高度近视与原发性开角型青光眼

临床上发现高度近视与原发性开角型青光眼密切相关 ,其可能的机制有 :( 1 )升压基因学说 ;( 2 )胶原基因学说。高度近视眼与原发性开角型青光眼对糖皮质激素反应增高表明 ,二者的基因在糖皮质激素诱导下最易表达特异性蛋白 ,这可能与高度近视、原发性开角型青光眼的TIGR基因突变有关。本文从流行病学、临床特征及诊断、遗传学说及机制等方面对高度近视与原发性开角型青光眼的关系及研究进展进行综述。     

高度近视与原发性开角型青光眼

临床上发现高度近视与原发性开角型青光眼密切相关，其可能的机制有：（1）升压基因学说；（2）胶原基因学说。高度近视眼与原发性开角型青光眼对糖皮质激素反应增高表明，二的基因在糖皮质激素诱导下最易表达特异性蛋白，这可能与高度近视，原发性开角型青光眼的TIGR基因突变有关。本从流行病学、临床特征及诊断，遗传学说及机制等方面对高度近视与原发性开角型青光眼的关系及研究进展进行综述。     

高度近视与原发性开角型青光眼关系的研究进展

临床和实验研究均发现,青光眼患者近视发生率高于非青光眼人群。反之,近视,尤其高度近视（high myopia,HM）人群较其它人群更常伴有青光眼。当HM与原发性开角型青光眼（primary open—angle glaucoma,POAG）并存时,病情变得尤其复杂。两者发病机制之间的关系,目前在分子和基因水平的研究重点是：胶原基因学说和升压基因学说。从病理学角度讲,高度近视与青光眼都是胶原病变;此外,二者的小梁网细胞在糖皮质激素诱导下易表达特异性蛋白,这可能与高度近视、原发性开角型青光眼的TIGR（trabecular meshwork induced glucocorticoid response protein）基因突变有关。本文从流行病学、发病机制、临床特征及诊断注意要点等方面对高度近视与原发性开角型青光眼的关系及研究进展进行综述。     

MYOC/TIGR基因与原发性开角型青光眼

近年来,原发性开角型青光眼的分子遗传学研究取得了飞速发展,尤其是1997年首次发现位于GLCIA基因位点上的开角型青光眼的致病基因小梁网糖皮质激素诱导反应蛋白基因(TIGR)以来,该领域得到了迅速发展.人们对TIGR基因及其编码产物的研究正在逐步深入,就该基因的发现、结构、功能、突变以及在原发性开角型青光眼病变过程中可能的作用作一综述.     

开角型青光眼的分子遗传学研究

青光眼是多因素多基因遗传性眼病。目前已知至少 8个染色体位点与开角型青光眼和正常眼压性青光眼的发病有关 ;并已确定MYOC/TIGR、OPTN基因为青光眼的致病基因。本文主要就近年来有关原发性开角型青光眼的分子遗传学研究进展 ,特别是有关MYOC/TIGR、OPTN基因表达的部位、特异性突变等进行综述。     

开角型青光眼的分子遗传学研究

青光眼是多因素多基因遗传性眼病。目前已知至少8个染色体位点与开角型青光眼和正常眼压性青光眼的发病有关；并已确定MYOC／TIGR、OPTN基因为青光眼的致病基因。本主要就近年来有关原发性开角型青光眼的分子遗传学研究进展，特别是有关MYOC／TIGR、OPTN基因表达的部位、特异性突变等进行综述。     

高度近视合并原发性开角型青光眼的临床特点研究进展

许多研究显示高度近视与青光眼密切相关,高度近视因患者眼轴长、前房深、房角宽的特点,并发青光眼的类型常为原发性开角型青光眼.然而,由于高度近视可导致一系列的眼底病变,使青光眼的早期眼底改变易被高度近视造成的眼底病变所掩盖,所以,认识高度近视合并原发性开角型青光眼的临床特点及诊断要点,有利于疾病的早期诊断和减少漏诊、误诊.本文对高度近视合并原发性开角型青光眼的临床特点进行总结归纳,提高对疾病的认识,为疾病的早期诊断提供依据.     

高度近视与原发性开角型青光眼关系的研究进展

近年来,在青光眼及近视发病机制研究中发现,高度近视与原发性开角型青光眼的发病有明显相关性.高度近视眼底病理改变是开角型青光眼的高危因素,且高度近视眼底改变与早期开角型青光眼眼底改变容易混淆,造成青光眼早期诊断困难.如何从高度近视患者中早期发现青光眼,并进行早期干预治疗成为难点.本文回顾分析近年文献,对高度近视与原发性开角型青光眼的关系做一综述.     

重庆地区开角型青光眼患者及其亲属和正常人群中小梁网糖皮质激素诱导反应蛋白基因突变的研究

目的 研究开角型青光眼患者及其亲属和正常人群中小梁网糖皮质激素诱导反应蛋白(TIGR)基因突变的情况。方法 (1)应用聚合酶链反应(PCR)方法,对15例开角型青光眼患者及其10例一级亲属和20例正常对照者的TIGR基因的3个外显子、部分内含子及部分启动子(7对引物)的各个片段进行扩增,应用单链空间构象多态(SSCP)分析法,筛选可能存在突变的PCR产物。(2)将筛选出的PCR产物交上海基康公司测序。(3)对突变片段行生物信息学分析。结果 (1)在重庆地区15例原发性开角型青光眼患者中,共发现TGR基因突变者5例,其中青少年型青光眼4例;在10例青光眼患者亲属中发现TIGR基因突变者2例;正常对照者20例中未发现TIGR基因突变。(2)PCR产物测序共发现4个序列改变,其中编码区2个,非编码区2个。编码区的2个突变位点(Ser55Thl、Asp247Stop)及第二内含子区bp35c→t的突变,均未见文献报道;而在启动子区域bp-83c→t的突变有文献报道为1个多态位点。(3)生物信息学分析结果显示编码区的突变可导致氨基酸序列、蛋白质的二级结构及等电点、抗原结合位点等发生改变。结论 TIGR基因突变与青少年开角型青光眼的发生密切相关,由此可推测青光眼患者的亲属发病率较正常人高。TIGR基因突变可引起TIGR蛋白结构及理化特性的变化,这些改变可能是引发开角型青光眼的危险因素之一。     

高度近视合并原发性开角型青光眼的临床诊断研究进展

临床和试验研究均发现,高度近视患者并发原发性开角型青光眼的概率高于非高度近视患者,特别是当高度近视与原发性开角型青光眼并存时,病情变得尤其复杂。对于个体而言,近视和青光眼之间的关系在很多情况下仍然很不明确,高度近视是造成青光眼的风险因素之一,多数情况下从青光眼的眼底变化中也很难分辨出是近视导致还是功能异常,因此高度近视合并原发性开角型青光眼的早期诊断非常困难但意义重大。本文从流行病学特征、视盘结构、视野改变、眼压测量等方面对高度近视与原发性开角型青光眼的关系及诊断进行综述。     

Truncations in the TIGR gene in individuals with and without primary open-angle glaucoma

PURPOSE: To investigate the coding exons in the trabecular meshwork-induced glucocorticoid response protein (TIGR) gene for mutations in primary open-angle glaucoma (POAG) in Chinese subjects. METHODS: Ninety-one Chinese patients with POAG and 113 of their family members without glaucoma were screened for sequence alterations in the TIGR gene by polymerase chain reaction, conformation-sensitive gel electrophoresis, and DNA sequencing. One hundred thirty-two unrelated individuals without glaucoma, aged 50 years or more, were studied as control subjects. RESULTS: Five sequence variants that lead to amino acid changes were identified. One was novel: Arg91Stop in one patient with POAG. Four had been reported: Arg46Stop in subjects with and without POAG, including an unaffected 77-year-old woman homozygous for Arg46Stop; Gly12Arg in subjects without glaucoma; and Asp208Glu and Thr353Ile in subjects with and without POAG. The previously reported 1-83(G-->A) and Arg76Lys polymorphisms were detected in both patients and controls and always occurred together. CONCLUSIONS: A different pattern of TIGR sequence variants exists in the Chinese than in non-Chinese populations. No common TIGR mutation that causes POAG was found. The occurrence of subjects without glaucoma who are heterozygous or homozygous for Arg46Stop suggests that reduction in the amount of TIGR protein does not cause glaucoma. Thus, the TIGR missense mutations known to cause POAG probably do not cause glaucoma by inactivating a normal TIGR function, but rather through the gain of a pathologic function.     

我国原发性开角型青光眼患者TIGR基因突变筛选、克隆及序列分析

目的　研究我国原发性开角型青光眼 (primaryopenangleglaucoma,POAG)患者小梁网糖皮质激素诱导反应蛋白 (trabecularmeshworkinducedglucocorticoidresponseprotein ,TIGR)基因的突变情况。方法　 (1)应用聚合酶链式反应 (polymerasechainreaction ,PCR)方法扩增 70例POAG患者、2 0例正常对照组的TIGR基因 3个外显子 (7对引物 )的各个片段 ,应用单链构像多态 (single strandedconformationpolymorphism ,SSCP)筛选可能突变的PCR产物。 (2 )将筛选出的样本 (PCR产物 ) ,克隆到PT Adv载体 ,以EcorI酶切鉴定重组质粒 ,然后用ABI 373自动测序仪行双向测序。结果　 (1)用SSCP方法筛选的 2例POAG患者在TIGR基因第 3外显子中部 (第 6对引物 )片段出现单链带型异常 ;正常对照组未见异常。 (2 )克隆测序的 2例样品 ,1例在 388密码子位置出现由GAT突变为AAT ,氨基酸由天冬氨酸替换为天冬酰胺 ,即Asp388Asn ;另 1例碱基序列无变化。提示我国POAG患者TIGR基因突变仅为 1 4% (1/ 70 ) ,远较国外为低。结论　我国POAG患者的发病机制可能与TIGR基因突变有关 ,但突变率较国外低 ,提示POAG发病存在地区或种族之间的差异。     

Study of TIGR gene in patients with primary open angle glaucoma

PURPOSE: The aim of the study was to identify the mutations of TIGR gene in Polish patients with primary open angle glaucoma (POAG), and to define the genotype-phenotype correlation, between the type of mutation and the clinical picture of POAG. MATERIAL AND METHODS: The study included 45 patients with verified and proved diagnosis of POAG. DNA was isolated from peripheral blood lymphocytes of patients. The PCR amplification of all three exons of TIGR gene was done for every patient. The screening for the sequence changes in the PCR products of TIGR gene was done using conformation sensitive gel electrophoresis (CSGE). The probes with identified heteroduplexes were sequenced using an automatic DNA sequencer. RESULTS: During amplification of the coding regions of TIGR gene and the promoter sequences and flanking sequences of introns, 315 PCR products were obtained. The CSGE analysis of these PCR products allowed to detect 60 possible changes of sequence in 28 patients. 34 heteroduplexes were chosen for sequencing, including 29 unique changes and 5 changes representative for repeated, identical heteroduplexes. Direct sequencing allowed to detect only four different changes in TIGR gene sequence. Three of them: 5'UTR -83G-->A (present in 14 patients), +227 exon 1 G-->A, Arg76Lys (present in 14 patient) and +311 exon 3 T-->C, Tyr347Tyr (present in 4 patients) were already described in literature as neutral polymorphisms of TIGR gene. Only one change in promoter: 5'UTR 126T-->C (present in 2 patients) was not described in the literature to date. However, because this change doesn't alter directly the sequence of aminoacids in protein product of TIGR gene, it is very difficult to conclude its pathogenetic role. CONCLUSIONS: Our studies have shown no TIGR gene changes that can be recognized as causative mutations in development of POAG. Thus, the definition of any genotype-phenotype correlation was impossible. The study on the role of the change in promoter sequence that was not yet described, will be continued. Exclusion of TIGR gene mutations in Polish patients with POAG means that they probably have mutations in other genes, what paves the way to the studies on other loci that predispose to POAG.     

Clinical phenotype of a Japanese family with primary open angle glaucoma caused by a Pro370Leu mutation in the MYOC/TIGR gene.

PURPOSE: To present the phenotype of two patients with primary open angle glaucoma (POAG) caused by a mutation of the myocilin/trabecular meshwork-inducible glucocorticoid response (MYOC/TIGR) gene. METHODS: Complete ocular examinations were performed on the 13-year-old proband, her father, mother, and sister. DNA analysis was performed to detect the mutant gene. RESULTS: The proband and her father were found to have a mutation of the MYOC/TIGR gene. Both patients carried a heterozygous mutation in the 1,109th nucleotide, which corresponds to the 370th amino acid residue of the MYOC/TIGR gene. The clinical characteristics of both patients were: (1) development of POAG at an early age, (2) high peaks of intraocular pressure. and (3) poor response to medical treatment. CONCLUSIONS: The phenotype of these patients with a mutation of the MYOC/TIGR gene agreed with reports of other patients with mutations at other loci in this gene. The discovery of the MYOC/TIGR gene not only makes early detection of glaucoma possible, but also presents a new direction for investigating the pathogenesis of glaucoma.     

Progress in understanding the association between high myopia and primary open‐angle glaucoma

Many clinical and fundamental studies have shown that high myopia (HM) and glaucoma are closely associated. In particular, the occurrence and progression of primary open‐angle glaucoma interact with the progression of HM. Two hypotheses have been proposed to explain the association between the two disorders: the hypertension gene theory and the collagen‐related gene theory. HM and primary open‐angle glaucoma patients show similar collagen changes and hypersensitive responses to glucocorticoids. Consequently, these common features may hold key information regarding their underlying mechanisms. Advances in life sciences, such as molecular genetics, provide opportunities for clarifying their association at the molecular level. This article reviews available research on the association between these two disorders from the perspectives of epidemiology, clinical manifestation, diagnosis and pathogenic mechanisms.     

原发性开角型青光眼MYOC- TIGR基因突变研究

目的 筛选并研究原发性开角型青光眼(POAG)小梁网糖皮质激素诱导反应蛋白MYOC- TIGR基因突变情况。方法 病例对照研究。抽取2002年1至12月就诊并诊断为POAG患者118例和150例非POAG对照者的外周静脉血4～8ml,采用酚-氯仿抽提全基因组DNA,应用聚合酶链反应(PCR)技术扩增全基因组DNA,以单核苷酸构象多态性(SSCP)分析MYOC基因的3个外显子（7对引物）编码区域序列改变。对SSCP分析异常者,采用双向测序法进一步证实。应用Cfr13I、Hinfl及BsmA1等限制性内切酶检测对照者MYOC基因编码区序列改变。POAG与非POAG人群MYOC基因各位点突变率比较采用x2检验。结果 基因序列分析发现G12R、I288M及Y353I共3个基因序列改变。118例POAG患者中仅有5例(4.23％)发生G12R位点突变,150例对照者中未见G12R位点改变;两组G12R位点突变率比较差异有统计学意义(x2=4.37,P=0.037)。POAG组和对照组均有I288M和Y353I位点改变,但两组突变率比较差异无统计学意义(x2=0.07,P=0.791和x2=0.56,P=0.453)。POAG患者基因突变率4.23％。结论 MYOC基因突变可能与POAG发病有关,MYOC基因突变可能是POAG发病的分子机制之一。     

TIGR/MYOC gene sequence alterations in individuals with and without primary open-angle glaucoma

PURPOSE: To discover sequence alterations in the TIGR/MYOC gene associated with primary open-angle glaucoma (POAG) in Chinese subjects. METHODS: Two hundred one unrelated Chinese patients with POAG and 291 unrelated individuals without glaucoma, aged 50 years or more, were screened for sequence alterations in the TIGR/MYOC gene by polymerase chain reaction, conformation sensitive gel electrophoresis, and DNA sequencing. Up to 111 more control subjects were screened for some of the alterations. RESULTS: Fourteen sequence variants that lead to amino acid changes were identified. Seven were novel: Pro16Leu, Ala17Ser, Leu95Pro, Leu215Pro, Glu300Lys, Glu414Lys, and Tyr471Cys. Of these, Glu300Lys and Tyr471Cys were found only in POAG. Arg46Stop was found in 4 patients with POAG (2.0%) and 9 of 402 control subjects (2.2%); one control subject was homozygous. IOP showed a trend (P = 0.11) toward a decrease of 1.5 mm Hg among the control subjects, with Arg46Stop compared with matched control subjects without Arg46Stop. Gly12Arg occurred four times as frequently in control subjects as in patients, but the difference was not statistically significant. CONCLUSIONS: Gly12Arg might be negatively associated with POAG, suggesting a protective effect. Three patients with POAG had a sequence change not found in control subjects, for a frequency of possible disease-causing TIGR/MYOC mutations of 1.5% (95% confidence interval [CI] = 0.3%-4.3%). Arg46Stop occurred with similar frequency in patients with POAG and control subjects, suggesting that the reduced amount of TIGR/MYOC predicted to result from this truncation does not dramatically increase or decrease risk of glaucoma.