【作者】 朱奇慧；

【导师】 王擎； 刘木根；

【作者基本信息】 华中科技大学 ， 生物化学与分子生物学， 2007， 硕士

【摘要】 耳聋(deafness,hearing impairment)系指听力下降乃至消失的一种耳病,是听觉传导通路发生器质性或功能性病变导致不同程度听力损害的总称。耳聋是一种十分常见的人类听觉系统疾病,约有1/1000的新生儿患有先天性耳聋。听觉系统的部位的疾病,都会导致耳聋。在所有造成耳聋的原因中,遗传因素是最主要的,50%以上的先天性耳聋都是由于遗传因素造成的。随着分子遗传学研究技术的发展,越来越多的与耳聋有关的基因被发现和克隆。已发现基因包括23个常染色体隐性非综合征性耳聋(nonsyndromic hearing impairment, NSHI)基因和21个常染色体显性非综合征性耳聋基因。这些研究对于进一步深入了解耳聋的生理病理机制有重要意义。本课题分别对一个常染色体隐性NSHI家系和一个常染色体显性NSHI家系进行分子遗传研究,阐明这两个家系致病的遗传基础。在本研究中,我们收集了江苏省盐城市和射阳市各一个非综合征性耳聋家系(分别命名为家系1和家系2),并对其进行了分子遗传学研究。家系1由家系图分析表明呈现常染色体隐性遗传,对所有已知常染色体隐性遗传的NSHI致病基因,选用其侧翼的微卫星标记进行连锁分析,发现该家系的致病基因与D13S175连锁。对编码β-2型间隙连接蛋白的基因GJB2进行整个编码区域的测序,发现235碱基处发生了碱基C的纯合缺失,导致蛋白质翻译提前终止,无法形成有功能的GJB2蛋白,这一突变是该家系中绝大多数患者致病的遗传基础。家系2为常染色体显性遗传,对已知的常染色体显性遗传的NSHI致病基因进行连锁分析,结果排除了所有已知的常染色体显性NSHI基因,表明导致家系2耳聋症状的可能是一个新的耳聋致病基因,有望通过进一步的研究更深入的了解耳聋的生理病理机制。更多还原

【Abstract】 Hearing impairment is a partial decrease or complete loss of one’s ability to detect sounds and occurs with structural or functional impairment and/or damage of the hearing system. Hearing impairment is the most common human disorder of the auditory system and approximately 1/1000 children are born with congenital hearing loss. Damages in any part of the auditory system can cause hearing impairment. Genetic factors are the most important factor that causes hearing impairment. More than 50% of the congenital hearing impairment cases are caused by genetic factors. With the rapid advances in molecular genetic technologies, many genes for hearing impairment have been cloned or identified including 23 genes for autosomal recessive hearing impairment 21 genes for the autosomal dominant form of the disease. These genetic studies have provided significant insights into the physiological and pathological mechanisms of hearing impairment. The present study employed the human molecular genetic approach to characterize two Chinese families with nonsyndromic hearing impairment (NSHI).We recruited the two NSHI families from Jiangsu Province of China: one family was from the city of Yancheng (referred to as family 1) and the other was from the city of Sheyang (family 2). Family 1 exhibits an autosomal recessive mode of inheritance and family 2’s inheritance is autosomal dominant. For family 1, we carried out linkage analysis with microsatellite markers flanking all known autosomal recessive NSHI genes and linked the causative gene in the family to polymorphic microsatellite marker D13S175. Direct DNA sequence analysis of the entire coding region of the GJB2 gene encoding connexin 26 (orβ-2 gap junction protein) revealed that a 1-bp homozygous deletion, 235delC, was responsible for the disease in the family. The deletion causes a frameshift and premature termination of translation. For family 2, we performed linkage analysis with the markers spanning all autosomal dominant NSHI genes. Our results excluded all the known autosomal dominant NSHI genes as the cause of the disease in the family, indicating that family 2 may harbor a new causative gene for NSHI. Future studies on family 2 may identify a new NSHI gene and provide significant insights into the physiological and pathological mechanisms of hearing impairment.更多还原