Identification of a novel mutation in the NTF4 gene that causes primary open-angle glaucoma in a Chinese population

Molecular Vision161640-1645MVEP

Analysis of conjunctival fibroblasts from a proband with Schnyder corneal dystrophy

Molecular Vision141277-128

Molecular analysis of CHX10 and MFRP in Chinese subjects with primary angle closure glaucoma and short axial length eyes

Molecular Vision141313-131

Lens status influences the association between CFH polymorphisms and age-related macular degeneration: Findings from two population-based studies in Singapore

10.1371/journal.pone.0119570PLoS ONE103e011957

SPARC Deficiency Results in Improved Surgical Survival in a Novel Mouse Model of Glaucoma Filtration Surgery

Glaucoma is a disease frequently associated with elevated intraocular pressure that can be alleviated by filtration surgery. However, the post-operative subconjunctival scarring response which blocks filtration efficiency is a major hurdle to the achievement of long-term surgical success. Current application of anti-proliferatives to modulate the scarring response is not ideal as these often give rise to sight-threatening complications. SPARC (secreted protein, acidic and rich in cysteine) is a matricellular protein involved in extracellular matrix (ECM) production and organization. In this study, we investigated post-operative surgical wound survival in an experimental glaucoma filtration model in SPARC-null mice. Loss of SPARC resulted in a marked (87.5%) surgical wound survival rate compared to 0% in wild-type (WT) counterparts. The larger SPARC-null wounds implied that aqueous filtration through the subconjunctival space was more efficient in comparison to WT wounds. The pronounced increase in both surgical survival and filtration efficiency was associated with a less collagenous ECM, smaller collagen fibril diameter, and a loosely-organized subconjunctival matrix in the SPARC-null wounds. In contrast, WT wounds exhibited a densely packed collagenous ECM with no evidence of filtration capacity. Immunolocalization assays confirmed the accumulation of ECM proteins in the WT but not in the SPARC-null wounds. The observations in vivo were corroborated by complementary data performed on WT and SPARC-null conjunctival fibroblasts in vitro. These findings indicate that depletion of SPARC bestows an inherent change in post-operative ECM remodeling to favor wound maintenance. The evidence presented in this report is strongly supportive for the targeting of SPARC to increase the success of glaucoma filtration surgery

Association of Common SIX6 Polymorphisms With Peripapillary Retinal Nerve Fiber Layer Thickness: The Singapore Chinese Eye Study

PURPOSE. Recently the common SIX6 missense variant rs33912345 was found to be highly associated with glaucoma. The aim of this study was to investigate the association between this SIX6 variant and peripapillary retinal nerve fiber layer (RNFL) thickness measured by spectral-domain optical coherence tomography (SD-OCT) in a population setting. METHODS. Study subjects were enrolled from the Singapore Chinese Eye Study (SCES), a population-based survey of Singaporean Chinese aged 40 years or older. Subjects underwent a comprehensive ocular examination. Spectral-domain OCT was used to measure RNFL thicknesses. Genotyping of SIX6 rs33912345 (Asn141His) was performed using HumanExome BeadChip. RESULTS. A total of 2129 eyes from 1243 SCES subjects (mean age: 55.0 6 7.4 years) with rs33912345 genotype data and SD-OCT images were included for the analysis. Of these, 26 eyes of 21 subjects had glaucoma. The frequency of rs33912345 risk variant C (His141) was 80% in the study subjects. Each rs33912345 C allele was associated with a decrease of 1.44 lm in RNFL thickness after adjusting for age, sex, genetic principal components, and axial length (P ¼ 0.001). These associations remained similar in 2096 nonglaucoma eyes in which each C allele was associated with a decrease of 1.39 lm in RNFL thickness (P ¼ 0.001). The strongest association was observed in the superior RNFL sector (a decrease of 2.83 lm per risk allele, P < 0.001) followed by the inferior RNFL sector (a decrease of 2.24 lm per risk allele, P ¼ 0.003), while the association did not reach significance in the nasal and temporal sectors. CONCLUSIONS. Nonglaucomatous individuals with the SIX6 missense variant have reduced RNFL thickness in regions known to be particularly affected in those with glaucoma. This may be the primary mechanism for increased risk of POAG in individuals who carry the SIX6 His141 risk variant

Characterization of Bietti crystalline dystrophy patients with CYP4V2 mutations

PURPOSE. Mutations of the CYP4V2 gene, a novel family member of the cytochrome P450 genes on chromosome 4q35, have recently been identified in patients with Bietti crystalline dystrophy (BCD). The aim of this study was to investigate the spectrum of mutations in this gene in BCD patients from Singapore, and to characterize their phenotype. METHODS. Nine patients with BCD from six families were recruited into the study. The 11 exons of the CYP4V2 gene were amplified from genomic DNA of patients by polymerase chain reaction and then sequenced. Detailed characterization of the patients' phenotype was performed with fundal photography, visual field testing, fundal fluorescein angiography, and electroretinography (ERG). RESULTS. Three pathogenic mutations were identified; two mutations, S482X and K386T, were novel and found in three patients. The third mutation, a previously identified 15-bp deletion that included the 3Ј splice site for exon 7, was found in all nine patients, with six patients carrying the deletion in the homozygous state. Haplotype analysis in patients and controls indicated a founder effect for this deletion mutation in exon 7. Clinical heterogeneity was present in the patients. Compound heterozygotes for the deletion in exon 7 seemed to have more severe disease compared to patients homozygous for the deletion. There was good correlation between clinical stage of disease and ERG changes, but age did not correlate with disease severity. CONCLUSIONS. This study identified novel mutations in the CYP4V2 gene as a cause of BCD. A high carrier frequency for the 15-bp deletion in exon 7 may exist in the Singapore population. Phenotype characterization showed clinical heterogeneity, and age did not correlate with disease severity. (Invest Ophthalmol Vis Sci. 2005;46:3812-3816

Trans-ancestry genome-wide association study identifies 12 genetic loci influencing blood pressure and implicates a role for DNA methylation

10.1038/ng.3405Nature Genetics47111282-1293GUSTO (Growing up towards Healthy Outcomes

Author Correction: Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases.

Emmanuelle Souzeau, who contributed to analysis of data, was inadvertently omitted from the author list in the originally published version of this Article. This has now been corrected in both the PDF and HTML versions of the Article