Splicing Factor Polymorphisms, the Control of VEGF Isoforms and Association with Angiogenic Eye Disease

Autor: Amanda J. Churchill, J. Cherry, K. J. Williams, David O. Bates, James G. Carter, Steven J. Turner
Rok vydání: 2011
Předmět:
Adult
Male
Vascular Endothelial Growth Factor A
Genotype
Angiogenesis
Pilot Projects
Heteroduplex Analysis
Retinal Neovascularization
Biology
Polymerase Chain Reaction
Polymorphism
Single Nucleotide
Macular Degeneration
Young Adult
Cellular and Molecular Neuroscience
Splicing factor
chemistry.chemical_compound
Exon
Humans
Protein Isoforms
splice
Chromatography
High Pressure Liquid
Aged
Aged
80 and over
Diabetic Retinopathy
Serine-Arginine Splicing Factors
Alternative splicing
Nuclear Proteins
RNA-Binding Proteins
Exons
Middle Aged
Phosphoproteins
Molecular biology
Choroidal Neovascularization
Sensory Systems
Vascular endothelial growth factor
Alternative Splicing
Ophthalmology
chemistry
Case-Control Studies
RNA splicing
Female
Restriction fragment length polymorphism
Polymorphism
Restriction Fragment Length
Zdroj: Current Eye Research. 36:328-335
ISSN: 1460-2202
0271-3683
Popis: Alternative splicing of the last exon (exon 8) of vascular endothelial growth factor (VEGF) pre-mRNA is a key element in the balance of pro- and anti-angiogenic VEGF isoforms in exudative age-related macular degeneration (exAMD) and proliferative diabetic retinopathy (PDR). Three splicing factors, SRp40, ASF/SF2, and SRp55 are predicted to control alternative splicing by binding to exonic splice enhancers (ESE) in VEGF exon 8. This pilot study examines whether there is an association between angiogenic eye disease and splicing factor polymorphisms, and whether there are sequence variations in the alternative splice sites of the VEGF gene.A case:control pilot study comparing 163 individuals with angiogenic eye disease (94 exAMD and 69 PDR patients) with 95 age-matched controls. Splicing factor polymorphisms were genotyped by Restriction Fragment Length Polymorphism (RFLP) and sequencing, and the VEGF alternatively spliced region was assessed by denaturing High Performance Liquid Chromatography (dHPLC) using a transgenomic WAVE heteroduplex analyzer.No variations were observed in the alternatively spliced region of VEGF exon 8. ASF/SF2 polymorphisms showed no association with exAMD or PDR. For PDR, we observed a trend in SRp40 (rs6573908) where the 5136CC genotype was more frequent in controls (p = 0.0517) and a significant association of the SRp55 (rs2235611), where the 2994C allele was more common in the PDR group (p = 0.03). This remained strong, but not significant, after logistic regression for age, sex, disease type, and duration (p = 0.06).The lack of variation in the VEGF alternatively spliced region suggests the importance of sequence conservation in this area in maintaining the balance of pro- and anti-angiogenic VEGF isoforms. The link between PDR and the SRp55 2994 polymorphism suggests a disease-specific association between factors controlling VEGF splicing and ocular angiogenesis.
Databáze: OpenAIRE
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