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P. Bitoun, D. Bremond–Gignac, D. Even, K. Frees, B. Benzacken, L. Benzacken, J.C. Murray, E. Semina; Identification of PAX6 and FOXE3 mutations in a sample of congenital cataracts and aniridia patients. . Invest. Ophthalmol. Vis. Sci. 2004;45(13):2463.
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Purpose: To identify frequency and spectrum of gene mutations causing congenital cataract (CC) and aniridia. Methods: Patients with CC or aniridia consented to the study to provide a sample for genetic analysis. DNA was analyzed for genes associated with autosomal dominant CC and/or aniridia phenotype by direct nucleotide sequencing of gene–specific PCR products. Results:A total of 50 samples from 33 unrelated families have been studied. Phenotypes included isolated CC (26), aniridia (5), aniridia with CC (1) and WAGR syndrome with CC (1). The complete coding region and, in some cases, additional functional genomic sequences were examined for the following genes: PITX2, PITX3, FOXE3 and PAX6, associated with anterior segment anomaly/cataract human phenotypes.4 families were found to have putative disease–causing mutations. 1 family with autosomal dominant anterior subcapsular lens opacities showed G to C substitution in FOXE3 that resulted in a change of termination codon into a serine codon and extension of FOXE3 protein for 72 additional aa. 2 families with aniridia, 1 isolated and 1 with CC, demonstrated C to T substitutions changing codons for arginine (CGA) at positions 203 and 240 to the termination codon (TGA) resulting in premature truncation of PAX6 protein. 1 family with aniridia, myopia and nystagmus demonstrated a combination of FOXE3 and PAX6 mutations: PAX6 mutation resulted in premature termination of protein and was identical to that found in a family with aniridia and congenital cataracts (R240STOP); the FOXE3 mutation represented 9 nucleotide insertion into coding region that resulted in a 3 aa in–frame insertion into protein. The significance of the second FOXE3 mutation is not obvious as PAX6 mutation is sufficient to cause aniridia. Additional variants identified need further investigation. Conclusions: Aniridia and CC have a strong genetic component. PAX6 the major gene for aniridia with 50% of aniridia (3 out of 6 in our sample) being due to PAX6 mutation. CC has multiple genetic causes. In our sample, 7% of congenital cataract appears to be due to mutations in PAX6 and FOXE3 genes. No putative disease–causing mutations were identified in PITX2 and PITX3 genes in our sample.
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