本文選題：先天性無虹膜　切入點：臨床分析　出處：《中南大學》2012年博士論文

【摘要】：第一章中國一個先天性無虹膜癥家系的經典遺傳學及臨床分析 目的分析中國一個先天性無虹膜家系的遺傳模式及其臨床特點。 方法將就診于中南大學湘雅二醫(yī)院門診的一個先天性無虹膜家系(ANL)進行詳細家系調查并繪制家系圖譜。對自愿參加研究的9名患者進行詳細病史采集及眼部檢查。4名可得到清晰黃斑光學相干斷層掃描(optical coherence tomography, OCT)圖像的患者采用儀器自動按黃斑9格分區(qū)分析視網膜厚度,取黃斑中央區(qū)讀數(shù)為中央區(qū)視網膜厚度,取上方內圈、鼻側內圈、下方內圈、顳側內圈視網膜厚度平均值為旁中心內圈視網膜厚度,取上方外圈、鼻側外圈、下方外圈、顳側外圈為旁中心外圈視網膜厚度,同時隨機選取10名正常志愿者作為正常對照。 結果先天性無虹膜家系(ANL)符合常染色顯性遺傳模式。ANL家系在相同的家庭條件下年齡大者較年齡小者最佳矯正視力(bestcorrected visual acuity, BCVA)差,而在相同年齡的條件下則農民家庭視力較工人家庭BCVA差。患者中央區(qū)視網膜厚度為290.38±12.49μm,旁中心凹內圈視網膜厚度為298.34±14.26μm,旁中心凹外圈視網膜厚度為267.22±11.27μm；與正常志愿者比較,前者P0.05,后兩者P0.05。先證者Ⅲ：9右眼晶體顳下方呈刀削狀,左眼行超聲乳化白內障手術及折疊型人工晶體植入,術中體會前囊膜脆弱,術后眩光現(xiàn)象嚴重。患者Ⅲ：16同時患精神分裂癥；患者Ⅳ：18同時患精神異常,但未分型,還同時患先天性青光眼�；颊撷簦�16是隨訪9人中殘存虹膜組織最多者,其左眼虹膜組織較右眼多,且在左眼瞳孔區(qū)鼻上方見瞳孔殘膜。 結論(1)先天性無虹膜癥ANL家系遺傳模式為常染色體顯性遺傳；(2)先天性無虹膜癥BCVA隨年齡下降可能與晶體混濁及視網膜的光損傷有關；(3)先天性無虹膜癥黃斑中心凹發(fā)育不良主要表現(xiàn)為黃斑中央區(qū)明顯增厚,中心凹處存在除神經纖維層以外的各層視網膜結構；(4)先天性無虹膜患者晶體形態(tài)可發(fā)育異常,其白內障可能在達到某個程度后即迅速發(fā)展；(5)先天性無虹膜患者白內障手術時需綜合考慮前囊膜脆弱及術后視覺質量問題；(6)先天性無虹膜ANL家系內存在虹膜形態(tài)及精神疾病的表現(xiàn)型變異；(7)先天性無虹膜患者瞳孔殘膜為發(fā)病機制的虹膜組織萎縮過多學說提供支持。 第二章中國一個常染色體顯性遺傳先天性無虹膜癥家系PAX6基因序列及外顯子拷貝數(shù)測定 目的確定中國一個常染色體顯性遺傳先天性無虹膜癥家系PAX6基因啟動子區(qū)、外顯子、外顯子與內含子交界處是否存在基因變異以及外顯子拷貝數(shù)是否有變化。 方法提取中國一個常染色體顯性遺傳先天性無虹膜家系ANL先證者Ⅲ：9基因組DNA,采用PCR擴增直接測序法測定其PAX6基因3個轉錄異構體的2個啟動子區(qū)、5’端非編碼區(qū)(5'-untranslated region,5'-UTR)、編碼區(qū)(coding region)、3’端非編碼區(qū)(3'-untranslated region,3'-UTR)以及剪接位點的DNA序列,采用實時定量PCR(real-time quantitative PCR, qPCR)方法測定3個轉錄異構體所有外顯子拷貝數(shù),qPCR采用ΔΔCt相對定量數(shù)據(jù)分析方法。 結果先證者Ⅲ：9的PAX6基因在轉錄異構體3啟動子區(qū)檢測到4個已報道的單核苷酸多態(tài)性(Single nucleotide polymorphism, SNP)rs1806155、rs5790870、rs1806156、rs1806157和rs1806180,并檢測到1個未報道為SNP但與疾病表型無共分離現(xiàn)象的堿基替換g.-1217CT；在第12號內含子檢測到1個SNP rs3026393;在3’-UTR檢測到1個SNP rs1506。轉錄異構體1和轉錄異構體2啟動子區(qū)因GC含量過高導致PCR經反復優(yōu)化條件仍擴增失敗。PAX6基因3個轉錄異構體各外顯子拷貝數(shù)均為雙拷貝。 結論先天性無虹膜家系ANL的致病突變與PAX6外顯子及外顯子內含子交界處序列及拷貝數(shù)變異無關,與轉錄異構體3啟動子區(qū)無關,但不能排除是否與轉錄異構體1和轉錄異構體2啟動子區(qū)有關。 第三章中國一個常染色體顯性遺傳先天性無虹膜癥家系的基因連鎖定位 目的先天性無虹膜家系ANL的致病基因是否與PAX6基因有關。 方法提取中國一個常染色體顯性遺傳先天性無虹膜家系ANL的2個分支現(xiàn)存21人基因組DNA,并在PAX6基因附近選取6個微衛(wèi)星標記D11S904、D11S1324、D11S914、D11S1776、D11S907和D11S935進行連鎖分析,采用LOD值兩點連鎖分析,并構建單體型。 結果6個微衛(wèi)星標記中在PAX6基因下游微衛(wèi)星標記D11S1324取得LOD最大值3.16(θ=0),且其附近標記物的LOD值均在θ=0時取得大于1的正數(shù)。單體型分析表明6個微衛(wèi)星標記構成的區(qū)域在家系中呈現(xiàn)出與疾病表型共分離現(xiàn)象。 結論先天性無虹膜癥家系ANL的致病基因定位與PAX6基因附近,并且位于PAX6基因下游的可能性大。
[Abstract]:The classic genetics and clinical analysis of a Chinese family with congenital irinsis
Objective to analyze the genetic pattern and clinical characteristics of a congenital ininirinid family in China.
Methods a congenital treatment in Xiangya No.2 Hospital of Central South University clinic aniridia family (ANL) detailed pedigree investigation and family maps were drawn. The 9 patients volunteered for the study detailed history collection and eye examination.4 can obtain clear macular optical coherence tomography (optical coherence tomography, OCT) instrument the 9 grid partition automatically according to the macular retinal thickness analysis by image were taken as the central retinal thickness of macular central readings, the top side of the nose below the inner ring, inner ring, inner ring, the inner retinal thickness of the temporal average paracentral inner retinal thickness, the top side of the nose below the outer ring, outer ring, outer ring, the outer ring is adjacent to the temporal side the center of the outer retinal thickness, and randomly selected 10 healthy volunteers as normal control.
The results of congenital aniridia family (ANL) with autosomal dominant genetic model.ANL family age in the same family conditions than the younger, the best corrected visual acuity (bestcorrected visual, acuity, BCVA), and in the same age under the condition of peasant family worker family vision was BCVA. Central retinal thickness with 290.38 + 12.49 m, parafoveal inner retinal thickness was 298.34 + 14.26 m, parafoveal outer retinal thickness was 267.22 + 11.27 m; compared with normal volunteers after the former P0.05, two P0.05. proband III: 9 under the right eye was cut crystal temporal shape, the left eye of phacoemulsification cataract surgery and foldable IOL implantation. The intraoperative experience of anterior capsule fragility, postoperative glare phenomenon is serious. At the same time: 16 patients of schizophrenia patients; IV: 18 patients with mental disorders, but not type, also from the first Natural glaucoma. Patients IV: 16, the most remaining iris tissues were followed up in 9 patients. The iris tissue in the left eye was more than that in the right eye, and the pupillary remnant membrane was seen above the nasal area in the left eye pupil area.
Conclusion (1) congenital aniridia family ANL is an autosomal dominant genetic model; (2) congenital aniridia with age BCVA decline may be related to lens opacity and retinal light injury; (3) congenital aniridia and foveal hypoplasia mainly manifested as thickening of central macular. The retinal nerve fiber layer in the layer structure outside the fovea; (4) congenital aniridia patients with abnormal development of the crystal morphology, in cataract may reach a certain level after the rapid development; (5) considering the quality problems of visual anterior capsule fragile and postoperative cataract surgery in patients with congenital aniridia required time; (6) congenital absence of phenotypic variation in iris morphology and iris ANL mental illness within the family; (7) the iris tissue of congenital aniridia patients with pupillary membrane for the pathogenesis of the atrophy of too much theory to provide support.
The second chapter of an autosomal dominant hereditary inirinosus family PAX6 gene sequence and the determination of the exon copy number
Objective to determine whether there is genetic variation in the promoter region of PAX6 gene, exon, exon and intron in Chinese family with autosomal dominant congenital irirma, and whether exon copy number is changed.
A method of extracting China autosomal dominant congenital aniridia proband ANL III: 9 genomic DNA 2 promoter region was amplified by PCR direct sequencing method for the determination of the PAX6 gene of 3 transcripts, 5 'non encoding region (5'-untranslated, region, 5'-UTR (coding) encoding region region), 3' non encoding region (3'-untranslated region, 3'-UTR) and splice sites of DNA sequences, using quantitative real-time PCR (real-time quantitative PCR, qPCR) method for the determination of 3 transcripts of all exon copy number of qPCR, adopting the analysis method of relative quantitative data of delta delta Ct.
Results the proband III: PAX6 9 gene transcription in the detection of 3 isomers of the promoter region to 4 reported single nucleotide polymorphisms (Single, nucleotide polymorphism, SNP) rs1806155, rs5790870, rs1806156, rs1806157 and rs1806180, and detected 1 reports for SNP but not with the disease phenotype without co segregation phenomenon base substitution g.-1217CT; in intron twelfth was detected in 1 SNP rs3026393; in the 3 '-UTR detected 1 SNP rs1506. transcripts of 1 and 2 transcripts of the promoter region due to the high content of GC to PCR by optimizing conditions still failed to amplify the.PAX6 gene transcripts of the 3 exon copy the number was two copies.
Conclusion the pathogenesis of congenital ironic pedigree ANL is independent of PAX6 exon and exon intron junction sequence and copy number variation, but has nothing to do with the promoter region of transcriptional isomer 3, but it cannot be excluded whether it is related to the promoter region of transcriptional isomer 1 and transcriptional isomer 2.
The third chapter of gene linkage localization in an autosomal dominant congenital inininosinic family
Objective whether the pathogenic gene of ANL in the congenital iririd family is related to the PAX6 gene.
A method of extracting Chinese autosomal dominant congenital aniridia family ANL of the 2 branches of the existing 21 human genomic DNA, and selected 6 microsatellite markers D11S904, D11S1324, D11S914, D11S1776 in D11S907 and D11S935 near the PAX6 gene, linkage analysis, the LOD value of two-point linkage analysis and haplotype.
The results of 6 microsatellite markers in the downstream of PAX6 gene microsatellite marker D11S1324 has a maximum value of 3.16 LOD (0 =0), and near the marker LOD was obtained in theta =0 greater than 1 positive. Haplotype analysis showed that 6 microsatellite markers of the region showing co segregated with the disease phenotype the phenomenon in the family.
Conclusion the pathogenicity of ANL in the congenital irinic family is located near the PAX6 gene, and the possibility of the downstream of the PAX6 gene is great.

【學位授予單位】：中南大學
【學位級別】：博士
【學位授予年份】：2012
【分類號】：R773.1

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