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ML Robinson, CM Rizo, Q Duong, Y Yang; Genetic Mapping of ari, A Spontaneous Mutation in Mice Causing Anterior Retina Inversion, Ciliary Body Dysgenesis, Loss of Vitreous Humor and Microphthalmia . Invest. Ophthalmol. Vis. Sci. 2002;43(13):3676.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose:The purpose of these studies was to find the genetic position of a new spontaneous, autosomal recessive mutation, anterior retinal inversion (ari), in mice and to further define the ocular phenotype in mutant animals. Methods:Genetic mapping was performed using a backcross analysis. Homozygous ari mutants on an FVB/N inbred background were bred to C57BL/6 wildtype inbred mice, and the resulting F1 progeny were backcrossed to homozygous FVB/N ari mutants. DNA samples and eyes were recovered for each of the backcross progeny. DNA samples were tested for polymorphic microsatellite markers and eyes were sectioned for routine histology. Results:Twenty four backcross animals were tested by genome scan using polymorphic markers distributed throughout the genome. Marker D16Mit169 only recombined with the phenotype in one out of 24 backcross animals localizing the mutation to mouse chromosome 16. Fine mapping was conducted on 656 backcross animals and localized the mutation between D16Mit126 and D16Mit61, a region of approximately 2.3 million base pairs on mouse chromosome 16. While ari appears to be completely penetrant and the result of a single genetic locus, backcross animals did display variation in the severity of the phenotype that was not present on the FVB/N inbred background. This demonstrates that loci in the C57BL/6 genome are capable of modifying the ocular phenotype of the ari mutation. In both the FVB/N and backcross background, the first ocular phenotype is an exaggerated space between the anterior margin of the inner and outer optic cup, which is evident at E15.5. Inversion of the anterior retina and a complete (in the FVB/N background) or partial (in backcross mutant mice) loss of vitreous follows this early phenotype. Abnormal development of the ciliary body is also a consistent feature in homozygous mutant mice. Cataracts and lens malformations are always present in FVB/N ari mutants by 2-3 weeks of age, but are not always present in the backcross animals having a mixture of C57BL/6 and FVB/N genes. Conclusion:The mouse autosomal recessive mutation, ari, has been mapped to a single locus on mouse chromosome 16. Modifier loci in the C57BL/6 genome can reduce some, but not all, ocular phenotypes associated with the mutation on an FVB/N inbred background. Although ari is a pleiotrophic mutation, affecting many ocular structures, the first morphological phenotype appears in the anterior retina several days before birth.
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