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M Faucher, J-L Anctil, M-A Rodrigue, A Duchesne, D Bergeron, G Côté, R Arsenault, J Bergeron, J Morissette, V Raymond; Founder Mutations for Glaucoma Caused by TIGR/Myocilin in the Québec Population . Invest. Ophthalmol. Vis. Sci. 2002;43(13):3390.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: Mutations in the trabecular meshwork-inducible glucocorticoid response (TIGR) gene, also known as myocilin, cause 2 to 4% of sporadic and familial forms of primary open-angle glaucoma (POAG). Because POAG is insiduous, identifying mutation carriers will be invaluable to identify at-risk individuals. Populations with frequent founder effects, like the Québec population, offer unique advantages for such investigations. To optimize molecular testing for POAG, we determined the prevalence of myocilin mutations in glaucoma patients living in Québec. To assess the clinical features associated with these mutations, genotype/phenotype correlations were performed. To estimate the number of founders who contributed to the mutation pool, allelic signatures of mutations present in at least two individuals were constructed. Methods: TIGR/myocilin exons 1 and 3 were screened in 422 unrelated patients by automated DNA sequencing. Probands from 18 French-Canadian families showing autosomal dominant POAG were screened on all 3 exons. Ophthalmologic records were revised to assess phenotypes. Allelic signatures were established by genotyping 12 polymorphic markers over a 7.2 Mb area centered on myocilin. Results: Of the 21 variations detected, 9 were considered as glaucoma-causing mutations. Four mutations were detected in our 18 families; these were the previously reported G367R, Q368X, K423E, P481L variants. Among our 422 unrelated cases, 8 different mutations were observed in 17 individuals. Six of these have been previously reported: T293K, E352K, G367R, Q368X, K423E, A445V. Two new variations were considered as probable disease-causing mutations: an A427T substitution in the olfactomedin domain and an R126W in the leucine zipper. Five (5) mutations (T293K, G367R, Q368X, K423E, A445V) showed a single allelic signature. Only the R126W variation displayed 2 signatures. The most severe mutations were the G367R and K423E. Conclusion: Frequencies of myocilin mutations were estimated, respectively, at 4.0 and 22.2% in sporadic and familial glaucomas in the French-Canadian population. Although the number (9) of mutations was higher than expected for a founder population, founder effects were observed for 5 of the 6 mutations tested. Genetic testing for myocilin mutations should be offered to selected families. Members of the Québec Glaucoma Network also participated in this study.
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