摘要: 目的:报道1个涉及5代17例患者的常染色体显性先天性白内障(ADCC)大家系,并进行致病基冈的定 位。
方法:对家系中8例患者进行眼科检查后明确临床表型,并提取所有血样的基因组DNA。首先对已报道的 中国ADCC家系致病位点(9个基因的16个突变位点)进行DNA测序,然后根据已报道的17个ADCC候选基凶 和13个染色体区域,选取27个微卫星分子标记,应用LINKAGE软件进行连锁分析。
结果:8例患者均为先天性核性白内障。直接DNA测序未发现有已报道的中国家系基冈突变。所选取的27个微卫星分子标记与该家系致病基冈均不连锁。
结论:该ADCC家系致病基因不在已报道的17个ADCC候选基因和13个染色体区域,该家系巾可能存在一个新的ADCC致病基因。
关键词: 先天性白内障; 常染色体显性遗传; 连锁分析
Gene mapping of a large Chinese family with autosomal dominant congenital cataract XIA Xin—yil,CUI Ying—xial,JIN Li2,XIE Ping—xin92,ZHANG Fen92,YANG Binl, ZHANG Li-jin93,WANG Li-li’,XUE Chun-yan3,LI Xiao-junl,HUANG Yu—fen91 (1.PLA Institute of Clinical Laboratory Medicine,School of Medicine,Nanjing University,Nanjing Gen— eral Hospital ofNanjing Military Command,PLA,Nanjing 210002,Jiangsu,China;2.Institute of Ge— neti岱,Fudan University,Shanghai 200433,China;3.Department ofOphthalmology,Nanjing General Hospital of Nanjing Military Command,PLA,Nanjing 2 10002,Jiangsu,China) Abstract: Objeeave:To report a large Chinese family in which 17 patients over 5 generations were diagnosed as autosomal dominant congenital cataract(ADCC)and map the related genes. Methods: Ophthalmic examinations were performed to verify the clinical phenotype in 8 patients of the ADCC fam— ily and genomic DNA of all blood samples was extracted.Firstly,direct DNA sequencing was carried out on all reported mutation points(16 points of 9 genes)in Chinese ADCC families.Then,27 microsatellite polymorphic mal'ker8,near 17 candidate genes and 13 chromosomal loci,were selected and
linkage analysis were performed with LINKAGE software package. Results:Eight patients involved in the study were diagnosed as congenital nuclear cataract.No mutations were found in 16 points of 9 genes by DNA sequencing.There was no linkage between the selected 27 marker8 and the genes causing ADCC in the family. Conclusion:The causative mutation is not located on the 17 candidate genes and 13 chromosomal loci,which might suggest that a novel ADCC—related gene be responsible for the phenotype of this family. Key words: Congenital cataract; Autosomal dominant;Linkage analysis
0引言
先天性白内障是儿童常见的致盲性眼病,其发病率为0.01%~0.06%,占儿童致盲眼病的第2 位。约有1/3先天性白内障是遗传性的,其遗传方式有常染色体显性、常染色体隐性和x连锁遗传3 种。其中常染色体显性先天性白内障(autosomaldominant congenital cataract,ADCC)最为常见¨,2J o迄今为止,已发现17个基因与ADCC的发生有关,包括8个晶状体蛋白基因(CRYAA、CRYAB、CRYBBl、CRYBB2、CRYBAl/A3、CRYGC、CRYGD、CRYGS)‘3—6|。3个膜蛋白基因即缝隙连接蛋白基因(伽3GJA8)p,81和主要内源性膜蛋白基因(M1P26)一J,念珠状纤丝蛋白基因(BFSP2)¨0。,铁蛋白轻链基因(肌)[ill以及4个转录调节因子基因(MAF、PITX3、船肘、朋舶)¨2。141。另外,至少还有12个尚未鉴定 出致病基因的染色体区域与ADCC连锁¨51。一般认为,收集有明确家族遗传史的大家系,进行致病基因 的定位与克隆,是研究遗传病发病机制、进行遗传咨询和产前诊断预防疾病发生的关键步骤。我们现报 道1个涉及5代17例患者的ADCC中国大家系,并进行致病基因定位的初步研究。
1资料和方法
1.1 研究对象一个先天性白内障大家系,来自江苏徐州地区。家系调查发现,该家系成员共计85人,患者17例(先天性白内障患者Ⅲ29为配偶,与该家系无血缘关系,故不计入其内),其中男12例,女5例(图1)。家系中所有健在成员均经全面的体格检查,并进行视力检查、散瞳裂隙灯和眼底镜检查。所有被检查的患者自诉出生后视力模糊,双眼视力均低于0.3。眼科检查发现,裂隙灯下可见晶状体混浊均位于瞳孔区。为白色圆盘状混浊,均为核性白内障,患者IV6的散瞳裂隙灯照片见图2。所有患者散瞳眼底检查无明显异常,亲代均无血缘关系。根据患者家系中男女均会发病,患者后代约1/2发病,非患者后代均正常,确定该家系的遗传方式为常染色体显性遗传,外显率100%。结合其先天性白内障的表型,诊断为ADCC。
和医院伦理委员会的批准后,分别抽取家系成员中的8例患者和48名健康者静脉血5ml。应用wi脚d删试剂盒(美国Promega公司)提取基因组DNA,一20%保存。
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