基于转录测序技术对KIT基因在听觉色素障碍类疾病初步研究  

A preliminary study on the role of KIT gene in auditory pigmentary disorders based on transcriptional sequencing technology

作　　者：李雨青 任巍[1] 石岩[1] 郑凡君 王晨晨 郭维维[1] 赵辉[1] LI Yuqing;REN Wei;SHI Yan;ZHENG Fanjun;WANG Chenchen;GUO Weiwei;ZHAO Hui(Senior Department of Otolaryngology Head and Neck Surgery,Chinese PLA General Hospital,Beijing 100853,China/State Key Laboratory of Hearing and Balance Science/National Clinical Research Center for Otolaryngologic Diseases Key/Laboratory of Hearing Science,Ministry of Education/Beijing Key Laboratory of Hearing Impairment Prevention and Treatment)

机构地区：[1]中国人民解放军总医院耳鼻咽喉头颈外科医学部,中国人民解放军总医院第六医学中心听觉与平衡觉全国重点实验室,国家耳鼻咽喉疾病临床医学研究中心,聋病教育部重点实验室,聋病防治北京市重点实验室,北京100853

出　　处：《中华耳科学杂志》2024年第2期257-262,共6页Chinese Journal of Otology

基　　金：国家自然科学基金(81970895,81970897);解放军总医院第六医学中心创新培育基金(CXPY202118);国家重点研发计划(2023YFB4705804)。

摘　　要：目的 利用KITF860S突变耳聋小鼠模型研究探讨KIT基因突变导致听觉色素障碍类疾病致聋的分子机制。方法 利用稳定遗传的KITF860S小鼠模型家系,并对家系中不同表型个体进行长期听觉电生理测试、同窝不同表型小鼠病理切片、进行全基因组转录测序分析其表达差异基因。结果 该小鼠模型家系内杂合型小鼠在初期与野生型小鼠听力表型并无明显差距,在5月龄时表现为渐进性听力下降,纯合型小鼠在听力形成初期即表现为先天性中重度听力下降,10周龄时即表现为全聋表现。转录测序结果显示,以野生型小鼠为对照,氧化磷酸化通路在KIT基因纯合突变及杂合突变中均表现为下调,紧密连接通路在KIT基因不同组别比较中为不同上下调表现。结论本研究结果表明,KIT基因突变所致听觉色素障碍类疾病表现与氧化磷酸化、紧密连接等通路相关目的基因靶蛋白表达异常有一定相关性,最终导致听力损失。对KIT基因突变致病分子机制的研究对于丰富人类耳聋基因库具有重要意义,也为后续相关综合征类疾病基因治疗提供理论基础。Objective To investigate the molecular mechanism of auditory pigmentary disorders using a KITF860S mutation hearing loss mouse model.Methods Long-term auditory electrophysiological tests were performed on individuals from a stable genetic KITF860S mouse model family with different phenotypes,together with histopathological observations and whole genome transcriptional sequencing to analyze gene expression differences.Results Hearing phenotypes in heterozygous mice were not significantly different compared to wild-type mice initially,but showed progressive hearing loss at the age of 5 months;while homozygous mice demonstrated congenital moderate and severe hearing loss at an early age and total deafness at the age of 10 weeks.Transcriptional sequencing indicated down-regulated oxidative phosphorylation pathway in both homozygous and heterozygous KIT gene mutations as compared with wild-type mice,with variable up or down regulation of tight junction pathways.Conclusion Manifestations of auditory pigmentary disorders caused by KIT gene mutations are related to abnormal expression of target gene and proteins related to oxidative phosphorylation,tight junction and other pathways,resulting in abnormalities of basement membrane and vascular structures,and ultimately hearing loss.Research on the molecular mechanism of KIT gene mutation is of great significance to enrich the human deafness gene pool,and provides a theoretical basis for gene therapy for related syndromes.

关 键 词：听觉色素障碍 KIT基因 转录测序 分子机制 神经嵴 

分 类 号：R764[医药卫生—耳鼻咽喉科]