Myocilin variations and familial glaucoma in Taxiarchis, a small Greek village (original) (raw)
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Molecular vision, 2007
The aim of this study was to determine if there is a common founder for the Thr377Met myocilin mutation in primary open angle glaucoma (POAG) families with various ethnic backgrounds. Genomic DNA of 24 POAG-affected individuals from nine pedigrees with the Thr377Met mutation and 104 unaffected family members was genotyped with six microsatellite markers and four single nucleotide polymorphisms. The families were from Greece, India, Finland, the USA, and Australia. To assess the degree of linkage disequilibrium across MYOC in the general population we also investigated data generated from the HapMap consortium. Three distinct haplotypes associated with the Thr377Met myocilin mutation were identified. The families from the USA and Greece, as well as the three Australian families originating from Greece and the former Yugoslavian Republic of Macedonia had one common haplotype. Interestingly, however, HapMap data suggest that linkage disequilibrium across MYOC was not strong. The Thr377...
Analysis of myocilin mutations in 1703 glaucoma patients from five different populations
Human Molecular Genetics, 1999
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 (∼2-4%) in all populations, suggesting that the increased rate of glaucoma in Afri-can Americans is not due to a higher prevalence of myocilin mutations.
Archives of Ophthalmology, 2003
To investigate the prevalence of myocilin (MYOC) mutations in Italian families with glaucoma and to determine the relationship of these mutations to primary open-angle glaucoma (POAG), juvenile openangle glaucoma (JOAG), and pigmentary dispersion glaucoma. Methods: Twenty-six patients with POAG were selected based on a positive family history of glaucoma. All patients and 210 relatives had an accurate clinical characterization. Main Outcome Measure: Each index patient was screened by single-stranded conformational polymorphism analysis for mutations in the MYOC gene. Results: A MYOC gene mutation was found in 2 families. In one family, a previously reported p.K423E mutation was transmitted from the index patient with POAG to the 2 sons with JOAG. In the second family, a p.C25R change, affecting the signal peptide, was transmitted from the index patient with POAG to the son with JOAG, but not to the son with pigmentary dispersion glaucoma. Conclusions: Clinical characterization of 2 families with MYOC gene mutations indicates that POAG and JOAG are the 2 sides of a continuum phenotypical spectrum due to a common molecular defect. On the other hand, our results confirm the different origin of pigmentary dispersion glaucoma. Clinical Relevance: Because MYOC gene mutations may be responsible for a fraction (2 [8%] of 26) of families with POAG/JOAG, a molecular genetic diagnosis should be included in the management of patients with glaucoma.
Ophthalmology, 2016
To assess the difference in severity of disease in primary open-angle glaucoma (POAG) patients with a Myocilin (MYOC) disease-causing variant who presented through normal clinical pathways (Clinical cases) versus those who were examined following genetic testing (Genetic cases). Retrospective clinical and molecular study. Seventy-three MYOC mutation carriers identified through the Australian and New Zealand Registry of Advanced Glaucoma. Individuals were classified based on how they first presented to an ophthalmologist: Clinical cases were referred by their general practitioner or optometrist, and Genetic cases were referred following positive results from genetic testing for the previously identified familial MYOC variant (cascade genetic testing). All cases were then sub-classified into 4 groups (unaffected, glaucoma suspect, glaucoma, advanced glaucoma) according to the severity of disease at the time of their first examination by an ophthalmologist. Glaucoma clinical parameters...
Journal of Glaucoma, 2008
Purpose: To search for MYOC mutations in Peruvian primary open angle glaucoma (POAG) families. Patients and Methods: Two patients from each of the 11 POAG Peruvian families were screened for sequence variants in MYOC coding exons by conformational sensitive gel electrophoresis and sequencing was performed on the samples indicating probable sequence changes. Results: We detected 2 families bearing distortions of conformational sensitive gel electrophoresis indicating mutations. Sequencing of these samples revealed coding sequence changes. A native Andean descent family presented with a MYOC mutation, Asn480Lys (C-G at nucleotide 1440). This is different from the previously reported C-A change at nucleotide 1440 that causes Asn480Lys in 2 unrelated French and Dutch families with glaucoma of variable expressivity, and indicates a third independent event. A second family of admixed origin showed the presence of the known Arg76Lys polymorphism. Conclusions: In the study of MYOC variants in 11 POAG Peruvian families, we have found a family of ethnically admixed origin with polymorphism Arg76Lys and a family of Andean descent bearing a third event of the Asn480Lys, the MYOC mutation that has been reported in the highest number of POAG patients (>80 cases). Analysis of this family could contribute with information about disease manifestation, progression, and treatment response in the context of a distinct genetic background and also climatic, altitude, and socioeconomical conditions.
Molecular Vision, 2009
Purpose: To search for the genetic cause of juvenile open-angle glaucoma (JOAG) in a Caucasian family and to perform genotype/phenotype correlation studies in the kindred. Methods: Six members of a three-generation family originating from Uzbekistan and now living in the Middle East were recruited from one large clinic in Israel. Ophthalmologic investigations comprised of visual field assessments, intraocular pressure measurements, optic disc evaluation, and gonioscopy. Medical charts were obtained to date the onset of glaucoma and to evaluate aggressivity of the trait. We screened the myocilin gene (MYOC, OMIM 601652) by direct genomic sequencing of its three exons in all family members. Results: JOAG segregated as an autosomal dominant trait in four members of the family. The proband, a 14-year-old girl, had been diagnosed with juvenile open-angle glaucoma at 12 years old. Her mother, maternal aunt, and maternal grandfather all had JOAG that started at an early age. The disorder progressed rapidly even under optimal medical treatment, and all four patients had to undergo trabeculectomy. One missense mutation, Y371D (1111t→g, Tyr [Y] 371 Asp [D]), was identified. This mutation cosegregated with the disorder in all affected members and was absent in 200 Caucasian controls. The Y371D MYOC mutation has not been reported before. One cousin of the proband was a silent heterozygotic carrier of the mutation and was still asymptomatic at nine years of age. Conclusions: We identified a novel mutation (Y371D) in MYOC from a Caucasian family who presented with an aggressive form of JOAG that required early trabeculectomy. Genetic screening of the MYOC mutation was beneficial in predicting one asymptomatic heterozygotic carrier. Open-angle glaucoma (OAG) is the most frequent form of glaucoma, accounting for more than half of all cases [1]. The increased frequency of OAG among relatives of patients with this condition indicates that its susceptibility is influenced by genetic factors. Ocular hypertension (OHT) above 21 mmHg is considered a major risk factor for OAG. According to the age of onset and aggressivity, OAG is divided into juvenile-onset OAG (JOAG) and adult-onset OAG. When associated with OHT, this form of OAG is known as primary open-angle glaucoma (POAG). JOAG has an earlier age of onset, between 10 and 35 years of age, and usually presents with high intraocular pressure (IOP), visual field loss, and optic disc damage. JOAG often requires early surgical treatment [2].
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.
Variations in the Myocilin Gene in Patients With Open-Angle Glaucoma
Archives of Ophthalmology, 2002
To determine the prevalence and associated phenotype of myocilin (MYOC) coding sequence variations and a specific promoter polymorphism (MYOC.mt1) in patients with glaucoma and glaucoma suspects. Methods: A consecutive, unselected series of 779 patients (652 with open-angle glaucoma and 127 glaucoma suspects) were recruited from a university medical center and clinically characterized. The coding sequences of the MYOC gene and the MYOC.mt1 locus in the promoter region were screened for sequence variations. We determined the prevalence of MYOC coding sequence mutations and the MYOC.mt1 promoter polymorphism. We also compared the clinical features of individuals with and without mutations and the MYOC.mt1 promoter polymorphism. Results: Plausible disease-causing sequence variations (DCVs) in the MYOC gene were found in 3.0% of the entire group. Such variations were found in patients with most forms of open-angle glaucoma studied. Patients with primary open-angle glaucoma (POAG) who harbored coding sequence DCVs were clinically similar to patients without them. Patients who harbored the rarer allele of the MYOC.mt1 promoter polymorphism were no different in any measure of disease severity from those who harbored the more common allele. Conclusions: MYOC DCVs were found in approximately 3% of patients with glaucoma and glaucoma suspects. The 2 alleles of the MYOC.mt1 promoter polymorphism were equally distributed among patients with POAG and healthy control subjects. Patients with POAG who harbored the rarer allele of the MYOC.mt1 promoter polymorphism were no different from those with the more common variant in any measure of disease severity. Clinical Relevance: Testing for the MYOC.mt1 promoter polymorphism appears to be of no value in the evaluation of patients with glaucoma.
Molecular vision, 2012
Mutations in the myocilin gene (MYOC) are associated with primary open-angle glaucoma (POAG) in many different populations. This study represents the first large survey of MYOC mutations in an African American population. We recruited 529 African American subjects with POAG and 270 African American control subjects in this study. A complete eye examination and blood collection was performed in all study subjects. Genomic DNA was extracted. The entire coding sequence of MYOC was amplified and sequenced using the Sanger method. Identified MYOC variants were compared with previously reported MYOC mutations. We identified a total of 29 MYOC variants including six potential MYOC mutations. Two mutations (Thr209Asn and Leu215Gln) are novel and are found only in cases and no controls. We also identified four previously reported MYOC mutations in cases and no controls (Tyr453MetfsX11, Gln368X, Thr377Met, and Ser393Arg). The overall frequency of glaucoma-causing MYOC mutations in our African...