本文選題：視網(wǎng)膜色素變性 + 基因��； 參考：《南昌大學》2017年碩士論文

【摘要】：背景:視網(wǎng)膜色素變性(retinitis pigmentosa,RP)是與視錐細胞和視桿細胞(光感受器)或色素上皮結構或功能異常相關的一類進行性致盲性遺傳眼病。國外患病率約為1/4000,我國患病率約為1/3467。視網(wǎng)膜色素變性的典型臨床特征為:早期出現(xiàn)夜盲,隨著病情進展逐漸出現(xiàn)進行性視野縮小和視力下降、視盤蠟黃色萎縮、視網(wǎng)膜骨細胞樣色素沉著等。視網(wǎng)膜色素變性具有高度的遺傳異質(zhì)性,據(jù)其遺傳方式可分為常染色體顯性遺傳(autosomal dominant RP,adRP)、常染色體隱性遺傳、X-連鎖遺傳、雙基因型遺傳和線粒體DNA遺傳。常染色體顯性遺傳在視網(wǎng)膜色素變性患者中所占比例為15%-20%,目前已確定與adRP有關的基因約有14個,包括CA4、CRX、GUCA1B、IMPDH1、NRL、PRPF8、PRPF3、PRPF31、RHO、RDS、ROM1、RP9、RP1、SEMA4A。NRL(neural retinal leucine zippe,神經(jīng)視網(wǎng)膜亮氨酸拉鏈基因)基因編碼堿性亮氨酸拉鏈蛋白(basic motif-leucine zipper,bZIP),其對光感受器特異性基因-視紫紅質(zhì)(rhodopsin,RHO)基因的表達起調(diào)控作用。目的:對一個視網(wǎng)膜色素變性家系進行臨床特點分析和遺傳學分析,明確其致病突變及可能發(fā)病機制。方法:收集一視網(wǎng)膜色素變性家系的所有家系成員的臨床資料,對本家系的5例患者和數(shù)名正常家庭成員進行全面的眼科檢查,各取外周血2ml,提取外周靜脈血細胞基因組DNA。應用眼科RP候選基因芯片(共包含59個目標基因),采用目標區(qū)域捕獲二代測序?qū)ο茸C者進行基因突變分析,應用一代測序驗證對家系成員突變位點情況驗證,應用UCSC在線及polyhpen-2對突變位點進行生物信息學分析。結果:該家系中連續(xù)3代,所有患者均有典型的色素型視網(wǎng)膜色素變性表現(xiàn),臨床上表現(xiàn)為不同程度夜盲、周邊視野縮窄、中心視力下降,該家系遺傳學研究發(fā)現(xiàn)該病在家系中呈現(xiàn)常染色體顯性遺傳,該家系3例患者的RP候選基因遺傳分析結果顯示,NRL基因第號外顯子上中均發(fā)現(xiàn)單一雜合突變c.152CT,該家系其他正常成員均未發(fā)現(xiàn)此突變,與該家系涉及的疾病呈共分離的特點。在蛋白水平,此突變導致NRL基因51位上編碼氨基酸由脯氨酸變?yōu)榱涟彼�。結論:我們對一個中國視網(wǎng)膜色素變性家系進行了詳細的臨床檢查,該本研究中家系成員共3代,每一代均有視網(wǎng)膜色素變性患者,家系中患者均有夜盲、視力下降、視野縮窄的臨床表現(xiàn);對該家系進行分子遺傳學分析,發(fā)現(xiàn)了導致該家系患者患病的致病性突變c.152CT(p.Pro51Leu),該突變導致bZIP蛋白第152位脯胺酸被亮氨酸取代,進而影響蛋白質(zhì)的功能。
[Abstract]:Background: retinitis pigmentosa RP (RP) is a kind of progressive blindness hereditary ophthalmopathy associated with conus cells and rod cells (photoreceptors) or abnormal structure or function of pigment epithelium. The prevalence rate in foreign countries is about 1 / 4 000 and in China is about 1 / 3 467. The typical clinical features of retinitis pigmentosa are as follows: early night-blindness, progressive narrowing of visual field and visual acuity, wax-yellow atrophy of optic disc, retinal osteocytoid pigmentation and so on. Retinitis pigmentosa has a high degree of genetic heterogeneity. According to its genetic pattern, it can be divided into autosomal dominant inheritance (autosomal dominant), autosomal recessive inheritance (X-), double genotype inheritance and mitochondrial DNA inheritance. The proportion of autosomal dominant inheritance in retinitis pigmentosa patients is 15 to 20. At present, there are about 14 genes related to adRP that have been identified. These genes include CA4, CRXG, GUCA1B, IMPDH1, NRLN, PRPF8, PRPF3, PRPF31, RDS-ROM1, RP9, RP1, SEMA4A.NRL (neural retinal leucine zippe, encoding basic leucine zipper protein (basic motif-leucine zipperbZIP), which plays a regulatory role in the expression of the photoreceptor specific gene rhodopsin Rho (rhodopsin Rho) gene. Objective: to analyze the clinical and genetic characteristics of a pedigree with retinitis pigmentosa, and to identify the mutation and possible pathogenesis of retinitis pigmentosa. Methods: the clinical data of all the family members of a family with retinitis pigmentosa were collected, and 5 patients and several normal family members were examined by ophthalmology. The peripheral blood 2ml was taken and the genomic DNA of peripheral venous blood cells (DNA) was extracted. Using ophthalmic RP candidate gene chip (including 59 target genes), the gene mutation of the proband was analyzed by target region capture second generation sequencing, and the mutation loci of the family members were verified by the first generation sequencing. UCSC and polyhpen-2 were used for bioinformatics analysis of mutation sites. Results: all the patients had typical pigmented retinitis pigmentosa. The clinical manifestations were night blindness, peripheral visual field constriction and central visual acuity decline. The pedigree genetic study found that autosomal dominant inheritance was present in the homelands. Genetic analysis of RP candidate genes in 3 patients in this family showed that a single heterozygous mutation c.152CTwas found in exon number 1 of the NRL gene, but no mutation was found in other normal members of the family, which was coisolated from the disease involved in the family. At the protein level, the mutation resulted in the conversion of amino acids from proline to leucine at position 51 of the NRL gene. Conclusion: a Chinese pedigree with retinitis pigmentosa was examined in detail. In this study, there were 3 generations of family members, each generation of patients with retinal pigmentosa, all the patients in the family had night blindness, visual acuity was decreased. The clinical manifestation of visual field constriction, molecular genetic analysis of the family, found the pathogenicity mutation c.152CT (p.Pro51Leu), which caused the 152nd proline of bZIP protein to be replaced by leucine, and then affected the function of protein.
【學位授予單位】：南昌大學
【學位級別】：碩士
【學位授予年份】：2017
【分類號】：R774.1

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