【摘要】：研究目的視網(wǎng)膜色素變性(retinitis pigmentosa,RP)是視網(wǎng)膜變性中最常見的一組以進(jìn)行性光感受器細(xì)胞及視網(wǎng)膜色素上皮(retinitis pigment epithelium,RPE)功能喪失為共同表現(xiàn)的遺傳性疾病。而原發(fā)性視網(wǎng)膜色素變性合并視網(wǎng)膜血管進(jìn)行性閉塞是近年來眼科醫(yī)師逐步認(rèn)識的一種疾病。國內(nèi)曾以原發(fā)性血管閉塞性視神經(jīng)視網(wǎng)膜病變做個(gè)案報(bào)道,強(qiáng)調(diào)不明原因,原發(fā)性血管閉塞為特點(diǎn)而國外未見報(bào)道。在進(jìn)一步完善資料的補(bǔ)充搜集之后,本研究對此病的臨床特點(diǎn)進(jìn)行總結(jié),并對部分患者進(jìn)行既往未曾做過的全基因組外顯子測序以試圖闡明其發(fā)病機(jī)制并印證既往我們對此病的認(rèn)識。研究方法回顧性分析23例(46只眼)原發(fā)性RP合并視網(wǎng)膜血管閉塞患者的臨床資料。其中男性12例,女性11例;年齡從6～70歲平均49.96±15.80歲。患者均雙眼受累。患者均進(jìn)行了包括眼底檢查、熒光素眼底血管造影、視網(wǎng)膜電圖等檢查。采集其中6個(gè)患者的血樣,還采集了其中1個(gè)患者父母(無臨床表現(xiàn))血樣,共8個(gè)樣本。進(jìn)行全基因組外顯子測序。測序主要包括目標(biāo)區(qū)域序列的富集、DNA測序、生物信息學(xué)統(tǒng)計(jì)三個(gè)主要步驟。測序結(jié)果中對出現(xiàn)在2個(gè)及以上case的位點(diǎn)進(jìn)行了分析,重點(diǎn)關(guān)注沒有注釋到單核苷酸多態(tài)性數(shù)據(jù)庫的位點(diǎn),可能是潛在的與RP相關(guān)的新的位點(diǎn);進(jìn)一步關(guān)注篩選突變類型為錯義突變等能直接引起氨基酸改變的位點(diǎn),這樣功能變化會相對比較明顯。這樣大概只有不到300個(gè)位點(diǎn),81個(gè)基因;跟進(jìn)位點(diǎn)depth≥10且quality≥20進(jìn)行過濾。然后對這些潛在位點(diǎn)應(yīng)用京都基因和基因組百科全書(Kyoto Encyclopedia of Genesand Genomes,KEGG)和基因本體論數(shù)據(jù)庫(gene ontology,GO)進(jìn)了功能富集分析。并結(jié)合臨床背景、經(jīng)驗(yàn),進(jìn)行綜合篩選過濾,尋找潛在的位點(diǎn)和致病基因。研究結(jié)果原發(fā)性RP合并視網(wǎng)膜血管閉塞患者的臨床表現(xiàn)為眼前節(jié)均無炎性反應(yīng),眼壓正常,晶狀體混濁20只眼,未見虹膜新生血管;患者眼底視乳頭色淡,其中蒼白如月者17只眼;視網(wǎng)膜血管變細(xì),鼻側(cè)血管更明顯,血管旁可見白鞘。由于患者病程不一,其視網(wǎng)膜血管閉塞程度亦不同,嚴(yán)重者血管可閉塞成白線。視網(wǎng)膜色素紊亂和脫色素點(diǎn),無典型骨細(xì)胞樣色素沉著。未見視網(wǎng)膜新生血管,無增生性視網(wǎng)膜病變及玻璃體積血。20只眼眼底熒光血管造影示視乳頭始終呈低熒光或晚期淡熒光充盈,局限于有光感眼或無光感眼。視乳頭部位有一小段血管有熒光素充盈或完全無血管充盈者17只眼。整個(gè)眼底可見椒鹽狀熒光素充盈。吲哚青綠造影檢查表現(xiàn)為脈絡(luò)膜血管較細(xì),熒光素充盈較弱,退行較快,視網(wǎng)膜血管閉塞表現(xiàn)同熒光素眼底血管造影所見。視網(wǎng)膜電圖檢查顯示晚期明視、暗視ERG的a,b波幅為無波型或近無波型。患者多有夜盲史。8個(gè)樣本全基因組外顯子測序結(jié)果出現(xiàn)了已報(bào)道的RP相關(guān)致病基因的單核苷酸多態(tài)性位點(diǎn),又在一些基因的編碼區(qū)發(fā)現(xiàn)了新的突變位點(diǎn),并導(dǎo)致了氨基酸改變�；蜃⑨尠l(fā)現(xiàn)與組織凋亡,神經(jīng)褪變,抑制細(xì)胞增殖等相關(guān)。應(yīng)用KEGG和GO數(shù)據(jù)庫尋找生物學(xué)相關(guān)通路,顯示存在有凋亡通路,神經(jīng)軸突導(dǎo)向通路,血管內(nèi)皮生長因子信號通路,視黃醇代謝通路等。結(jié)論本組研究患者眼底均表現(xiàn)為視乳頭色淡,視網(wǎng)膜血管變細(xì),廣泛視網(wǎng)膜色素上皮受累,可見脫色素斑點(diǎn)及有或無細(xì)小色素點(diǎn);ERG檢查a、b波均為無波型或近無波型,支持本組原發(fā)性RP合并視網(wǎng)膜血管閉塞患者屬于原發(fā)性RP(毯層RP)范疇。同時(shí)也有其自身臨床特點(diǎn):1.晚期血管可完全閉塞成白線或近完全閉塞,視神經(jīng)明顯萎縮可以蒼白如月。2.視網(wǎng)膜色素上皮以進(jìn)行性萎縮為主、無典型骨細(xì)胞樣色素增殖沉著,未見視網(wǎng)膜新生血管及玻璃體出血。3.此病病程進(jìn)展速度似較原發(fā)性RP為快。全基因組外顯子測序結(jié)果中出現(xiàn)了已報(bào)道的RP致病基因的單核苷酸多態(tài)性位點(diǎn),是否這些位點(diǎn)在疾病中高發(fā)并與RP相關(guān)有待驗(yàn)證。在一些基因編碼區(qū)發(fā)現(xiàn)了引起氨基酸改變的很多未見報(bào)道的新突變位點(diǎn),基因注釋發(fā)現(xiàn)與組織凋亡,神經(jīng)褪變,抑制細(xì)胞增殖等相關(guān)。并有基因參與凋亡、神經(jīng)軸突導(dǎo)向、血管內(nèi)皮生長因子信號等生物學(xué)通路。若從理論上完全解釋還有待進(jìn)一步的工作來證實(shí)。
[Abstract]:Retinitis pigmentosa (RP) is one of the most common genetic diseases in the degeneration of retina, which is characterized by progressive photoreceptor cells and retinal pigment epithelium (RPE). Primary retinal pigment degeneration and progressive occlusion of retinal vessels are a disease which has been gradually recognized by the ophthalmologist in recent years. A case report of primary angiitis obliterans optic neuropathy was reported in China. It was emphasized that it was not reported in foreign countries due to unknown reasons and primary vascular occlusion. After further improvement of the data collection, this study summarized the clinical features of the disease and sequenced all genome exons that had not been previously done by some patients in an attempt to elucidate the pathogenesis of the disease and confirm our knowledge of the disease. Methods The clinical data of 23 cases (46 eyes) with primary RP combined with retinal vessel occlusion were analyzed retrospectively. Among them, 12 males and 11 females were females, and the average age ranged from 6 to 70 years, and the average age ranged from 49. 96 to 15. 80 years. Both eyes of the patient were involved. All patients underwent examinations including fundus examination, fluorescein angiography, electroretinogram, etc. Blood samples were collected from six of these patients, and a total of 8 samples were collected from one of the patients (no clinical presentation). All genome exons were sequenced. The sequencing mainly includes three main steps: enrichment of target region sequence, DNA sequencing and bioinformatics statistics. The results of sequencing showed that the sites of 2 and more cases were analyzed, and the sites that were not annotated to the single-point polymorphism database might be potential new sites related to RP. Further attention is paid to screening mutation types such as missense mutation and so on, which can directly cause amino acid changes, so that the functional changes can be relatively obvious. Thus, there are only less than 300 sites, 81 genes, a follow-up site depth column 10, and a quality table 20 for filtering. These potential sites were then subjected to functional enrichment analysis using Kyoto Encyclopedia of Genesand Genes (KEGG) and Gene Ontology Database (GO). Combined with the clinical background and experience, the comprehensive screening and filtration were carried out to find the potential sites and pathogenic genes. Results The clinical manifestations of primary RP-combined retinal vascular occlusion were no inflammatory reaction in anterior segment, normal intraocular pressure, 20 eyes with posterior lens opacity, and no iris neovascularization. The blood vessels at the nose side are more obvious, and white blood vessels can be seen near the blood vessels. Because the course of the patient is not one, the degree of retinal blood vessel occlusion is different, and the blood vessel of the serious person can be blocked into white line. Retinal pigment disorder and depigmentation point, no typical osteoclast-like pigmentation. No retinal neovascularization, no proliferative retinopathy and vitreous hemorrhage were seen. 20 eyes with fundus fluorescein angiography showed that the nipple was always low or late fluorescent filling, limited to light-sensitive eyes or no light-sensitive eyes. There is a small segment of blood vessel at the papillary site with fluorescein filling or no blood vessel filling 17 eyes. The whole fundus of the fundus can be filled with salt-like fluorescein. Angiographic examination showed that the choroid vessels were thinner, the fluorescein filling was weak, the regression line was faster, and the retinal vessel occlusion was seen with fluorescein angiography. The examination of electroretinogram showed that the amplitude of a and b of dark ERG was wave-free or nearly wave-free. The results showed that there was a single polymorphic site of the reported RP-related pathogenic gene, and a new mutation site was found in the coding region of some genes, which led to amino acid change. Gene annotation has been found to be related to tissue apoptosis, neurodegeneration, inhibition of cell proliferation, and the like. The KEGG and GO databases were used to find biological correlation pathways, and there were apoptotic pathways, neurite-directed pathways, vascular endothelial growth factor signaling pathways, retinal metabolism pathways, and the like. Conclusion The fundus of the patients in this group is characterized by pale nipple color, thinning retinal vein, extensive retinal pigment epithelium involvement, visible depigmentation spot and or without fine pigment spot, ERG examination a and b wave are wave-free or near-wave type, The patients with primary RP combined with retinal vascular occlusion belong to the category of primary RP (blanket layer RP). At the same time, it has its own clinical features: 1. Late blood vessels may be completely occluded into white lines or near complete occlusion, and the optic atrophy may pale as pale as month. Retinal pigment epithelium is mainly composed of progressive atrophy, no typical osteoclast-like pigment proliferation, no retinal neovascularization and vitreous hemorrhage. The progress of the disease progression seems to be faster than that of the primary RP. The results of all-genome exon sequencing showed the reported single-site polymorphic sites of RP-pathogenic genes, and whether these sites were high in the disease and associated with RP-related needs to be verified. In some gene coding regions, many novel mutation sites have been found to cause amino acid changes, and gene annotation has been found to be related to tissue apoptosis, neurodegeneration, inhibition of cell proliferation, and the like. and has genes involved in biological pathways such as apoptosis, neurite outgrowth, vascular endothelial growth factor signaling, and the like. If the theory is fully explained and the work to be further worked out, it is proved.
【學(xué)位授予單位】：天津醫(yī)科大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2014
【分類號】：R774.1

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