WFS1基因新突变致非综合征性耳聋的致病机制研究

项目名称： WFS1基因新突变致非综合征性耳聋的致病机制研究

项目编号： No.81470704

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： 白晓卉

作者单位： 山东大学

项目金额： 73万元

中文摘要： 耳聋是最普遍的感官缺陷疾病之一，对个人、家庭和社会造成巨大负担。66%的感音神经性聋由遗传因素导致，但耳聋相关基因众多，遗传方式复杂多样，遗传性聋的发病机制亟待发现。我们前期发现了一个常染色体显性遗传的非综合征性感音神经性耳聋大家系，通过全外显子组测序，致聋基因定位在WFS1基因的一个新突变c.2389G>A，这是WFS1基因突变可导致全频听力损失的新发现。本课题拟利用原位杂交和免疫荧光染色的方法，研究WFS1基因在小鼠不同发育时期和不同内耳区域的精细表达定位；利用突变质粒转染细胞、建立knock-in小鼠模型、并分析突变和内质网应激及其他相关听觉基因的关系，揭示该突变致非综合征性耳聋的致病机制；通过与WFS1基因已知的其它位点突变致聋的knock-in小鼠进行比较分析，探讨c.2389G>A造成耳聋频率特异的原因。本研究对遗传性耳聋的分子诊断、预防、新药研发和基因治疗等具有重要的价值。

中文关键词： WFS1基因；基因突变；非综合征性耳聋；致病机制；基因敲入

英文摘要： Hearing loss is one of the most common sensory disorders, which imposes a heavy social and economic burden on disabled individuals, families and the community as a whole. Now, 66% of hearing loss patients can be attributed to genetic causes. Although many loci have been linked to hereditary hearing impairment, most of the pathogenic mechanism of the causative genes has not been identified yet. Taking advantage of exome sequencing, we identified a novel mutation c.2389G>A in WFS1 gene from an autosomal dominantly non-syndromic sensorineural hearing loss family. To the best of our knowledge, this is the first time to report a new mutation in WFS1 gene that causes non-syndromic hearing loss in all frequencies. Based on the preliminary study, the present project is designed to investigate that: 1) the localization of WFS1 in the inner ear at different development periods, 2) the pathogenic mechanism underlying c.2389G>A mutation in WFS1 gene related non-syndromic hearing loss, 3) the reason why different mutations in WFS1 gene result in distinct phenotype. This research will lay the foundation of effective molecular diagnosis, intervention, development of drugs and genetic treatment measure for hereditary deafness.

英文关键词： WFS1 gene;gene mutation;non-syndromic hearing loss;pathogenic mechanism;knock in