Founder TIGR/myocilin mutations for glaucoma in the Québec population.
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 approximately 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, assessment 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.
Molecular Endocrinology and Oncology, Laval University Hospital (CHUL) Research Center, Québec City, QC, Canada G1V 4G2.
Mathieu
M
Faucher
Jean-Louis
JL
Anctil
Marc-André
MA
Rodrigue
Annie
A
Duchesne
Dan
D
Bergeron
Pierre
P
Blondeau
Gilles
G
Côté
Stéphane
S
Dubois
Josée
J
Bergeron
Rose
R
Arseneault
Jean
J
Morissette
Vincent
V
Raymond
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019943:Amino Acid Substitution; D002648:Child; D003598:Cytoskeletal Proteins; D005136:Eye Proteins / Q000235:genetics*; D005260:Female; D018703:Founder Effect; D005838:Genotype; D005902:Glaucoma, Open-Angle / Q000235:genetics*; D006023:Glycoproteins / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D011110:Polymorphism, Genetic; D011792:Quebec; D044465:White People; D000099179:Myocilin
D003598:Cytoskeletal Proteins; D005136:Eye Proteins; D006023:Glycoproteins; D000099179:Myocilin