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K. F. Schilter, T. M. Bardakjian, A. Schneider, R. C. Tyler, L. M. Reis, E. V. Semina; The Identification of Mutations in the OTX2 Gene in Anophthalmia/Microphthalmia Patients. Invest. Ophthalmol. Vis. Sci. 2009;50(13):4098.
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Anophthalmia and microphthalmia (A/M) are rare (1-19 of 10,000) developmental disorders associated with the absence of an eye or the presence of a small eye. A number of genes have been shown to be involved in A/M, with SOX2 mutations being the most common, at a mutation rate of about 25%. OTX2 is a homeodomain transcription factor that is important in eye and brain development. Mutations in OTX2 have also been reported in patients with A/M but there is varying data as to the mutation frequency. We screened A/M patient samples for mutations in OTX2 to determine the mutation spectrum and frequency in our population.
A total of 50 human DNA samples collected from A/M patients were used in this study. The three OTX2 coding exons were amplified by PCR and used for direct sequencing.
We identified heterozygous mutations in four patients with A/M. Patients 1 and 2 have bilateral microphthalmia and were found to have, respectively, a 1-nt insertion within exon 4 and a C to T transition in exon 5; both mutations predicted to result in a premature termination of the protein. Patient 3 has anophthalmia in one eye and severe microphthalmia in the other eye and was found to carry G to A transition in exon 5 resulting in a premature stop codon and an A to T transversion resulting in an amino acid change immediately downstream of the stop codon mutation. Patient 4 displays bilateral microphthalmia and was identified to have a 4-nt insertion in exon 5 resulting in a frame shift and premature stop codon.
Our screen identified mutations in 8% of the patients affected with A/M in our sample, which is higher than previously reported. All mutations identified in our study are predicted to result in a premature termination of the protein which is consistent with previous reports. Interestingly, in our study there appears to be a positive correlation between the more C-terminal position of mutation and the severity of the phenotype.
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