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C. Zou, Sr., E. Levine; Generation and Analysis of Two Mutant Alleles of Vsx2 That Cause Microphthalmia in Humans and Mice. Invest. Ophthalmol. Vis. Sci. 2010;51(13):2938.
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Mutations in the Vsx2 homeobox gene cause non-syndromic congenital microphthalmia in humans and mice. Because the mouse mutation, a spontaneous null mutation named ocular retardation J (orJ), is genetically distinct from those found in humans, the phenotypic profiles caused by each of the mutations might vary. To address this and to gain further insight into the etiology of human micropthalmia, we generated knock-in mice with the missense mutations Arg200Glu (R200Q) and Arg227Trp (R227W), both of which are identical to those found in humans. R200Q is located in the homeodomain and disrupts DNA binding. R227W is located in the CVC domain, which is of unknown function.
Each mouse line was generated by gene targeting. The phenotypes of these mutants and the Vsx2orJ/orJ mutant were examined by immunohistochemistry and quantitative RT-PCR.
The extent of microphthalmia and spectrum of ocular phenotypes are similar between the orJ and R200Q mutant mice, indicating that the homeodomain is essential for Vsx2 function. Surprisingly, the phenotypes caused by the R227W mutation are more severe as indicated by smaller eyes and highly penetrant transformation of neural retina into pigmented tissue. The more severe phenotypes are attributed to novel changes in the expression levels of the transcription factor Mitf and the cyclin dependent kinase inhibitor p27Kip1, two genes previously identified as causal factors in the ocular phenotypes caused by the orJ mutation. Genetic interaction studies indicate a pathway by which p27Kip1 mediates the pigment-transforming effect of Mitf on the neural retina.
Our results indicate that the expression levels of Mitf or P27 in Vsx2 mutant retinal progenitor cells determine the severity of microphthalmia. Our results also reveal that the homeo- and CVC domains are essential for Vsx2 function.
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