Abstract
Abstract: :
Purpose: Approximately 50 million people around the world are blind and an additional 150 million significantly vision impaired. Except for trauma and infections, the majority of human eye diseases are genetic in nature. The number of human loci causing retinal disease is ∼ 9–fold greater than the number of available associated animal models, indicating a large gap in models for studying diseases that are known to occur in humans. The Mouse Models for Vision Research Program seeks to identify, characterize and positionally clone mouse mutants with heritable retinal diseases and make them available to the vision research community. Methods: C57BL/6 mice mutagenized with ethyl nitrosourea are screened by indirect ophthalmoscopy and slit lamp biomicroscopy. Once heritability is established, anterior segment or fundus photodocumention, electroretinography and histology are carried out for all models at two appropriate ages to determine if the disease is stationary or progressive. An in vitro fertilization approach is used to hasten the positional cloning process. Results: Thus far, we have screened 1,300 G3 mice representing ∼100 completed or partially completed G1 families. From these we identified 21 putant MMVR lines that are bilaterally affected, five of which had 2 or more family members affected. Retinal spots, drusen–like deposits, regions of hypo– and hyper–pigmentation, and abnormalities in retinal blood vessels are phenotypes that have been observed. Eighteen of the 21 putant strains have bred and produced F1 mice. From these crosses, we have confirmed in multiple matings that 2 are heritable, dominant mutations (MMVR7 and 24). Interestingly, in MMVR24, loss of PR cells occurs only in the central retina, slightly offset from the optic nerve head. This phenotype is reminiscent of a transgenic strain carrying a human mutant ELOVL4 allele that causes Stargardt–like3 (Locke et al. 2004). The F1 progeny of the remaining 16 putants were unaffected, suggesting that they are either recessive or non–genetic in nature; these have been intercrossed to generate F2 progeny for testing. Based on past experience, we expect that ∼50% or 9 of the putants will prove to carry a heritable mutation. Conclusions: Chemical mutagenesis is one of the most efficient methods to produce mice with eye diseases. ENU–induced mutations allow unbiased identification of a wide array of genes with different effects on ocular biology. The models generated in the MMVR program will not only generate well characterized ocular models, but will potentially identify entry points into new pathways that are important in eye biology and afford us the opportunity to test hypotheses about normal ocular function and disease pathology.
Keywords: retinal degenerations: hereditary • genetics • mutations