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      Correlation between genotype and phenotype in primary open angle glaucoma of Brazilian families with mutations in exon 3 of the TIGR/MYOC gene Translated title: Correlação entre genótipo-fenótipo em famílias brasileiras com glaucoma primário de ângulo aberto determinada por mutações no exon 3 do gene TIGR/MYOC

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          Abstract

          PURPOSE: To investigate the phenotype of primary open-angle glaucoma (POAG) in Brazilian families with mutation in exon 3 of TIGR/MYOC. METHODS: Seventy-eight POAG patients with a positive family history and eighteen unrelated patients with POAG were screened by automated DNA sequencing for mutations in exon 3 of the TIGR/MYOC gene. The pedigrees of POAG patients with mutations that lead to amino acid change were built. All available relatives of the index cases were also examined and genotyped by sequencing. RESULTS: Four sequence variants were identified in exon 3 of the TIGR/MYOC gene (Tyr347Tyr, Pro370Pro, Lys398Arg and Cys433Arg) from the 96 initially screened patients. The Lys398Arg mutation was previously described as a polymorphism and in our study did not segregate with POAG. The most prevalent mutation was Cys433Arg, affecting 3 index cases (3.1% or 3/96). In two different families, 8/56 subjects presented Cys433Arg mutation and had POAG, 5/56 had ocular hypertension and 8/56 had no disease manifestation. POAG patients had a median age at diagnosis of 43.25 yr (17-58 yr) and intraocular pressure (IOP) with a mean of 36.3 ± 3.8mmHg for the right eye and 37.6 ± 9.75 mmHg for the left eye. The group of patients with Cys433Arg mutation had significantly higher IOP (p<0.0007) and vertical cup/disc ratio when compared to the patients without mutation (p<0.023). CONCLUSIONS: Cys433Arg mutation in exon 3 of the TIGR/MYOC gene is related to juvenile-onset POAG (J-POAG) in Brazilian families and autosomal dominant inheritance. The phenotype of this mutation is characterized by varied ages at diagnosis, causing J-POAG and late-onset POAG, associated with high IOP.

          Translated abstract

          OBJETIVO: Identificar nos representantes de famílias com glaucoma primário de ângulo aberto (GPAA) mutações no exon 3 do gene TIGR/MYOC e avaliar a expressão fenotípica associada às mutações encontradas em seus respectivos núcleos familiares. MÉTODOS: Setenta e oito pacientes (81,2%), com pelo menos um representante na família com GPAA, e dezoito pacientes (18,7%) com glaucoma esporádico tiveram o exon 3, do gene TIGR/MYOC, submetido a seqüenciamento automático para identificação de mutações. Os pacientes, com mutação não silenciosa identificadas nesta triagem inicial, tiveram os heredogramas de suas famílias construídos. Todos os seus familiares disponíveis foram submetidos a exame oftalmológico e seqüenciamento automático do exon 3, do gene TIGR/MYOC. RESULTADOS: Foram identificados quatro tipos de variações na seqüência do exon 3 do TIGR/MYOC (Cys433Arg, Pro370Pro, Lys398Arg e Tyr347Tyr) nos 96 pacientes inicialmente estudados. A mutação Lys398Arg previamente descrita como polimorfismo não segregou com a doença na família estudada. A mutação Cys433Arg foi a mais prevalente afetando 3,1% da amostra inicial (3/96). Em duas diferentes famílias (56 integrantes disponíveis para exame), 8/56 carregavam a mutação Cys433Arg e tinham GPAA, 5/56 com mutação eram hipertensos oculares e 8/56 com mutação não apresentavam manifestações da doença. Pacientes com GPAA apresentaram mediana de idade de diagnóstico de 43,25 anos, variando entre 17-58, e média de pressão intra-ocular (PIO) de 36,3±3,8 mmHg para olho direito e 37,6±9,75 mmHg para olho esquerdo. O grupo com a mutação Cys433Arg apresentou PIO significantemente mais elevada (p<0,0007) e relação escavação/disco vertical mais comprometida (p<0,023) que o grupo de pacientes sem mutação. CONCLUSÃO: A mutação no exon 3 do gene TIGR/MYOC associa-se com famílias brasileiras portadoras de GPAA de início precoce. O fenótipo desta mutação é caracterizado por variável idade de diagnóstico, causando GPAA-juvenil e GPAA do adulto, PIO bastante elevada, de difícil controle, freqüentemente levando a grave comprometimento visual.

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          Adult-onset primary open-angle glaucoma caused by mutations in optineurin.

          Primary open-angle glaucoma (POAG) affects 33 million individuals worldwide and is a leading cause of blindness. In a study of 54 families with autosomal dominantly inherited adult-onset POAG, we identified the causative gene on chromosome 10p14 and designated it OPTN (for "optineurin"). Sequence alterations in OPTN were found in 16.7% of families with hereditary POAG, including individuals with normal intraocular pressure. The OPTN gene codes for a conserved 66-kilodalton protein of unknown function that has been implicated in the tumor necrosis factor-alpha signaling pathway and that interacts with diverse proteins including Huntingtin, Ras-associated protein RAB8, and transcription factor IIIA. Optineurin is expressed in trabecular meshwork, nonpigmented ciliary epithelium, retina, and brain, and we speculate that it plays a neuroprotective role.
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            Identification of a gene that causes primary open angle glaucoma.

            Glaucoma is a major cause of blindness and is characterized by progressive degeneration of the optic nerve and is usually associated with elevated intraocular pressure. Analyses of sequence tagged site (STS) content and haplotype sharing between families affected with chromosome 1q-linked open angle glaucoma (GLC1A) were used to prioritize candidate genes for mutation screening. A gene encoding a trabecular meshwork protein (TIGR) mapped to the narrowest disease interval by STS content and radiation hybrid mapping. Thirteen glaucoma patients were found to have one of three mutations in this gene (3.9 percent of the population studied). One of these mutations was also found in a control individual (0.2 percent). Identification of these mutations will aid in early diagnosis, which is essential for optimal application of existing therapies.
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              Analysis of myocilin mutations in 1703 glaucoma patients from five different populations.

              A glaucoma locus, GLC1A, was identified previously on chromosome 1q. A gene within this locus (encoding the protein myocilin) subsequently was shown to harbor mutations in 2-4% of primary open angle glaucoma patients. A total of 1703 patients was screened from five different populations representing three racial groups. There were 1284 patients from primarily Caucasian populations in Iowa (727), Australia (390) and Canada (167). A group of 312 African American patients was from New York City and 107 Asian patients from Japan. Overall, 61 different myocilin sequence variations were identified. Of the 61 variations, 21 were judged to be probable disease-causing mutations. The number of probands found to harbor such mutations in each population was: Iowa 31/727 (4.3%), African Americans from New York City 8/312 (2.6%), Japan 3/107 (2.8%), Canada 5/167 (3.0%), Australia 11/390 (2.8%) and overall 58/1703 (3. 4%). Overall, 16 (76%) of 21 mutations were found in only one population. The most common mutation observed, Gln368Stop, was found in 27/1703 (1.6%) glaucoma probands and was found at least once in all groups except the Japanese. Studies of genetic markers flanking the myocilin gene suggest that most cases of the Gln368Stop mutations are descended from a common founder. Although the specific mutations found in each of the five populations were different, the overall frequency of myocilin mutations was similar ( approximately 2-4%) in all populations, suggesting that the increased rate of glaucoma in African Americans is not due to a higher prevalence of myocilin mutations.
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                Author and article information

                Journal
                abo
                Arquivos Brasileiros de Oftalmologia
                Arq. Bras. Oftalmol.
                Conselho Brasileiro de Oftalmologia (São Paulo, SP, Brazil )
                0004-2749
                1678-2925
                June 2006
                : 69
                : 3
                : 289-297
                Affiliations
                [02] São Paulo SP orgnameUSP orgdiv1Hospital das Clínicas orgdiv2Clínica Oftalmológica Brasil
                [03] São Paulo SP orgnameUSP orgdiv1Faculdade de Medicina orgdiv2Laboratório de Investigação Médica Brasil
                [01] São Paulo SP orgnameUniversidade de São Paulo orgdiv1Faculdade de Medicina Brasil
                Article
                S0004-27492006000300002 S0004-2749(06)06900302
                10.1590/S0004-27492006000300002
                65a35db3-d0ab-4afe-a2c6-ca1ae4dceedd

                This work is licensed under a Creative Commons Attribution 4.0 International License.

                History
                : 13 September 2005
                : 01 June 2005
                Page count
                Figures: 0, Tables: 0, Equations: 0, References: 31, Pages: 9
                Product

                SciELO Brazil

                Categories
                Original Article

                Glaucoma, open-angle,Triagem genética,Mutação,Genótipo,Fenótipo,Genes,Glaucoma de ângulo aberto,Brazil,Genetic screening,Mutation,Genotype,Genes, Phenotype,Brasil

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