MicroRNA相关单核苷酸多态性与眼部疾病关系的研究进展

MicroRNA是一类长为18~25 nt的小分子非编码RNA,它们通过与靶mRNA的3’UTR区结合来调控基因表达。单核苷酸多态性与眼部疾病的发生发展密切相关。近年来研究发现,microRNA相关单核苷酸多态性与某些眼部疾病的发生、发展和预后有关联,这些单核苷酸多态性可发生在microRNA基因(pri-、pre-和mature-miRNA)序列中,也可发生在与靶基因mRNA的结合位点。本文就此研究进展作一简要综述。     

MicroRNA在葡萄膜炎发病过程中的调控作用研究进展

微小ＲＮＡ（ｍｉｃｒｏＲＮＡ,ｍｉＲＮＡ）是生物体内源性的、约１９～２４个核苷酸构成的非编码单链ＲＮＡ分子。ｍｉＲＮＡ可以与靶标ｍＲＮＡ基因的３’端非编码区域（３’ＵＴＲ）互补结合,从而在转录后水平负调控靶基因的表达。ｍｉＲＮＡ通过降解靶基因或者抑制转录后的翻译水平,进而影响细胞的分化、增殖和凋亡,并在生物生长发育和疾病发生发展过程中发挥重要的调节作用。近年来研究表明,ｍｉＲＮＡ在葡萄膜炎的发生发展进程中同样发挥重要的调控作用。本文就ｍｉＲＮＡ在葡萄膜炎发生发展过程中的调控作用作一综述,为深入研究葡萄膜炎的发病机理提供新思路。     

MicroRNA与白内障相关性的研究进展

ＭｉｃｒｏＲＮＡ是一类高度保守,非编码的小分子ＲＮＡ,长２１～２５个核苷酸,它们通过与靶ｍＲＮＡ的３’端非编码区结合,促使ｍＲＮＡ降解或抑制来调节靶基因的表达,在细胞的分化、增生、凋亡、个体发育以及机体代谢中都具有重要的作用。白内障是全球首位的致盲性眼病。研究表明,ＭｉｃｒｏＲＮＡ在白内障发生发展过程中起到了重要的调控作用。本文就ＭｉｃｒｏＲＮＡ在晶状体中的表达,以及在白内障发生发展过程中作用机制的最新研究进展进行综述。     

microRNA与眼部疾病的相关性

microRNA是近年来发现的一类长度约21～25个核苷酸非编码小分子RNA,它们通过与靶mRNA的3'端非编码区结合促使mRNA降解或抑制其翻译来调节靶基因的表达,在细胞的分化、增生、凋亡、个体发育以及机体代谢中都具有重要的作用.研究发现microRNA在眼部广泛并特异性表达,并可能参与了多种疾病的发生发展过程,但其功能还有待进一步研究.而microRNA作为眼部疾病的检测指标和治疗工具也越来越受到关注,并可能成为治疗的新热点.     

小梁细胞表达的miRNA研究新进展

ｍｉＲＮＡ是一种长约２２个核苷酸的非编码蛋白质的单链小ＲＮＡ,其对基因的调控主要是在转录后和翻译水平来调节基因表达。目前发现与眼部相关的ｍｉＲＮＡ已达上百种,有不少研究旨在探索ｍｉＲＮＡ在人小梁细胞上的表达及其与靶基因之间的调控机制,为进一步阐述青光眼的发病机制及其诊断、治疗提供更好的理论依据。近年来,有关ｍｉＲＮＡ与眼部组织发育、眼部疾病关系的探讨已成为眼科领域研究热点之一。本文就小梁细胞表达的ｍｉＲＮＡ研究最新进展作一综述。     

微小RNA在视网膜疾病中表达及功能的研究进展

微小RNA(miRNA)是一类内源性、非编码单链RNA,长度约为22个核苷酸,他们通过与靶mRNA的3’端非编码区结合来抑制基因的表达,参与调节组织器官的生长发育、分化、功能维持和凋亡等重要的生理过程.miRNA是近年来生命科学领域中的研究热点,越来越多的研究表明多种miRNA在眼部表达,其中超过250种miRNA在视网膜组织中表达并影响其生长、发育和功能.本文就近年来miRNA在视网膜疾病的表达及功能作一综述.     

MicroRNAs在晶状体中的功能

MicroRNAs(miRNAs)是一类包含21～23个碱基的非编码单链小分子RNA。通过与靶基因3'端非翻译区(UTR)不完全碱基配对,使mRNA降解或抑制靶mRNA的翻译,进而发挥基因调控作用。miRNAs广泛参与生物体内的多种生理和病理过程,通过其表达量的上调或下调,影响细胞发育和疾病的进程。近年来许多研究表明,miRNAs在眼部的多种组织,包括晶状体、视网膜和角膜中均有表达,其异常表达可能与某些眼部疾病的发生、发展有密切关系。本文综述近年来miRNAs在晶状体中的表达、功能及研究进展,以期寻求可用于临床诊断、治疗晶状体混浊的新型靶点。     

单核苷酸多态性与高度近视发生发展的研究进展

目前,近视已成为一种全球性公共卫生疾病,其发生多是由遗传和环境等因素引起。单核苷酸多态性(SNPs)是指在基因组水平上发生的、由单个碱基的改变引起的脱氧核糖核酸(DNA)序列多态性。近年来有文献报道,相关基因位点上的SNPs的变化与近视的发生发展密切相关。本文就近视相关基因的SNPs与近视发生发展的关联研究现状作一综述,以期为近视病因和病理机制的研究提供新的思路。     

miRNA与眼部纤维增生性疾病

miRNA是一类长度约21～25个核苷酸的小分子RNA,通过与目的mRNA 3’端非编码区结合促使靶基因抑制或降解,在细胞的增殖、凋亡、分化、个体发育以及机体代谢等一系列生命过程中扮演重要角色.miRNA在心、肝、肾等全身器官纤维化疾病的治疗中显示出了巨大的潜力,已经成为进一步开发抗纤维增生和新生血管药物的新靶点.眼部纤维增生性疾病种类繁多,治疗棘手.通常的手术或激光治疗效果往往不令人满意.作为一种常见的不可逆性疾病,眼部纤维增生性疾病面临着与全身性器官纤维化相似的治疗挑战.在眼部很多组织中检测出与其它器官相同的miRNA表达意味着可能存在共同的抗纤维增生策略.已经用于其它器官的成功的miRNA治疗可能用于眼部纤维增生性疾病的治疗.     

关注和跟踪表观遗传研究在眼科疾病诊治中的应用

不涉及修改基因编码序列的、可遗传的基因表达变化称为表观遗传改变,眼科表观遗传学是当前生物医学研究的热点之一.表观遗传机制主要包括DNA甲基化、组蛋白修饰、染色质重排及非编码RNA.异常的DNA甲基化和组蛋白修饰与许多年龄相关性疾病密切关联,如癌症、自身免疫性疾病和其他疾病.近年来,表观遗传对眼科疾病发生和发展的调控机制及其在治疗中的作用日益引起研究者的关注,不仅加深了人们对相关眼病发病机制的理解,而且由于表观遗传性改变是可逆的,因此对与相关眼病有关的基因标志进行修饰也为这些疾病的预防、早期诊断和治疗提供了新的思路.我们讨论眼科表观遗传学的机制及表观遗传改变在眼病发生和发展过程中的作用,希望眼科研究人员重视基因表达改变与环境因素的相互作用及其对眼部发育和眼部疾病发病过程的影响,更重要的是应将这些研究成果更好地用于眼科疾病的预防和治疗.     

Assessment of TGIF as a candidate gene for myopia

PURPOSE: Transforming growth beta-induced factor (TGIF) has been identified as a candidate gene for high myopia through genetic linkage studies and through its role in ocular growth in animal studies. However, the association of single nucleotide polymorphisms (SNPs), based solely on myopia refraction, has so far been inconclusive. This is the first study conducted to investigate the association of TGIF with refraction and ocular biometric measurements. METHODS: Twelve tag SNPs (tSNPs) encompassing the TGIF gene and 2 kb upstream of its promoter region were used to evaluate the association between TGIF variants with both ocular biometric measures and refraction. A total of 257 cases of myopia (spherical equivalent [SE] worse than -0.50 D) and 294 control subjects (no myopia) were genotyped. Genotype frequencies were analyzed by chi(2) test and one-way ANOVA. RESULTS: Two tSNPs showed significant association with biometric measures, with the SNP rs8082866 being associated with both axial length (P = 0.013) and corneal curvature (P = 0.007) and the SNP rs2020436 being associated with corneal curvature (P = 0.022). However, these associations became nonsignificant after multiple testing (Bonferroni correction). CONCLUSIONS: Findings of this study suggest that the TGIF gene is unlikely to play a major role in either ocular biometric measures or refraction in a Caucasian population. Future studies should focus on other genes in the MYP2 linkage region or other linked regions to identify myopia-causing genes.     

Toll-like receptor 3 gene polymorphisms in Japanese patients with Stevens-Johnson syndrome

BACKGROUND and AIM: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are acute-onset mucocutaneous diseases induced by infectious agents and/or inciting drugs. Given the association between the onset of SJS/TEN and infections, the possibility that there is an association between SJS/TEN and a disordered innate immune response was considered. The first line of defence against infection is comprised of evolutionarily conserved sets of molecules, the Toll-like receptors (TLRs). TLR3 recognises double-stranded RNA associated with viral infections. METHODS: The Japanese single-nucleotide-polymorphism (JSNP) database reports 7 polymorphisms consisting of 7 SNPs in the human TLR3 gene; 3 of the 7 SNPs are coded in exon regions, (ie, 293248A/G, 293391A/G and 299698T/G), and the other 4 are coded in intron regions, (ie, 294440G/C, 294732C/T, 208036T/C and 298054C/T). These 7 SNPs were analysed in 57 Japanese patients with SJS/TEN with ocular surface complications and in 160 Japanese healthy controls. RESULTS: SNP 299698T/G and the genotype patterns of 293248A/A and 299698T/T were strongly associated with SJS/TEN. CONCLUSION: The results suggest that polymorphisms in the TLR3 gene could be associated with SJS/TEN in the Japanese population.     

Association of combined IL-13/IL-4R signaling pathway gene polymorphism with Stevens-Johnson syndrome accompanied by ocular surface complications

PURPOSE: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are acute-onset mucocutaneous diseases induced by infectious agents or inciting drugs. The authors previously reported an association between SJS/TEN and IL-4R gene polymorphism that is essential for IL-4 and IL-13 signaling. To examine IL-4 and IL-13 gene polymorphisms and the combination of these polymorphisms with IL-4R polymorphism, the authors performed polymorphism analysis. METHODS: In 76 Japanese SJS/TEN patients with ocular surface complications and 160 healthy controls, the authors analyzed polymorphisms of the promoter -590C/T in the IL-4 gene and of the promoter -1111C/T and Arg110Gln in the IL-13 gene and assessed Gln551Arg in the IL-4R gene. Because Arg110Gln affects serum IL-13, plasma IL-13 levels were also examined. RESULTS: In the SJS/TEN patients, the Arg110Gln SNP of IL-13 was significantly associated with the disease, and the frequency of Arg110 alleles was significantly higher than that in the controls. Plasma IL-13 tended to be lower in SJS/TEN patients than in the controls. Analysis of the genotype pattern of IL-4R SNP Gln551Arg and IL-13 SNP Arg110Gln showed that the Gln551Gln(A/A)-Arg110Arg(G/G) genotype pattern was also associated with SJS/TEN. CONCLUSIONS: IL-13 gene polymorphisms might be associated with SJS/TEN with ocular surface complications. The present findings suggest that SJS/TEN is different from allergic diseases such as atopy and asthma because the ratio of each allele in the IL-13 SNP Arg110Gln was the opposite of the ratio in those diseases. They also reveal that combined polymorphisms in the IL-13/IL-4R signaling pathway were associated with SJS/TEN with ocular surface complications.     

Whole genome genotyping mapped regions on chromosome 2 and 18 in a family segregating Waardenburg syndrome type II

ObjectivesWaardenburg syndrome is a rare genetic disorder. It is characterized by sensorineural hearing impairment and pigment defects of the skin, hair and iris. In some cases abnormalities in the tissues derived from neural crest have also been reported. Mutations in several genes have been reported as an underlying cause of Waardenburg syndrome. Objective of this study is to identify the chromosomal region(s) associated with Waardenburg syndrome in an extended Saudi family.MethodsGenomic DNA was extracted from fifteen individuals of a Saudi family segregating Waardenburg syndrome. Whole genome SNP genotyping was performed to identify common identity by descent chromosomal region(s) shared by affected individuals.ResultsPedigree analysis confirm autosomal dominant inheritance of Waardenburg syndrome type II in a family. Whole genome SNP genotypes were analyzed using AutoSNPa and DominantMapper tools. Shared identity by descent chromosomal regions were identified on chromosome 2 and chromosome 18. Regions were checked for known Waardenburg syndrome genes. No known gene is present in both regions.ConclusionsIn summary, we identified novel chromosomal regions associated with Waardenburg syndrome type II in a Saudi family. Deep sequencing of a complete candidate regions are required to identify the gene underlying Waardenburg syndrome in this family.     

Innate immunity of the ocular surface and ocular surface inflammatory disorders

Ocular surface epithelial cells selectively respond to microbial components and induce limited inflammation, whereas immune competent cells such as macrophages can recognize various microbial components through Toll-like receptors (TLRs), induce inflammation, and, thereby, exclude microbes. The difference between macrophages and ocular surface epithelial cells could be due to their dissimilarity in coexistence with commensal bacteria. The unique innate immune response of the ocular surface epithelium might contribute to its coexistence with commensal bacteria. Moreover, we suspect that some ocular surface inflammatory disorders might be caused by abnormality of the mucosal innate immunity. We considered the possibility that there is an association between Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN)--a severe variant of SJS--and a disordered innate immune response. In gene expression analysis of CD14 cells, we found that interleukin-4 receptor (IL-4R) gene expression was different between patients with SJS/TEN and normal control subjects upon lipopolysaccharide (LPS) stimulation: it was downregulated in the former and slightly upregulated in the latter. Furthermore, expression of mRNA specific for IkappaBzeta and interleukin (IL)-1alpha was lower in patients with SJS/TEN than in normal controls after 1-hour culture. We next performed single nucleotide polymorphism (SNP) association analysis of IL-4R, IkappaBzeta, and IL1alpha genes and TLR2 and TLR3--genes associated with innate immunity--in 80 Japanese patients with SJS/TEN and 160 Japanese healthy volunteers. IL4R SNP Gln551Arg (rs.1801275) (P = 0.0004), TLR3 rs.3775296T/G SNP (P = 0.0001) and TLR3 rs.3775290A/G SNP (P = 0.009) showed a significant association with SJS/TEN. IkappaBzeta SNP rs.595788G/A showed a weak inverse association (P = 0.04). Genetic and environmental factors may play a role in an integrated etiology of SJS/TEN, and there is possibly an association between SJS/TEN and a disordered innate immunity.     

Molecular genetic analysis of two functional candidate genes in the autosomal recessive retinitis pigmentosa, RP25, locus

PURPOSE: To identify the disease gene in five Spanish families with autosomal recessive retinitis pigmentosa (arRP) linked to the RP25 locus. Two candidate genes, EEF1A1 and IMPG1, were selected from the region between D6S280 and D6S1644 markers where the families are linked. The genes were selected as good candidates on the basis of their function, tissue expression pattern, and/or genetic data. METHODS: A molecular genetic study was performed on DNA extracted from one parent and one affected member of each studied family. The coding exons, splice sites, and the 5' UTR of the genes were amplified by polymerase chain reaction (PCR). For mutation detection, direct sequence analysis was performed using the ABI 3100 automated sequencer. Segregation of an IMPG1 single nucleotide polymorphism (SNP) in all the families studied was analyzed by restriction enzyme digest of the amplified gene fragments. RESULTS: In total, 15 SNPs were identified of which 7 were novel. Of the identified SNPs, one was insertion, two were deletions, five were intronic, six were missense, and one was located in the 5' UTR. These changes, however, were also identified in unaffected members of the families and/or 50 control Caucasians. The examined known IMPG1 SNP was not segregating with the disease phenotype but was correlating with the genetic data in all families studied. CONCLUSIONS: Our results indicate that neither EEF1A1 nor IMPG1 could be responsible for RP25 in the studied families due to absence of any pathogenic variants. However, it is important to notice that the methodology used in this study cannot detect larger deletions that lie outside the screened regions or primer site mutations that exist in the heterozygous state. A role of both genes in other inherited forms of RP and/or retinal degenerations needs to be elucidated.     

Of mice and men: tyrosinase modification of congenital glaucoma in mice but not in humans

PURPOSE: Primary congenital glaucoma (PCG) is an autosomal recessive ocular trait caused by mutations in the gene for cytochrome P4501B1 (CYP1B1). Although PCG is often considered to be fully penetrant, the disease shows 50% penetrance in some Saudi Arabian families. The familial segregation of the nonpenetrance suggests a genetic modifier. Recently, tyrosinase (Tyr) deficiency was found to worsen the drainage structure/ocular dysgenesis phenotype of Cyp1b1-/- mice, suggesting that Tyr is a modifier of the phenotype. In the current study, tyrosinase (TYR) was investigated in human PCG. METHODS: A genome-wide screen, a single nucleotide polymorphism (SNP) analysis in the TYR chromosomal region 11q13-q21, and sequencing of the TYR gene was performed with individuals from Saudi Arabian families with multiple, clinically confirmed, molecularly proven, nonpenetrant members. RESULTS: The study outcome did not support TYR as a modifier of the PCG phenotype in this population. The sequencing data showed no TYR mutations in the nonpenetrant family members and no difference in polymorphism frequencies between nonpenetrant or fully penetrant families. CONCLUSIONS: TYR is not a modifier of the CYP1B1-associated PCG phenotype in the Saudi Arabian population.     

Resveratrol and the eye: activity and molecular mechanisms

Purpose

Alcohol consumption is inversely correlated with the incidence of cardiovascular disease. It is thought that red wine is specifically responsible for these cardiovascular benefits, due to its ability to reduce vascular inflammation, facilitate vasorelaxation, and inhibit angiogenesis. This is because of its high polyphenolic content. Resveratrol is the main biologically active polyphenol within red wine. Owing to its vascular-enhancing properties, resveratrol may be effective in the microcirculation of the eye, thereby helping prevent ocular diseases such as age-related macular degeneration, diabetic retinopathy, and glaucoma. Such conditions are accountable for worldwide prevalence of visual loss.

Method

A review of the relevant literature was conducted on the ScienceDirect, Web of Science, and PubMed databases. Key words used to carry out the searches included ‘red wine’, ‘polyphenols’, ‘resveratrol’, ‘eye’ and ‘ocular’. Articles relating to the effects of resveratrol on the eye were reviewed.

Results

The protective effects of resveratrol within the eye are extensive. It has been demonstrated to have anti-oxidant, anti-apoptotic, anti-tumourogenic, anti-inflammatory, anti-angiogenic and vasorelaxant properties. There are potential benefits of resveratrol supplementation across a wide range of ocular diseases. The molecular mechanisms underlying these protective actions are diverse.

Conclusion

Evidence suggests that resveratrol may have potential in the treatment of several ocular diseases. However, while there are many studies indicating plausible biological mechanisms using animal models and in-vitro retinal cells there is a paucity of human research. The evidence base for the use of resveratrol in the management of ocular diseases needs to be increased before recommendations can be made for the use of resveratrol as an ocular supplement.