本文選題：晶狀體脫位 + 馬凡氏綜合征��； 參考：《天津醫(yī)科大學(xué)》2010年博士論文

【摘要】： 目的 應(yīng)用連鎖分析、基因測(cè)序的方法,對(duì)一個(gè)常染色體顯性遺傳的晶狀體脫位(Ectopia lentis, EL)家系進(jìn)行基因篩查及定位,探討該家系的發(fā)病原因；分析該家系的臨床特點(diǎn),回顧總結(jié)該家系的治療效果及并發(fā)癥,討論晶狀體脫位的治療方法。 方法 1分子遺傳學(xué)研究 1.1取家系成員外周血5-8ml,采用Roche Biochemical公司的DNA分離試劑盒提取基因組DNA。 1.2基因分型和連鎖分析：選取15號(hào)染色體上微衛(wèi)星標(biāo)記物進(jìn)行基因組掃描。利用聚合酶鏈反應(yīng)擴(kuò)增微衛(wèi)星標(biāo)記物,通過ABI3130-avant全自動(dòng)分析儀讀取微衛(wèi)星標(biāo)記物的等位基因片段大小,應(yīng)用Genescan3.7軟件進(jìn)行單體型結(jié)構(gòu)分析,利用LINKAGE5.1軟件包中MLINK程序進(jìn)行兩點(diǎn)法計(jì)算LOD值,并構(gòu)建單體型。 1.3基因序列分析：對(duì)所有家系患病成員及正常同胞進(jìn)行FBN-1基因全部編碼序列分析,包括FBN1基因的全部65個(gè)外顯子,5’及3’端與外顯子拼接的內(nèi)含子序列。通過ABI3130測(cè)序儀讀取基因序列。利用單鏈構(gòu)象多態(tài)性分析對(duì)突變基因進(jìn)行篩查。 2.回顧性臨床研究 2.1 EL家系患者的臨床特點(diǎn) 2.2 EL家系患者病史采集。收集原始病歷,分別進(jìn)行視力,屈光狀態(tài),裂隙燈,前節(jié)照相,超聲生物顯微鏡(UBM)檢查,眼底等眼部檢查。同時(shí)注意全身情況,尤其注意骨骼系統(tǒng)包括身高四肢及心血管系統(tǒng)如心臟超聲波的檢查。 2.3該家系患者晶狀體脫位的治療用晶狀體囊內(nèi)摘除法。 結(jié)果 1分子遺傳學(xué)研究 經(jīng)過對(duì)15號(hào)染色體上的微衛(wèi)星位點(diǎn)進(jìn)行連鎖分析并計(jì)算LOD值,發(fā)現(xiàn)在15號(hào)染色體著絲粒附近的兩個(gè)微衛(wèi)星標(biāo)記物D15S994和D15S978均獲得正值,其中在D15S978取得最大LOD值為3.01。單體型分析發(fā)現(xiàn)該家系臨床表型與D15S978等位基因片段存在共分離現(xiàn)象,支持該家系致病基因位于常染色體15q21.1-15q21.3區(qū)間。在此區(qū)間內(nèi)的候選基因FBN1與晶狀體脫位以及MARFAN綜合征的發(fā)病相關(guān)。 對(duì)FBN1基因直接測(cè)序顯示家系中所有患者在FBN1基因的第29外顯子存在雜和性突變,mRNA第3519位堿基出現(xiàn)C→G的雜合性堿基改變,導(dǎo)致了野生型基因編碼的谷氨酰胺(Asparagine, Asn或N)被賴氨酸(Lysine, Lys或K)替代,使第1173編碼子發(fā)生了N1173K的突變,并且該突變與疾病表型共分離。通過SSCP篩查100名正常對(duì)照未發(fā)現(xiàn)類似改變,說明c.C3519T(p.Asn1173Lys)為致病性基因突變,而非多態(tài)性堿基序列改變。說明FBN1基因c.C3519T(p.Asn1173Lys)突變是導(dǎo)致該家系的致病性基因突變。 2臨床研究 2.1臨床表現(xiàn)該EL家系三代同胞13人,共有8名患者,男5例女3例。具有完全外顯的常染色體顯性遺傳特性�；颊叩呐R床特征都表現(xiàn)為晶狀體脫位,均向顳側(cè)脫位,脫離范圍大于1／2。該家系患者多數(shù)在30歲以后視力逐漸下降,之前均為1.0視力(主訴)。身高無明顯馬凡氏特征。復(fù)習(xí)以前的病歷診斷均為原發(fā)性晶狀體脫位。但是只有1名患者(第三代,待手術(shù)。照片1左1),身高及相貌類似馬凡氏特征,但超聲心動(dòng)圖檢查無明顯陽性體征,建議隨訪觀察。其他患者也無心血管系統(tǒng)的陽性發(fā)現(xiàn)。因此不能診斷為馬凡氏綜合征。因此我們將該家系診斷為原發(fā)性晶狀體脫位。 2.2治療效果及并發(fā)癥：家系8名患者6例已行晶狀體囊內(nèi)摘除術(shù)。6例(8眼)患者手術(shù)后矯正視力均較術(shù)前明顯提高；1例1眼術(shù)前矯正視力1.0,因?yàn)閷?duì)側(cè)眼發(fā)生晶狀體全脫位,導(dǎo)致失明,因此為防止晶狀體全脫位要求手術(shù),術(shù)后矯正視力0.6。有3例3眼發(fā)生晶狀體全脫位于前房,合并繼發(fā)性青光眼,急診手術(shù)取出晶狀體,術(shù)后角膜失代償,2例導(dǎo)致失明,1例矯正視力0.3。1例1眼術(shù)后10年發(fā)生黃斑出血,視網(wǎng)膜脫離,手動(dòng)視力。因此目前該家系術(shù)后12眼失明3眼。2例4眼仍然待手術(shù)。 結(jié)論 1確定了一個(gè)常染色體顯性遺傳的晶狀體脫位家系,家系同胞13人,8名患者。經(jīng)序列分析發(fā)現(xiàn)晶狀體脫位家系患者均存在FBN-1基因第29外顯子的N1173K突變。SSCP分析證實(shí)了這一突變于與疾病表型共分離。因此,FBN1基因c.C3519T(p.Asn1173Lys)突變可能是導(dǎo)致該家系的致病性基因突變。 2家系患者間表現(xiàn)型存在異質(zhì)性。第三代1名患者身高與馬凡氏綜合征類似,而第一代與第二代身高無明顯異常。 3晶狀體脫位的手術(shù)時(shí)機(jī)應(yīng)恰當(dāng)選擇,發(fā)生晶狀體全脫位后預(yù)后較差。
[Abstract]:objective
Using the method of linkage analysis and gene sequencing, the genetic screening and localization of an autosomal dominant Ectopia lentis (EL) family were carried out to explore the causes of the family, the clinical characteristics of the family, the therapeutic effects and complications of the family, and the treatment of the dislocation of the lens were reviewed and summarized.
Method
1 molecular genetics research
1.1 the peripheral blood 5-8ml of family members was extracted and genomic DNA. was extracted by Roche Biochemical DNA separation kit.
1.2 genotyping and linkage analysis: the microsatellite markers on chromosome 15 were selected for genome scans. The microsatellite markers were amplified by polymerase chain reaction, and the size of the allele fragments of microsatellite markers was read by ABI3130-avant automatic analyzer, and Genescan3.7 software was used to analyze the haplotype structure and use LINKAGE5 The MLINK program in the.1 software package calculates the LOD value by two point method and constructs the haplotype.
1.3 gene sequence analysis: all family members and normal compatriots in all the FBN-1 gene sequence analysis, including all 65 exons of the FBN1 gene, 5 'and 3' end and exons intron sequence. The gene sequence was read by ABI3130 sequencer. Single strand conformation polymorphism analysis was used to screen the mutant gene. Check.
2. retrospective clinical study
Clinical characteristics of 2.1 EL families
2.2 EL family history collection. Collect the original medical records for visual acuity, refractive state, slit lamp, anterior segment photography, ultrasound biomicroscope (UBM) examination, eye fundus and other eye examination. Meanwhile, pay attention to the whole body, especially the skeletal system including the height and limbs and the heart blood tube system such as echocardiography.
2.3 the removal of lens dislocation in the family is treated by intracapsular cataract extraction.
Result
1 molecular genetics research
After linkage analysis of the microsatellite sites on chromosome 15 and calculating the LOD value, it was found that two microsatellite markers near the 15 chromosome centromere of the 15 chromosome were positive. The maximum LOD value of D15S978 was 3.01. haplotype analysis and found that the family bed phenotype and D15S978 allele fragments existed in common. The segregation phenomenon supports the disease gene of the family in the autosomal 15q21.1-15q21.3 interval. The candidate gene FBN1 in this interval is associated with the dislocation of the lens and the incidence of MARFAN syndrome.
Direct sequencing of the FBN1 gene showed that all the patients in the family had a heterozygous mutation in the twenty-ninth exon of the FBN1 gene, and the heterozygosity of the mRNA 3519th bases appeared C to G, which led to the substitution of the glutamine (Asparagine, Asn or N) encoded by the wild type gene by lysine (Lysine, Lys or K), and the 1173rd codons occurred in N1173K. 100 normal controls were screened by SSCP without similar changes, indicating that c.C3519T (p.Asn1173Lys) was a pathogenicity gene mutation, not a polymorphic base sequence change. The FBN1 gene c.C3519T (p.Asn1173Lys) mutation was a pathogenic gene mutation leading to the family.
2 clinical study
2.1 the clinical manifestations of the EL family were 13 people of three generation compatriots. There were 8 patients and 5 male and 3 women. The clinical features of the patients were completely autosomal dominant. The clinical features of the patients showed dislocation of the lens, the temporal dislocation of the patients were more than 1 / 2., and the majority of the families were gradually decreased after the age of 30, and all were 1 visual acuity. There was no obvious Marfan characteristic of height. Review of previous medical records were all primary lens dislocation. But only 1 patients (third generation, surgery, 1 left 1), height and appearance resembling the Marfan features, but no obvious positive signs were found in echocardiography. Therefore, we can not diagnose Marfan's syndrome. Therefore, we diagnosed this family as primary lens dislocation.
2.2 treatment effect and complications: 6 cases of 8 patients in the family had undergone intraocular lens extirpation in 6 cases (8 eyes). The corrected visual acuity after operation was significantly higher than that before operation. 1 cases 1 eyes corrected visual acuity before operation 1, because of the total dislocation of the lens in the lateral eye, resulting in blindness, so the operation was required to prevent the total dislocation of the lens, and the corrected visual acuity was 0.6. after operation. In 3 cases, 3 eyes had complete lens detachment in the anterior chamber, combined with secondary glaucoma, emergency surgery to remove the lens, postoperative corneal decompensation, 2 cases of blindness, 1 cases of corrected visual acuity in 0.3.1 1 eyes and 10 years after the operation of macular hemorrhage, retinal detachment, and manual vision. So at present, 12 eyes, 3 eyes, and 4 eyes, 4 eyes and 4 eyes of 3 eyes still remain to be operated.
conclusion
1 a family of autosomal dominant hereditary lens dislocation, 13 people in family and 8 patients, the N1173K mutation.SSCP analysis of the FBN-1 gene twenty-ninth exon confirmed by sequence analysis that the mutation was common to the disease phenotype. Therefore, the FBN1 gene c.C3519T (p.Asn1173Lys) mutation can be found. It can be a pathogenic gene mutation that leads to the family.
There was heterogeneity between the 2 family patients. The height of third generation 1 patients was similar to Marfan syndrome, but there was no significant difference between the first and second generations.
3 the operation time of lens dislocation should be properly chosen. The prognosis of lens dislocation is poor.

【學(xué)位授予單位】：天津醫(yī)科大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2010
【分類號(hào)】：R776

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