genes to similar disease phenotypes, including fundus spots, decreased axial length, and photoreceptor degeneration has yet to be examined. We performed a gene-interaction study where homozygous Adipor1tm1Dgen and Mfrprd6 mice were bred together and the resulting doubly heterozygous F1 offspring were intercrossed to produce 210 F2 progeny. Four-month-old mice from all nine genotypic combinations obtained in the F2 generation were assessed for white spots by fundus photo documentation, for axial length by caliper measurements, and for photoreceptor degeneration by histology. Two-way factorial ANOVA was performed to study individual as well as gene interaction effects on each phenotype. Here, we report the first observation of reduced axial length in Adipor1tmlDgen homozygotes. We show that while Adipor1 and Mfrp interact to affect spotting and degeneration, they act independently to control axial length, highlighting the complex functional association between these two genes. Further examination of the molecular basis of this interaction may help in uncovering mechanisms by which these genes perturb ocular homeostasis.

Structured AbstractPurposeTo quantify changes in axial and retinal biometry in aging hyperopic mouse models.MethodsFundus photographs and ocular biometric measurements from Mfrprd6, Prss56glcr4, Adipor1tm1Dgen, C1qtnf5tm1.1(KOMP)Vlcg and Prss56em2(IMPC)J homozygotes and C57BL/6J control mice were ascertained longitudinally up to one year of age. Parameters including axial length (AL), central corneal thickness (CCT), anterior chamber depth (ACD), lens thickness (LT), outer nuclear layer thickness (ONLT), retinal thickness (RT), vitreous chamber depth (VCD) and posterior length (PL) were measured using Spectral Domain-Optical Coherence Tomography imaging. Mixed-model analysis of variance and factorial analysis of covariance, using body size as a covariate, followed by post-hoc analysis was performed to identify significant strain differences.ResultsStrain specific changes in axial and retinal biometry along with significant effects of age, sex and body size on AL were noted. Mfrprd6, Prss56glcr4, Adipor1tm1Dgen and Prss56em2(IMPC)J homozygotes had significantly shorter AL than controls. While a comparable decrease in PL was observed in Mfrprd6, Prss56glcr4, and Adipor1tm1Dgen homozygotes, the decrease was attributed to changes in different posterior components from each mutant. Mfrprd6 and Adipor1tm1Dgen homozygotes developed regularly sized fundus spots across the ocular globe, which differed from the large bright spots seen in aged Prss56glcr4 and Prss56em2(IMPC)J homozygotes. While ONLT of C1qtnf5tm1.1(KOMP)Vlcg mice was less than controls, AL and fundus images appeared normal.ConclusionsThis study highlights differences in contributions of ocular components to AL among hyperopic mouse models with decreased AL. Understanding the mechanisms through which these proteins function, will help to elucidate their role in controlling ocular growth.

Adipor1tm1Dgen and Mfrprd6 mutant mice share similar eye disease characteristics. Previously, studies established a functional relationship of ADIPOR1 and MFRP proteins in maintaining retinal lipidome homeostasis and visual function. However, the independent and/or interactive contribution of both the genes to similar disease phenotypes, including fundus spots, decreased axial length and photoreceptor degeneration has yet to be examined. We performed a gene-interaction study where homozygous Adipor1tm1Dgen and Mfrprd6 mice were bred together and the resulting doubly heterozygous F1 offspring were intercrossed to produce 210 F2 progeny. Four-month-old mice from all nine genotypic combinations obtained in the F2 generation were assessed for white spots by fundus photo documentation, for axial length by caliper measurements, and for photoreceptor degeneration by histology. Two-way factorial ANOVA was performed to study individual as well as gene interaction effects on each phenotype. Here, we report the first observation of reduced axial length in Adipor1tmlDgen homozygotes. We show that while Adipor1 and Mfrp interact to affect spotting and degeneration, they act independently to control axial length, highlighting the complex functional association between these two genes. Further examination of the molecular basis of this interaction may help in uncovering mechanisms by which these genes perturb ocular homeostasis.