摘要
Leber眼病包括Leber先天性黑矇(Leber congenital amaurosis,LCA)和Leber遗传视神经萎缩(Leber's hereditary optic neuropathy LHON),先天性白内障(congenitalcataract)是眼科系统内比较重要儿童致盲性的遗传眼病,遗传方式有常染色体显性、常染色体隐性和性连锁遗传等方式。本课题对这两类遗传疾病进行了临床方面研究和分子遗传学研究,涉及家系鉴定,致病基因的定位和基因突变分析。
第一部分内容对LCA的临床特征及其致病基因RPE65进行突变检测研究。收集分析9例年龄4～28岁的Leber先天性黑蒙先证者临床资料。检查包括最好矫正视力,屈光度,眼底照相,荧光造影和视网膜电图。对其中5例LCA患者提取基因组DNA,应用PCR及变性高效液相色谱分析法(Denaturing High Performance LiquidChromatography,DHPLC)分析RPE65基因十四个外显子,对可能有变异的外显子进行直接测序。结果表明9例患者均在12个月以内出现视力差或对视觉刺激无反应,症状年龄最小在3个月。9例患者最好矫正视力均小于0.2。9例均有眼球震颤。眼底彩照9例均有异常。6例行眼底荧光造影显示异常。2例有家族史并呈常染色体隐性遗传。3例为近亲婚配。ERG锥杆反应重度下降或记录不到波。对5例患者行RPE65基因十四个外显子的检测,未发现突变,5例患者均在第7外显子前发现同一位点单核苷酸多态性改变。
第二部分对一四代LHON家系NADH基因进行测序分析(ubiquinoneoxidoreductase,ND),对已知发现三个碱基的突变G3640A,G11778A,and T14484C,分别位于ND1,ND4和ND6亚基,在周围设计三对引物,进行PCR扩增,对产物进行直接测序。已知的LHONmtDNA(G3460A,G11778A,and T14484C)三个位点进行突变分析,结果发现所有六个患者T14484C位点处的ND6发生T到C的突变-T14502C,Tle58Val。
第三部分鉴定中国一先天性白内障家系进行分子遗传连锁分析和致病基因的定位筛选,首先分析22个家系成员中的17个先天性白内障患者的临床资料,确定诊断。每10cM选择一个微卫星标记物,共用382对微卫星标记物对所有家系成员进行全基因组扫描和基因连锁分析,确定致病基因的染色体位点,对候选基因直接测序。结果发现此家系的致病基因定位于染色体20p12.2-p11.23上D20S915和D20S912之间7.4Mb的区域内,在D20S471测得最高LOD值5.15(θ=0)。候选基因BFSP1和CHMP4B中均未检测到突变。推测在染色体20p12.2-p11.23上存在一个新的先天性白内障的致病基因,这有助于进一步对染色体20q位点候选基因进行鉴定,对先天性白内障的发病机制的研究具有指导意义。
Leber Inherited eye diseases include Leber congenital amaurosis(LCA) and Leber's hereditary optic neuropathy(LHON),and congenital cataract,both of them two important autosomal dominant,autosomal recessive and X-linked blinded eye disease in ophthalmology.In the present study,we have employed the molecular genetic technology, including clinical characterization of large families,linkage mapping of the chromosomal location of the disease causing genes,and mutational analysis,to study the two types of diseases.
First part focus on the LCA,research on the clinic feature and screening the RPE65 mutation on 9 cases we had collected,the age from 4～28.Ocular examination included the:corrected visual acluity,optometry degree,ocular fundus image,fluorescein fundus angiography(FFA),and ERG Of 5 blood DNA samples had been isolated and used Denatuing High Performance Liquid Chromatography(DHPLC) to screen the mutation of all 14 exons of RPE65.If found some positive sign in DHPLC,direct sequencing would be performed for mutation analysis.The results showed the there is no visual stimuli and appear the visual impairment within 12 months after birth in all 9 patients,and the earliest symptom appeared in 3-month-old baby.The best corrected less than 20/100,and companied the nystagmus,ocular fundus images showed abnormal,and FFA also showed the abnormal.Of 2 families had the autosomal recessive inherited history,and of 3 the loop families history.Three patients were form consanguineous mating family.ERG cone and rod responses were markedly reduced or non-recordable in all cases.Mutation in the all fourteen exons of the RPE65 gene was not detected in the collected five patients.But the same single nucleotide polymorphisms(SNP) were found in the collected five patients. Second part analyzed a four generation family with LHON,and screened the NADH gene mutation,we clinically characterized a Chinese family with complete panetrance of LHON symptom.The patients in the family present with variable clinical features.By direct DNA sequence analysis,we identified both T14484C mutation and nearby T to C variant at nucleotide 14502 of mitochondria DNA.The T14502C variant altered I58 to V of the protein ND6,which was present in all patients of the family,but not in four unaffected family members and 200 normal controls.The co-existence of both T14484C mutation and T14502C substitution in all patients from the same LHON family suggests that T14502C may play a synergistic role with the primary mutation,and account for complete penetrance and absence of marked gender bias and visual recovery in the Chinese LHON family.
The third part we had analyzed a family with autosomal dominant congenital cataract, and maped a gene responsible for infantile cataract in a large four-generation, non-consanguineous Chinese family.Congenital cataract is a clinically diverse and genetically heterogeneous disorder of the crystalline lens,and a leading cause of visual impairment.Twenty two family members including 17 cataract patients in the Chinese family were analyzed clinically.All of family members were genotyped with 382 microsatellite markers that provide genome-wide coverage by every 10 cM.Linkage analysis was carried out to identify the chromosomal location of the infantile cataract gene in the family.Candidate genes were studied by direct DNA sequence analysis.The results showed:Genome-wide linkage analysis provided evidence for a genetic locus for infantile cataract on chromosome 20p12.2-p11.23.The maximum LOD score was 5.15 for marker D20S471 at a recombination fraction of 0.Fine mapping defined the cataract gene within a 7.4 Mb interval between markers D20S915 and D20S912.No mutation was detected in potential candidate genes BFSP1 and CHMP4B.Our results suggest that there is a new gene for infantile cataract on chromosome 20p12.2-p11.23.Our results provide a frame to identify a new gene for infantile cataract by future studies of candidate genes at the 20q locus,which should provide insights into the pathogenic mechanisms of cataracts.
引文
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