Eye diseases identified in the ENU-Ageing Screen

MRC Harwell is generating cohorts of mutagenized mice, bred to reveal recessive mutations. Cohorts are repeatedly screened for a range of phenotypes at different ages up to 18 months. Included among the screens is optokinetic response to test visual acuity, pupillometry and examination by slit lamp and indirect ophthalmoscopy. We identify both early and late onset disease models, and document disease progression over the lifetime of the mouse. The genetic design of the screen means that the mutant gene can be rapidly identified by mapping and next-generation sequencing To date we have identified early onset phenotypes including retinal degeneration due to mutation of Rpgrip1, a model for Leber congenital amaurosis-6, and abnormal pupil response due to mutation in Chrm3. Late onset phenotypes include corneal opacity, caused by mutation of Ikzf2, and progressive vision loss with retinal degeneration. We have identified a missense mutation in Idh3a that results in reduced visual acuity and retinal degeneration from 12 months. Idh3a encodes the α subunit of the mitochondrial enzyme, isocitrate dehydrogenase. This mouse is a model for retinitis pigmentosa 46, due to mutation in the β subunit of human mitochondrial IDH enzyme.