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V Raymond, S Dubois, MA Rodrigue, F Couture, G Côté, JL Anctil, P Blondeau, E Bergeron, MA Walter, J Morissette; Chromosomal Duplication at the IRID1 Locus on 6p25 Associated With Wide Variability of the Glaucoma Phenotypes . Invest. Ophthalmol. Vis. Sci. 2002;43(13):3016.
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Purpose: Glaucoma in a large French-Canadian family: pedigree BV-001, was mapped at the IRID1 locus on chromosome 6p25. No mutations were detected in three forkhead/winged-helix transcription factors: FOXC1, FOXQ1, and FOXF2, encoded within the disease locus. One microsatellite marker: UT7184 (D6S967), segregated as a three allele system in branches of the pedigree. We therefore assessed the possibility that a chromosomal duplication event may be the cause of the genetic defect. Methods: Thirty affected members of the family were reinvestigated and their ophthalmological records reviewed to update their glaucoma phenotypes. To develop new microsatellite markers, we constructed a high resolution physical map in silico. Saturation mapping with all available markers was then performed to test for duplication and to refine the disease interval. Results: The glaucoma phenotypes displayed wide phenotypic variability in the pedigree, ranging from asymptomatic anomalies of the eye to typical primary open-angle glaucoma (POAG). 89 BACs/PACs were mapped within the disease interval between D6S1600 and D6S344. Two novel SNPs positioned the disease interval centromeric to FOXQ1. A total of six microsatellites: 13J16-CA51, 668J24-GT, AFMb034ya5, UT7184 (D6S967), 118B18-CA7 and 279J9-C184, showed a three allele system in the pedigree. Segregation analysis of these markers confirmed the presence of a small 6p25 duplication in affected persons carrying the disease haplotype. The minimal duplicated region spanned at least 450 kb. Conclusion: Our data demonstrate that a duplication event at 6p25 may be associated with mild ocular abnormalities as well as with wide variability of the glaucoma phenotypes, including POAG. This duplication event may increase dosage of FOXC1 and/or FOXF2 and/or alter the transcriptional activity of these two genes by unrecognized positional effects.
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