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B.P. Brooks, R.P. Alur, H. Liu, M. Jones, C.–C. Chan, F. Wang, V. Hoffman, X. Gong; Optic Nerve and Kidney Abnormalities in a New Mouse Model of Papillorenal Syndrome . Invest. Ophthalmol. Vis. Sci. 2006;47(13):3880.
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Papillorenal syndrome is a rare autosomal dominant condition characterized by congenital anomalies of the optic disc and a spectrum of kidney abnormalities. Mutations in the PAX2 gene are found in many patients with papillorenal syndrome. We describe a novel mouse model of this disease.
A line of C57BL/6J mice previously mutagenized with ENU were found on clinical examination to have congenital excavation of the optic nerve. Genetic mapping of the trait was performed by crossing affected mice to the C3H/HeN strain and assessing polymorphic DNA markers across the genome. Adult and embryonic mice were evaluated clinically and histopathologically.
The trait is transmitted in an autosomal dominant fashion with close to 100% penetrance in C57BL/6J mice. Whole–genome scanning of polymorphic markers in G2 mice outbred to C3H/HeN showed 0% recombination at D19Mit17.1, suggesting a mutation in the Pax2 gene. A missense sequence change in the Pax2 gene is currently being evaluated for pathogenicity. No homozygous progeny were noted in crosses of affected mice (n=31, p<0.01), suggesting embryonic or early post–natal lethality. Affected heterozygous mice show congenital optic nerve excavation, occasional retinal vascular abnormalities and retinal dysplasia, Histopathological analysis of their kidneys reveal frequent, mild tubular pathologies (n=32 kidneys). Seven of 35 E10.5–14.5 embryos from heterozygous intercrosses were homozygous for the mutation, indicating that the embryologic defect in these mice is not lethal until a later time point. Compared to wild–type embryos, homozygous embryos appear to have abnormalities in the tunica vasculosis lentis and abortive development of metanephric tubules.
This mouse line recapitulates the clinical and genetic findings of patients with papillo–renal syndrome and will be useful in studying the pathogenesis of this condition
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