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Benjamin Bakall, Megan Riker, Prithviraj Patankar, Rebecca Johnston, Dianna Brack, Janet Riley, Robert Mullins, Michael Anderson, Edwin Stone; Analysis of Phenotype in Mouse Models of Stargardt Disease for Identification of Modifying Genes. Invest. Ophthalmol. Vis. Sci. 2013;54(15):1369.
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ABCA4-related retinal disease exhibits a wide range of severity from Stargardt disease to cone-rod dystrophy and retinitis pigmentosa. Moreover, the severity of the disease can vary among individuals with the same genotype (i.e. siblings), which has been attributed to more than one modifying factor (Schindler et al. HMG 2010). The purpose of this study was to use genetic and phenotypic analysis of ABCA4 mouse models to identify potential modifying gene candidates for human ABCA4-related retinal disease.
A high-resolution RNA expression microarray was used to identify differences in gene expression in neural retina from mice with a targeted Abca4-deletion (a gift from G. Travis) compared to wildtype control mice at different times during development. In addition, mice with a double knockout of both the Abca4 and the Rdh8 genes (a gift from K. Palczewski) were crossed with JF1 mice that harbor a spontaneous large deletion in the Abca4 gene. The offspring mice were backcrossed with the Abca4 and Rdh8 double knockout mice in order to generate a cohort of mice for further analysis. The genotype was confirmed with PCR analysis. In vivo imaging of the retina was performed using a Micron III fundus camera and a Bioptigen OCT machine during development for grading of disease severity and progression.
Comparison of RNA expression analysis of neural retina from Abca4 knock-out mice and age-matched control mice revealed several genes with altered expression levels in the Abca4 knock-out mice. None of these differentially expressed genes are currently known retinal disease genes. A cohort of mice was generated with a targeted deletion of the Rdh8 gene in combination with either a targeted deletion or a large spontaneous deletion of the Abca4 gene. Evaluation of fundus exam and OCT of the retina from the mice revealed a variety of disease severity ranging from a normal appearance to extensive retinal dystrophy.
Modifying genes are responsible for the difference in disease severity in individuals with ABCA4-retinal dystrophy. Mouse models with either targeted disruption of the Abca4 gene or a disruption of both the Abca4 and Rdh8 genes are useful tools for identification of candidates for genes that modify the severity of human ABCA4-related retinal disease.
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