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PH Mathers, EA Kozhemyakina, VA Voronina, CM O'Kernick, JV Linberg, AS Schneider; Mouse Models Of Anopthalmia Mutations In The Human Rx Gene . Invest. Ophthalmol. Vis. Sci. 2002;43(13):2002.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: Mouse embryos carrying a deletion of the Rx homeobox gene fail to form the optic pit, the first morphological representation of retinal cell fate. Therefore, the resulting Rx-null mouse pups are born anophthalmic. Based on these findings, we performed mutational screening on a population of patients exhibiting either anophthalmia or microphthalmia. Our goal is to create an animal model for RX gene mutations identified in humans. Methods: Mutational screening was performed on 75 patients with anophthalmia or microphthalmia (either bilaterally and unilaterally affected). Direct genomic sequencing was achieved by PCR amplification of four regions from the human RX gene, representing the three coding exons. Gene targeting in mouse embryonic stem cells was used to introduce one novel mutation into the mouse genome for further analysis. Results: We have identified three patients carrying RX gene mutations. All three patients carry a premature termination codon allele at amino acid 147 (Q147X), with two of these mutations arising sporadically. One of these patients carries an additional missense mutation at amino acid 192 (R192Q). The R192Q mutation has been targeted to the mouse genome for analysis of its effects in homozygous animals and in animals heterozygous for R192Q and a null allele, mimicking the genotype of the compound heterozygous patient. Conclusion: With identification of RX gene mutations in both anophthalmic and microphthalmic patients and published reports of Rx mutations leading to eyeless phenotypes in other organisms, we conclude that the RX/Rx gene is crucial for the proper establishment of retinal cell fate during early embryogenesis in all vertebrates.
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