SLC26A4基因新发现变异位点鉴定及致聋机制研究

耳聋已成为世界性公共卫生问题，遗传性耳聋占60％。目前认为SLC26A4基因变异是引起感音神经性聋的第二位遗传学病因，其致聋问题受到关注。截止至今，全球已发现SLC26A4基因变异587种，多数变异可致聋，而有些未报道的新发现变异位点是否致聋及致聋机制如何？尚不明确。课题组首次发现携带SLC26A4基因变异位点c.574delC和c.1211C>A的复合杂合先证者表现为双侧感音神经性聋伴双侧前庭水管扩大，基于听力表型和基因型分析，提出这两个新发现变异位点可能具有致病性的理论假设。为解决这两个变异位点是否致聋的问题，拟通过构建变异体质粒转染的细胞模型及变异敲入小鼠模型，研究变异对听力变化及耳蜗形态、以及Pendrin蛋白表达及离子转运能力的影响，以阐明新发现变异位点的致病性及致聋机制。研究成果将丰富SLC26A4基因变异谱，补充国际耳聋数据库生物学信息，为SLC26A4基因相关研究提供依据。

Deafness has become a worldwide public health problem and hereditary deafness constitutes, approximately, 60% of the deaf populations. Currently, domestic researchers have recognized SLC26A4 gene mutation is the second common genetic causes of sensorineural hearing loss(SNHL). To date, 587 variants on this gene have been discovered worldwide, and most mutations result in the changes of Pendrin protein, leading to hearing loss, however, it’s unclear whether some are pathogenic or not, and the pathogenic mechanism of the novel mutations. Our research team first found that the probands with c.574delC or c.1211C>A compound heterozygous mutations, could perform with bilateral SNHL as well as enlarged vestibular aqueduct ( EVA ) , based on the theoretical hypothesis that novel mutations c.574delC and c.1211C>A, might be pathogenic. To determine their pathogenicity, we construct a cell model of the mutant plasmid transfection and a variant knock-in mouse model to study the variation on hearing changes and cochlear morphology, exploring the effects of mutations on protein expression and transport capabilities of related icons to clarify the pathogenicity and deafness mechanism of newly discovered mutation sites. The aims, in this study, are to enrich spectrums of the SLC26A4 gene mutations, as well as update the international deafness databases, and provide a basis for SLC26A4 gene related research.