摘要
背景 约50％的先天性白内障与遗传因素有关,最常见的遗传方式是常染色体显性遗传（AD）.迄今为止,已证实AD性先天性白内障（ADCC）相关的候选基因位点39个及相关基因26个,确定先天性白内障的致病基因及突变位点是治疗的前提.目的 对1个3代AD性后极性白内障中国家系的致病基因进行分析,确定其发病的遗传学基础.方法 于2009年6-12月由山西省眼科医院收集1个中国汉族ADCC家系,家系的19名成员中共8例后极性白内障,11名表型正常.在获得所有受试者的知情同意后,对该家系成员进行临床检查,采集家系所有成员外周静脉血各8 ml并提取DNA.对微卫星标志物进行PCR扩增及其等位基因的检测,并在染色体1 q21-25、1p22.3、2q33-36、11 q22.1-23.21、7q11-12、21q22.3、22q11.2-12.1的区段内分别选取21个多态性微卫星标志物进行连锁分析,计算对数优势（LOD）值;对可能致病的候选基因外显子进行扩增和测序验证突变基因;对新发现的突变用PolyPhen2软件进行突变致病性预测,预测范围值按渐增的风险程度定为0～1.结果 该家系3代中各代均有后极性白内障患者,共8例,各代患者中男女发病机会均等,符合AD发病特征.连锁分析结果显示,在微卫星标志物D11S3178处最大LOD值为4.06（θ=0）.单体型分析表明,该致病基因位于D11S4176 ～ D11S908区域内.对编码区的测序结果表明,CRYAB基因的第2个外显子有1个错义突变（c.209T＞C）,导致其编码的晶状体蛋白第70位的亮氨酸被脯氨酸替代（p.Leu 70 Pro）.PolyPhen2软件分析测试结果表明,该新突变引起所编码的蛋白质结构和功能的损害预测分值为0.996.结论 CRYAB基因为该家系中遗传性先天性后极性白内障的致病基因.
Background About 50％ congenital cataract is associated with inheritance,and the autosomal dominant （AD） inheritance is the most common mode.At least 39 candidate genetic locus and 26 cataract-related genes have been identified to be relevant with AD congenital cataract （ADCC）.To identify the disease-causing gene is important.Objective This study was to identify the mutation gene in a three-generation Chinese family with AD congenital posterior polar cataract.Methods A Chinese family of AD congenital posterior polar cataract was investigated in Shanxi Eye Hospital from June to December in 2009.Nineteen families were included in this pedigree with 8 patients and 11 normal phenotypes.Regular ocular examinations were performed and 8 ml periphery blood simples were collected for the extraction of DNA under the informed consent in each subject.PCR amplification and allele detection were carried out in microsatellite markers.Logarithm of the odds（LOD） scores were calculated using the linkage analysis of 21 polymorphic microsatellite markers in the region of chromosome of 1q21-25,1p22.3,2q33-36,11 q22.1-23.21,7q1 1-12,21q22.3,22q1 1.2-12.1.Mutations were detected by DNA sequence analysis of the candidate genes.Mutation pathogenicity was predicted by PolyPhen2 software for new mutations with the risk intensity from 0 to 1.Results Eight ADCC patients distributed in each generation with the similar subjects in male and female members,complying with the AD mode.Linkage analysis showed the maximal limit of detection （LOD） scores of 4.06 （θ =0） in microsatellite marker D11 S3178.Haplotype analysis showed that the candidate gene located in the region between D11S4176 and D11S908.Direct DNA sequence of CRYAB revealed a T—＞C mutation at nucleotide 209,resulting in a novel 209 T—＞C （p.Leu 70 Pro） mutation.Analysis with polyphen-2 software indicated that this new mutation caused the damage of structure and function of encoded protein （prediction score =0.996）.Conclusions A missense mutation of the CRYAB gene is the major cause of AD congenital posterior polar cataract in this family.
出处
《中华实验眼科杂志》
CAS
CSCD
北大核心
2015年第4期333-337,共5页
Chinese Journal Of Experimental Ophthalmology
基金
山西省自然基金项目（2008011086）
