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Human Molecular Genetics, 2002, Vol. 11, No. 18 2077-2090
© 2002 Oxford University Press

Founder TIGR/myocilin mutations for glaucoma in the Québec population

Mathieu Faucher1, Jean-Louis Anctil2,3, Marc-André Rodrigue1, Annie Duchesne1, Dan Bergeron3, Pierre Blondeau4, Gilles Côté2,3, Stéphane Dubois1, Josée Bergeron1, Rose Arseneault1, The Québec Glaucoma Network{dagger}, Jean Morissette1 and Vincent Raymond1,*

1Molecular Endocrinology and Oncology, Laval University Hospital (CHUL) Research Center, Québec City, QC, Canada G1V 4G2, 2Department of Ophthalmology, St-Sacrement Hospital, Québec City, QC, Canada G1S 4L8, 3Department of Ophthalmology, CHUL, Québec City, QC, Canada G1V 4G2 and 4Department of Ophthalmology, Sherbrooke University Hospital, Sherbrooke, QC, Canada J1H 5N4

Received March 18, 2002; Accepted July 1, 2002

Primary open-angle glaucoma (POAG) is a complex disorder characterized by a progressive and treatable degeneration of the optic nerve. TIGR/myocilin (MYOC) gene mutations are found in ~4% of all POAG patients. Populations with frequent founder effects, such as the French-Canadians, offer unique advantages to implement genetic testing for the disorder. To assess molecular diagnosis for POAG in this population, we determined the prevalence of TIGR/MYOC mutations in 384 unrelated glaucoma patients, 38 ocular hypertensive subjects and 18 affected families (180 patients). We further analyzed the clinical features associated with these variations. Nine coding sequence variants were defined as mutations causing mostly, but not exclusively, POAG. Four families segregated distinct mutations (Gly367Arg, Gln368Stop, Lys423Glu and Pro481Leu), while 14 unrelated glaucoma patients harbored six known mutations (Thr293Lys, Glu352Lys, Gly367Arg, Gln368Stop, Lys423Glu and Ala445Val) and two novel (Ala427Thr and Arg126Trp). The frequencies of these mutations were respectively 3.8% and 22.2% in the unrelated and family studies. The Gly367Arg and Lys423Glu variants caused the earliest ages at onset. When achievable, assement of relatives of unrelated mutation carriers showed the Arg126Trp and Gly367Arg to be familial. Characteristic allele signatures, indicative of specific founder effects, were observed for five of the six mutations conveyed by at least two patients. Recombination probability estimates suggested that the French-Canadian population had most probably inherited these six mutations from 7–10 Québec settlers. Our data demonstrated that genetic screening for TIGR/MYOC mutations should be offered to glaucoma families and to close relatives of unrelated patients aware of a family history for the disorder.

* To whom correspondence should be addressed at: Molecular Endocrinology and Oncology, Room T-367, CHUL Research Center, 2705 Laurier Blvd, Québec City, QC, Canada G1V 4G2. Tel: +1 4186542296; Fax: +1 4186542761; Email: vincent.raymond{at}crchul.ulaval.ca

{dagger} The Québec Glaucoma Network is: M. Amyot, A. Assalian, G.A. Balazsi, E. Bergeron, P. Brais, J. Carignan, M. Carrière, P. Cortin, C. Deschênes, B. Des Marchais, G. Doyon, Y. Dubé, J. Dugré, B. Dumas, J. Duperré, S. Fanous, C. Fortin, D. Gauthier, A. Goyette, C. Gravel, F. Guay, B.-J. Guertin, E.N. Hladky, N. Isabelle, O.P. Kasner, N. Labrecque, P. Laflamme, G. Lafond, S. Lahoud, G. Lalonde, J.-L. Lavallée, J.-P. Leblanc, M. Lesk, M. Malenfant, Y. Molgat, J. Morency, R. Morrissette, L. Robidas, J. Samson, G. Smith and P. Turcotte.


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