Novel and known MYOC exon 3 mutations in an admixed Peruvian primary open-angle glaucoma population.

PURPOSE: The aim of this study was to characterize a representative sample of the Peruvian population suffering open-angle glaucoma (OAG) with respect to the myocilin gene (MYOC) mutations, glaucoma phenotype, and ancestry for future glaucoma risk assessment. METHODS: DNA samples from 414 unrelated Peruvian subjects, including 205 open-angle glaucoma cases (10 juvenile glaucoma [JOAG], 19 normal-tension glaucoma [NTG], and 176 POAG) and 209 randomly sampled controls, were screened for nucleotide changes in MYOC exon 3 by conformational sensitive gel electrophoresis (CSGE) and mutation screening. RESULTS: We identified a probable causative novel MYOC missense mutation, Gly326Ser, in one POAG case and found a consistent genotype-phenotype correlation in eight of his relatives. We also found the known causative MYOC mutation Trp286Arg in one JOAG case and one POAG case. A known causative single base MYOC deletion, T1357, was found in one POAG case. Two previously reported silent polymorphisms, Thr325Thr and Tyr347Tyr, were found in both the case and the control populations. A novel missense variant, Met476Arg, was identified in two unrelated controls. CONCLUSIONS: The screening of exon 3 of MYOC in a representative sample of 205 independent POAG patients from Peru and 209 matched controls identified novel and previously reported mutations (both pathogenic and nonpathogenic) from other global regions. These results reflect the complex admixture of Amerindian and Old World ancestry in urban populations of Latin America, in general, and in Peru, in particular. It will be important to gather information about the ancestral origin of MYOC and other POAG gene mutations to develop screening panels and risk assessment for POAG in Peru.

Trabeculectomy with Suprachoroidal Derivation in Eyes with Uncontrolled Glaucoma: A Case Series with a 24-Month Follow-up.

INTRODUCTION: The aim of this study was to evaluate the efficacy of trabeculectomy with suprachoroidal derivation in eyes with uncontrolled glaucoma after a 24-month follow-up period. METHODS: This was a prospective uncontrolled non-randomized case series. All patients scheduled for a trabeculectomy due to uncontrolled glaucoma at the "Instituto de Glaucoma y Catarata" (Lima, Peru) between 2011 and 2014 were included. Thee patients underwent trabeculectomy with mitomycin C and suprachoroidal derivation with two autologous scleral flaps. Postsurgical follow-up visits took place on day 1, and at 1, 6, 12, 18 and 24 months. Best corrected visual acuity (BCVA), intraocular pressure (IOP) and complications at each control were registered. Main outcome measures were IOP reduction, number of glaucoma medications and complication rate. Postoperative IOP of > 21 mmHg, < 5 mmHg, additional glaucoma surgery or severe complications were considered as indications of failure. RESULTS: Thirty-three participants (41 eyes) were included in the study, of whom 27 (81.82%) (31 eyes [75.61%]) finished the 24 months of follow-up. At the end of the follow-up, mean IOP had decreased by 11.29 ± 9.32 mmHg (p < 0.001), and glaucoma medication usage in 25 (25/31; 80.65%) eyes had stopped. Ten (10/41; 24.39%) patients complained of blurred vision, and 15 (15/41; 36.59%) patients referred to foreign body sensation the first day after surgery; both sensations resolved spontaneously after 1 week in all cases. No failures, significant changes in BCVA (p = 0.387) or severe complications were found. CONCLUSIONS: In this case series, trabeculectomy with suprachoroidal derivation exhibited high efficacy and safety after a 24-month follow-up. A larger sample with a control group is needed to confirm our initial findings.

Recurrent Myocilin Asn480Lys glaucoma causative mutation arises de novo in a family of Andean descent.

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.

Variation in optineurin (OPTN) allele frequencies between and within populations.

PURPOSE: To evaluate the extent to which mutations in the optineurin (OPTN) glaucoma gene play a role in glaucoma in different populations. METHODS: Case-controlled study of OPTN sequence variants in individuals with or without glaucoma in populations of different ancestral origins and evaluate previous OPTN reports. We analyzed 314 subjects with African, Asian, Caucasian and Hispanic ancestries included 229 cases of primary open-angle glaucoma, 51 cases of juvenile-onset open-angle glaucoma, 33 cases of normal tension glaucoma, and 371 controls. Polymerase chain reaction-amplified OPTN coding exons were resequenced and case frequencies were compared to frequencies in controls matched for ancestry. RESULTS: The E50K sequence variant was identified in one individual from Chile with normal tension glaucoma, and the 691_692insAG variant was found in one Ashkenazi Jewish individual from Russia. The R545Q variant was found in two Asian individuals with primary open-angle glaucoma; one of Filipino ancestry and one of Korean ancestry. In addition to presenting OPTN allele frequencies for Caucasian and Asian populations that have been the subject of previous reports, we also present information for populations of Hispanic and black African ancestries. CONCLUSIONS: Our study contributes additional evidence to support the previously reported association of the OPTN E50K mutation with glaucoma. After finding an additional 691_692insAG OPTN variant, we can still only conclude that this variant is rare. Combined analysis of our data with data from more than a dozen other studies indicates no association of R545Q with glaucoma in most populations. Those same studies disagree in their conclusions regarding the role of M98K in glaucoma. Our analysis of the combined data provides statistically significant evidence of association of M98K with normal tension glaucoma in Asian populations, but not in Caucasian populations; however, the validity of this conclusion is questionable because of large differences in allele frequencies between and within populations. It is currently not possible to tell how much of the underlying cause of the allele frequency difference is attributable to demographic, technical, or ascertainment differences among the studies.

Genome-wide association study identifies five new susceptibility loci for primary angle closure glaucoma.

Primary angle closure glaucoma (PACG) is a major cause of blindness worldwide. We conducted a genome-wide association study (GWAS) followed by replication in a combined total of 10,503 PACG cases and 29,567 controls drawn from 24 countries across Asia, Australia, Europe, North America, and South America. We observed significant evidence of disease association at five new genetic loci upon meta-analysis of all patient collections. These loci are at EPDR1 rs3816415 (odds ratio (OR) = 1.24, P = 5.94 × 10(-15)), CHAT rs1258267 (OR = 1.22, P = 2.85 × 10(-16)), GLIS3 rs736893 (OR = 1.18, P = 1.43 × 10(-14)), FERMT2 rs7494379 (OR = 1.14, P = 3.43 × 10(-11)), and DPM2-FAM102A rs3739821 (OR = 1.15, P = 8.32 × 10(-12)). We also confirmed significant association at three previously described loci (P < 5 × 10(-8) for each sentinel SNP at PLEKHA7, COL11A1, and PCMTD1-ST18), providing new insights into the biology of PACG.

Estudio genético-molecular de glaucoma primario de ángulo abierto en una familia peruana sugiere nuevo locus para glaucoma / Molecular genetic study of primary open-angle glaucoma in a Peruvian family suggests new locus for glaucoma

La contribución de la genética molecular al estudio de enfermedades hereditarias es innegable. Existen numerosos reportes de genes responsables de enfermedades hereditarios que facilitan al diagnóstico, pronóstico y también la posibilidad de terapias cuando se conoce el defecto molecular involucrado. Además, hay cientos de enfermedades en donde la identificación del defecto molecular está cerca porque se han localizado regiones cromosómicas específicas en donde se sabe, residen genes responsables de estas enfermedades. Una estrategia es precisamente, refinar paulatinamente esta ubicación a fin de caracterizar el defecto molecular, todo ello con miras a establecer posibles tratamientos. El glaucoma primario de ángulo abierto (GPAA) es una enfermedad hereditaria que puede llevar a la ceguera si no hay un diagnóstico temprano y tratamiento. Hasta ahora, se conocen seis genes que son responsables de la enfermedad y nuestro grupo está trabajando en la caracterización genético-molecular de GPAA en familias peruana usando marcadores microsatélites a fin de caracterizar su asociación con los seis grupos de marcadores. Reportamos el hallazgo de una familia peruana afectada con GPAA que no segrega con ninguno de los marcadores microsatélites de las diferentes regiones cromosómicas que se sabe están asociadas con la enfermedad. Esto apunto a la existencia de un nuevo locus responsable del GPAA en esta familia.

Molecular genetic studies are increasingly important for the study of heredity diseases and its contribution is well known. There are several hundred reports of genes responsible of genetic diseases that help in diagnosis, prognosis and possible treatment when the molecular defect is known. Primary open-angle glaucoma (POAG) is a hereditary disease that can lead to blindness if untreated. There are six known loci that can cause it and or group is working on the characterization of Peruvian families using microsatellite markers located on regions known to harbor glaucoma genes. We found a Peruvian family that does not segregate with any of the markers located near known glaucoma loci. This would account for a new locus responsible for the disease in this family.

Mapeo cromosómico y refinamiento de la localización de un gen de glaucoma en 2cen-2q12 en una familia peruana: avances hacia la identificación del gen GLC1B / Chromosome mapping and refinement of the location of a gene of glaucoma in 2cen-2q12 in a Peruvian family: advances towards to identification of the gene GLC1B

La genética molecular es una herramienta que está revelando los genes responsables de enfermedades hereditarias, incluso algunos de ellos han sido ya identificados y caracterizados. En otros genes la identificación está más cercana porque se les ha localizado (mapeado) en regiones cromosómicas específicas donde su búsqueda se refina paulatinamente. El glaucoma primario de ángulo abierto (GPAA) es una anomalía hereditaria que sin tratamiento puede llevar a la ceguera, pero si es detectado tempranamente, permite preservar la visión. Hay 6 loci (genes) para GPAA: GLC1A localizado en la región cromosómica 1q24.3-q25.2, GLC1B (2cen-q13), GLC1C (3q21-q24), GLC1D (8q23), GLC1E (10p14-p15) y GLC1F (7q35-q36). Hemos estudiado varias familias peruanas con GPAA para analizar su asociación con marcadores en las regiones mencionadas. Una familia de Chincha ha mostrado cosegregación con marcadores de 2cen-q13 indicando que el glaucoma en esta familia pertenece a GLC1B. Un análisis posterior con más familiares nos revela una recombinación que restringe la región crítica para GLC1B a 2cen-q12. Esta reducción en términos genómicos descarta varios millones de nucleótidos y muchos genes de 2q13 facilitando la identificación de GLC1B.

Molecular genetics is an important tool to elucidate the cause of hereditary diseases. One of the strategies used in this type of studies, is to map the gene responsible of the disease to a specific chromosome region. This has helped in the characterization of some genes, but others remain to be identified. Primau Open Angle Glaucoma (POAG) is a hereditary disease that can lead to blindness if untreated. There are six loci for POAG: GLClA on chromosome region lq24.3-q25.2, GLClB (2cenq13), GLClC (3q21-q24), GLClD (8q23), GLClE (10p14p15) y GLClF (7q35-q36). In a study of several POAG Peruvian families we have characterized one that cosegregates with markers of chromosome 2 corresponding to a new reported family for GLCIB located at 2cen-2q13. One additional individual in the family reveals genetic recombination that refines the position to a smaller region in 2cen-q12 eliminating several millions of base pairs in the search of the GLCIB gene.