Primary open angle glaucoma due to T377M MYOC: Population mapping of a Greek founder mutation in Northwestern Greece (original) (raw)
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Myocilin variations and familial glaucoma in Taxiarchis, a small Greek village
Molecular …, 2008
PurposeTo initiate a prospective study of glaucoma in a Greek village reported over 30 years ago to have several large families with primary open-angle glaucoma (POAG).MethodsA random group of 126 villagers from Taxiarchis, Greece was examined in the village community center. The detailed evaluation included ophthalmic and general history, measurement of blood pressure, intraocular pressure (IOP), and central corneal thickness (CCT) as well as evaluation of the optic nerve status.ResultsThe incidence of glaucoma approached 18% in this small isolated village. Myocilin variants were present in almost half of the individuals screened with Arg76Lys and Thr377Met being the most common finding (25% and 17%, respectively). Over half of the individuals with the Thr377Met mutation were diagnosed with glaucoma. Two of these patients were homozygous for the Thr377Met mutation. Three individuals with the Arg76Lys polymorphism had glaucoma; however, two of these individuals also had the Thr377Met mutation. Only two patients with pseudoexfoliation were identified.ConclusionsThe incidence of glaucoma and the Thr377Met MYOC mutation in this population is much higher than that reported for other European populations.
Molecular vision, 2011
Primary open angle glaucoma (POAG) is the most common type of glaucoma. Among the POAG genes identified so far, myocilin (MYOC) is the most frequently mutated gene in POAG patients worldwide. The MYOC Gln48His mutation is unique among Indian POAG patients. This mutation has not been observed in some populations within India and in other populations worldwide. The objectives of this work were to characterize and compare the mutation spectrum among POAG patients from two places of South India and identify the occurrence and prevalence of Gln48His mutation in our study populations. One hundred-one (101) POAG patients from Chennai, South India were recruited for the study. Earlier, 100 patients from the southernmost part of India, Kanyakumari district, were screened. MYOC was screened by polymerase chain reaction based single stand conformation polymorphism (PCR-SSCP) methodology. DNA sequencing of deviant samples was performed. Secondary structures of the proteins with amino acid seque...
Founder TIGR/myocilin mutations for glaucoma in the Quebec population
Human Molecular Genetics, 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 Qué bec 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 vision, 2007
Purpose: To retrospectively investigate the contribution of myocilin (MYOC) and optineurin (OPTN) sequence variations to adult-onset ocular hypertension (OHT) and primary open-angle glaucoma (POAG) in Spanish patients. Methods: The promoter region and the three exons of MYOC were analyzed by direct PCR DNA sequencing in 40 OHT and 110 POAG unrelated patients. We used 98 subjects in whom OHT or glaucoma had been ruled out as controls. We also screened the complete coding region of the OPTN gene (exons 4-16) in all subjects by single-stranded conformational polymorphisms (SSCPs). Results: We identified six common single nucleotide polymorphisms (SNPs) in the promoter region of MYOC (-1000C>G, -387C>T, -306G>A, -224T>C, -126T>C and -83G>A) and a polymorphic GT microsatellite . In addition, we detected four novel, rare DNA polymorphisms. None of these DNA sequence variations were associated with either OHT or POAG. We also found three (2.7%) POAG patients with MYOC pathogenic mutations. Two of these pathogenic mutations (Gln368Stop and Ala445Val) were previously described whereas the third (Tyr479His) was novel. Transient expression of the novel mutation in 293T cells supported its pathogenicity. Only two OPTN polymorphisms, which are not associated with the disease, were detected. Conclusions: Overall, our data show that in Spain a minority of adult-onset high-pressure POAG patients carry heterozygous disease-causing mutations in the MYOC gene and that OPTN is not involved in either OHT or POAG. 862 mutations in the olfactomedin-like domain, encoded by the third exon of MYOC, are present in 2.7% of sporadic POAG cases. Our data also enable us to rule out a role of OPTN sequence variations in the development of POAG in Spanish patients.
Myocilin analysis by DHPLC in French POAG patients: Increased prevalence of Q368X mutation
Human Mutation, 2003
Primary open-angle glaucoma (POAG) is a prevalent optic neuropathy with complex genetics. A small number of patients carry a mutation in the coding region of the myocilin (MYOC) gene. The nature and the frequency of these mutations, however, vary substantially, notably with the age at onset and the ethnic origin of the patients. Here, we showed that denaturing high performance liquid chromatography (DHPLC) is an appropriate method for screening carriers of MYOC mutations. We have applied the method to a group of 237 POAG patients and 108 control subjects from France. Mutations were found in 17 (7.5%) patients and in none of the controls. A single mutation, Q368X (c.1102C>T), accounted for the majority (12/17) of these mutations, corresponding to a frequency of 5% among POAG patients, the highest ever reported for this mutation. Furthermore, analysis of allelic associations at closely linked microsatellite markers indicated that most, if not all, patients inherited Q368X from a same ancestor. Five other patients carried four distinct mutations, including N480K (c.1440C>A) (2 cases), I499F (c.1495A>T), G367R (c.1099G>A) and T438I (c.1313C>T), which is reported here for the first time. Altogether, MYOC mutations in French patients were associated with a significantly increased intraocular pressure at diagnosis. In addition, the age at diagnosis of patients with a mutation other than Q368X was significantly younger than that of Q368X carriers or of patients with a normal MYOC. Based on these observations, a screening strategy of MYOC mutations in French POAG patients is briefly outlined.