项目名称： 神经嵴异常相关综合征型耳聋的遗传因素分析及其致病机制研究

项目编号： No.81470705

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 冯永

作者单位： 中南大学

项目金额： 73万元

中文摘要： 综合征型耳聋（SHL）现已报道400多种，其极强的临床和遗传异质性使得系统地研究其遗传基础及发病机制十分困难。SHL绝大部分少见，临床常见的有Waardenburg综合征（WS）、先天性小耳畸形综合征、前庭导水管扩大综合征等。以SOX10与PAX3为中心的基因作用网络引起的神经嵴细胞功能异常与WS、小耳畸形及前庭导水管扩大等表型相关。本课题组的前期研究也证实该基因网络参与WS的发病机制。本研究拟以神经嵴异常相关基因网络可能参与上述SHL表型的发病机制作为研究假设，收集上述表型的家系及病例，使用全外显子测序定位克隆SHL新基因，从分子和细胞水平（诱导多潜能干细胞（iPSCs）技术）系统的研究导致SHL的共同通路和致病机制。本研究将丰富SHL的分子遗传背景，为SHL的系统研究提供新思路并为进一步的干预治疗奠定研究基础

中文关键词： 综合征型耳聋；神经嵴；基因突变；蛋白互作；诱导多潜能干细胞技术

英文摘要： Over 400 types of syndromic hearing loss (SHL) has been reported now. However, it is difficult to study the genetic basis and pathogenesis of SHL systematically, because of the strong clinical and genetic heterogeneity of SHL.The incidence of most SHL was low. Waardenburg syndrome (WS), Congenital microtia syndrome, and Large vestibular aquduct syndrome (LVAS) are three common SHL in clinical. The dysfunction of neural crest cells caused by the gene interaction network extending from SOX10 and PAX3 not only could lead to WS , but also involved in multiple craniofacial syndrome including microtia, which indicated that there was a commonality in the pathogenesis of WS and microtia syndrome. Interestingly, our previous studies also confirmed the interaction of PAX3, SOX10 and MITF in the pathogenesis of WS. The hypothesis of this study is that the neural crest gene interaction network might play an important role in the SHL phenotypes including pigment abnormalities, microtia and expanded vestibular aqueduct. Based on the hypothesis, we will collect pedigrees and Sporadic cases related to the phenotypes mentioned above,and Exome-sequencing will be performed to gene mapping and cloning of the common SHL in this study. And then, we will try to find out the potential common pathway and pathogenic mechanisms of the neural crest abnormal gene interaction network involved in the syndromic deafness phenotypes mentioned above at the molecular and cellular(induced pluripotent stem cells (iPSCs) technology) levels, respectively. Our study will enrich the molecular genetic background of SHL, provide new ideas for studies of SHL, and lay the research foundation for further exploration of the new intervention strategies of SHL.

英文关键词： syndromic hearing loss;neural crest;gene mutation;protein interaction;iPASCs