先天性内耳畸形家系致病基因的定位克隆  

Positional cloning in Chinese X-linked congenital inner ear malformation family

作　　者：李庆忠[1] 王秋菊[2,3] 赵亚丽[2] 袁虎[2] 李丽娜[2] 韩东一[2] 

机构地区：[1]复旦大学附属眼耳鼻喉科医院耳鼻咽喉科,上海200031 [2]解放军总医院耳鼻咽喉头颈外科,解放军耳鼻咽喉研究所,北京100853 [3]国家人类基因组北方中心

出　　处：《中国耳鼻咽喉头颈外科》2006年第10期678-682,共5页Chinese Archives of Otolaryngology-Head and Neck Surgery

基　　金：国家自然科学基金面上项目(30370782;30470956;30572016);北京市重大科技项目(H020220020610);高等学校全国优秀博士学位论文作者专项资金资助项目(200463);军队"十一五"杰出人才项目(06J018)联合资助

摘　　要：目的应用分子遗传学的方法揭示一个X-连锁遗传先天性内耳畸形家系的分子病理机制。方法利用X染色体上的微卫星标记进行基因组扫描,通过连锁分析的方法进行致病基因的定位;在定位区域内选取候选基因进行突变筛查。结果①家系所有患者成员均为男性,表型特征为先天性极重度耳聋,颞骨CT扫描发现内耳道扩大,其基底部骨质缺损,蜗轴发育不全,遗传特点符合X-连锁遗传模式;②通过连锁分析在DXS990处得出的最大LOD值为3．27(θ=0．0),将该家系定位在Xq13．1-23之间的区域内;③对定位区域内的基因进行分析后将POU3F4基因作为候选基因对家系成员进行突变检测,发现了与家系中患者成员内耳畸形表型共分离的POU3F4基因新的突变形式(925T→C),该突变位于POU同源结构域中的保守位点,导致编码蛋白氨基酸第309位的丝氨酸突变成脯氨酸(Ser309Pro),110例正常对照者中没有发现同样的突变。结论POU3F4基因一种新的突变形式是导致中国先天性内耳畸形家系中患者的分子病理机制。OBJECTIVE This study aimed at identifying inner ear malformation underlying molecular determinant（s） using a large five-generation Chinese family with multiple familial cases. METHODS Model- based genetic linkage analyses were performed with the use of microsatellite polymorphisms to determine the disease locus. Mutation screening was performed with the family and unrelated population-based controls to establish molecular evidence that caused the specific X-linked inheritance pattern in the family. RESULTS Clinical investigations of the pedigree demonstrated the extremely high penetrance in the male members, but no penetrance in the female members. Linkage analyses mapped the disease to the chromosomal region Xq13.1-Xq23 （maximum X-linkage LOD score = 3.27）. Mutation screening of the candidate genes in the linkage region by direct sequencing revealed a de novo missense substitution （925T→C） in the well- known deaf gene POU3F4. Direct sequencing on 110 unrelated controls did not detect any mutation. CONCLUSION a novel mutation of POU3F4 gene was identified to be the causative reason for the hearing loss in family with inner ear malformation.

关 键 词：迷路疾病 畸形 基因 突变 定位克隆 

分 类 号：R764.7[医药卫生—耳鼻咽喉科]