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RW Williams, L Lu, XF Wang, S Qu, J Gu, MM Jablonski; Mapping And Initial Characterization Of A Spontaneous Mutation Affecting Lens Development In RIIIS/J Inbred Mice . Invest. Ophthalmol. Vis. Sci. 2002;43(13):486.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: We have discovered a spontaneous mutation that affects eye and lens development in the RIIIS/J inbred line of mice. Here we describe the ocular phenotype of this mutation. Using an F2 intercross, we have mapped the mutation as a first step in positional candidate gene cloning. Methods: Eyes from a sample of 48 fully inbred RIIIS/J animals, 24 F1, and 243 F2 intercross progeny between RIIIS/J and DBA/2J F2 were weighed followed by fixation in 4% paraformaldehyde. Selected lenses were also weighed. Both sexes and a range of ages (97 to 365 days of age) were used in these analyses. Two cases with anomolously large eyes were excluded from the analysis (≷29 mg). Variation in eye size associated with age, sex, and body weight was eliminated by multiple regression. An ophthalmic exam was performed on eyes from 3 inbred RIIIS/J mice (age=9 weeks), and eyes from inbred RIIIS/J mice and F2 progeny were evaluated histologically. Genomic DNA was extracted from F2 progeny and typed at 67 microsatellites spanning the genome. The mutation was mapped using MapManagerQT. Results: The mean eye weight of the RIIIS/J animals was 16.9 ± 0.36 mg, which is significantly less than that of the F2 intercross progeny (mean=18.0 mg ±0.25 mg, p<0.05). Nine RIIIS/J cases had eye weights less than 15 mg. Lenses of all RIIIS/J mice were deformed and often small. Weights typically averaged 3 mg, but varied extensively (range 0-5 mg). By ophthalmoscopic exam, the lens was completely opaque in RIIIS/J mice. The lens was translocated temporally, rather than being centered, and a secondary lens-like structure was evident. Histologic analysis of RIIIS/J eyes revealed severe abnormalities in lens structure. In all cases, the lens failed to form a spherical shape and often a secondary or duplicate lens filled the vitreous chamber of the eye. The epithelial cells that are normally present on the anterior lens and abruptly terminate at the lens equator often circumscribe the primary lens in the RIIIS/J mice. The retina appeared relatively normal morphologically. All ocular structures in the F2 intercross mice appeared morphologically normal. The responsible mutant gene was mapped between D8Mit242 (48 cM) and D8Mit199 (56 cM) on chromosome 8. The best linkage is near the esterase complex on chromosome 8. The homologous human region is 16q22.1. Conclusion: We have mapped a novel mutation with selective effects upon lenticular development to an 8 cM interval on mouse chromosome 8. We are currently fine-mapping and further characterizing the mutant. A search of OMIM reveals no obvious human candidate genes.
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