KITLG基因致非对称性聋及单侧聋的分子机制研究

Hearing loss is one of the most common sensory disorders, hindering the development of individuals’ language and cognitive, which affects their social development. Hearing loss in patients with deafness is divided into symmetrical, asymmetric and unilateral deafness. The pathogenic mechanism of the asymmetric deafness and unilateral deafness has not been identified yet. KITLG has been found to be associated with the asymmetric deafness and unilateral deafness. However, the expression of KITLG during the development of the inner ear and the pathogenic mechanism of KITLG causing the asymmetric and unilateral deafness are still not clear. We identified a novel pathogenic mutation c.437G>T in KITLG from a Chinese family affected by asymmetric deafness. We also found that Kitl protein was widely expressed in the cochlea of mice. We aim to construct the KITLG knock-out mouse model by CRISPR/Cas system. The present project is designed to investigate that: 1) the localization of KITLG in the inner ear at different development periods, 2) the pathogenic mechanism of KITLG causing asymmetric and unilateral hearing loss, 3) the spectrum and frequency of KITLG variants in the Chinese subjects with asymmetric and unilateral deafness in Shandong province. This research will lay the foundation of effective molecular diagnosis, intervention, development of drugs and genetic treatment measure for the asymmetric deafness and unilateral deafness.

耳聋是最普遍的感官缺陷疾病之一，耳聋严重阻碍患者的言语和认知发育，对其人际交往造成障碍。耳聋患者的听力表现分为对称性耳聋、非对称性耳聋和单侧耳聋。目前对于非对称性耳聋和单侧耳聋的发病机制鲜有研究，有研究发现KITLG基因与非对称性耳聋及单侧耳聋相关，但KITLG基因在内耳中的表达及其致聋机制还不清楚。我们在一个患有非对称性耳聋的中国家系中发现了KITLG基因的新致病突变c.437G>T；同时，我们发现Kitl蛋白在小鼠耳蜗中广泛表达。基于以上研究，本课题拟利用CRISPR/Cas技术建立KITLG基因敲除小鼠模型，在动物水平研究KITLG基因在内耳发育中的时空表达定位及致聋机制，同时利用Sanger 测序技术对山东非对称性耳聋及单侧耳聋人群的突变频谱进行分析。本研究在非对称性耳聋及单侧耳聋的分子诊断、预防、药物开发及基因治疗等方面具有重要的意义。

研究背景：耳聋是最普遍的感觉障碍性疾病之一，严重影响患者的言语和认知发育。根据患者的听力表现，可以分为对称性耳聋、非对称性耳聋和单侧耳聋。目前对于非对称性耳聋和单侧耳聋的发病机制鲜有研究，有少量研究发现KITLG基因与非对称性耳聋及单侧耳聋相关，但KITLG基因在内耳中的表达及其致聋机制还不清楚。.研究内容和结果：本项目在一个患有非对称性耳聋的中国家系中发现了KITLG基因的新致病突变c.437G>T；同时发现Kitl蛋白在小鼠耳蜗中广泛表达。基于以上研究，本课题利用CRISPR/Cas技术建立了KITLG基因敲除小鼠模型，在动物水平研究了KITLG基因在内耳发育中的时空表达定位及致聋机制，同时利用Sanger测序技术对山东非对称性耳聋及单侧耳聋人群的突变频谱进行了分析。.研究意义：本研究对非对称性聋和单侧聋的发病机制进行了初步探索，在其分子诊断、预防、药物开发及基因治疗等方面具有重要的意义。