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Role of MYOC and OPTN sequence variations in Spanish patients with primary open-angle glaucoma.

ABSTRACT: 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.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).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 (-339(GT)11-19). 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.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.

SUBMITTER: Lopez-Martinez F

PROVIDER: S-EPMC2770203 | biostudies-literature | 2007 Jun

REPOSITORIES: biostudies-literature

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Role of MYOC and OPTN sequence variations in Spanish patients with primary open-angle glaucoma.

Lopez-Martinez Francisco F Lopez-Garrido Maria-Pilar MP Sanchez-Sanchez Francisco F Campos-Mollo Ezequiel E Coca-Prados Miguel M Escribano Julio J

Molecular vision 20070614

<h4>Purpose</h4>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.<h4>Methods</h4>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 th ...[more]

PMID: 17615537

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Project description:PURPOSE: Mutations in the CYP1B1, MYOC, OPTN, and WDR36 genes result in glaucoma. Given its expression in the optic nerve, it is likely a mutation in the OPTC gene is also involved in initiating glaucoma. This study was designed to evaluate the involvement of the CYP1B1, MYOC, OPTN, and OPTC genes in the etiology of adult-onset primary open-angle glaucoma (POAG) found in 251 Indian patients. METHODS: Blood samples were obtained from individuals for DNA isolation. A combination of polymerase chain reaction-single strand conformation polymorphism, allele-specific PCR, and DNA sequencing techniques were used to detect mutations in four genes. Four microsatellite markers from the CYP1B1 candidate region and three intragenic CYP1B1 single nucleotide polymorphisms (SNPs) were used to determine the origin of the most common CYP1B1 mutations. RESULTS: Three previously known mutations (Pro193Leu, Glu229Lys, and Arg368His) and one novel (Met292Lys) mutation were found in the CYP1B1 gene. Frequencies of the most common mutations, Glu229Lys and Arg368His, in patients were 5.12% and 3.98%, respectively. The Glu229Lys and Arg368His mutations were also found in normal controls at frequencies of 5% and 2%, respectively, suggesting that these mutations might be polymorphic variants in our population. The absence of allele sharing for D2S177, D2S1346, D2S2974, and D2S2331 markers and three intragenic CYP1B1 SNPs in patients suggested multiple origins for the Glu229Lys and Arg368His variants. Two of 251 (0.8%) patients had the Gln48His mutation in MYOC. There was no difference in the frequency of a MYOC -83G>A promoter polymorphism between patients and controls. A novel OPTN mutation, Thr202Arg, was detected in one of 251 (0.4%) patients. The OPTN variant Met98Lys was detected in similar frequencies in patients and controls. No mutation was detected in OPTC. Taken together, 3.59% (9/251) of our POAG patients had mutations in the CYP1B1, MYOC, and OPTN genes. CONCLUSIONS: This is the first report to document the involvement of the CYP1B1, MYOC, and OPTN genes in the etiology of POAG in the same set of Indian patients. Our study shows that mutations in these genes are rare in Indian POAG patients.

Project description:AIM:To report the first discovery of Ser341Pro myocilin (MYOC) variant in Korea and analyze its clinical characteristics and genetic significance. METHODS:Ten family members from three generations participated in this study and received the thorough ophthalmologic examination. Focused exome sequencing on a proband was performed to confirm the target mutations (MYOC c.1021T>C) in the family members, and the direct sequencing was conducted. Variant was analyzed according to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) guidelines. RESULTS:A nucleotide change from thymine to cytosine at c.1021T>C was found in eight family members. Three members diagnosed with primary open angle glaucoma (POAG) were characterized by severe clinical presentations, high intraocular pressure, and poor response to medical treatment (100% of the patient required filtering surgery). On variant analysis by ACMG/AMP guidelines, Ser341Pro is not found in normal population. Multiple computational predictive programs support a deleterious effect of Ser341Pro variant (PolyPhen 2, SIFT, Mutation Taster). Ser341Pro could be involved in moderate (PM) and supporting (PP) criteria (PM1, PM2, PP2, PP3). Combining the criteria, Ser341Pro has a combination of 2 moderate (PM1+PM2) and 2 supporting (PP2+PP3) criteria, which is interpreted to "likely pathogenic". CONCLUSION:The Ser341Pro variant is correlated with severe phenotype of POAG. There are similar clinical aspects to previous studies: autosomal dominant inheritance, incomplete penetrance (62.50% and 66.67%), and proportion of patients requiring trabeculectomy (100% in both study). According to ACMG/AMP guidelines and the previous basic researches, the Ser341Pro variant had a "strong evidence of pathogenicity (PS3)" and then it could be interpreted to "pathogenic (PS3, PM1, PM2, PP2, PP3)". Additionally, Ser341Pro variant can be reported as "c.1021T>C (p.Ser341Pro), likely pathogenic, POAG, autosomal dominant" according to guideline.

Dataset Information

Role of MYOC and OPTN sequence variations in Spanish patients with primary open-angle glaucoma.

Publications

Role of MYOC and OPTN sequence variations in Spanish patients with primary open-angle glaucoma.

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