遗传性耳聋为常见的听觉障碍性疾病，现已发现150多个致聋基因，仍有大量耳聋基因有待发现。我们通过外显子组测序及基因共分离验证，首次在一个常染色体显性遗传耳聋家系中发现转化/转录域相关蛋白（TRRAP）基因存在p.R171C突变，并在66例非综合征型感音神经耳聋患者中发现TRRAP的其它3种突变；下调该基因或该基因突变的斑马鱼出现耳石异常、毛细胞与支持细胞减少等表型。据此我们推断TRRAP可能是一种新的耳聋致病基因，它的突变可能通过影响c-MYC、β-catenin等导致毛细胞发育异常，最终产生听力损伤。本课题拟完成：1.确定500例感音神经性耳聋患者TRRAP突变的类型与频率；2.制备TRRAP点突变和移码突变2种转基因小鼠，明确这些突变位点的致病性；3.寻找并确定TRRAP靶蛋白和靶基因，阐明其突变导致耳聋的分子机制。为遗传性耳聋的防治提供新的依据和方法。

Hearing loss is one of the most common neurosensory disorders in human patients. More than 150 genes have been identified as deafness causative genes, but many others remain to be discovered as researchers predicted. We found the p.R171C mutation of Transformation/Transcription Domain-associated Protein(TRRAP) in an autosomal dominant deafness family for the first time through whole exon sequencing and by co-separation verification, and then found other three TRRAP mutations in 66 cases of non-syndromic hearing loss. Zebrafish with TRRAP downregulated or carrying TRRAP mutations showed hearing loss, abnormal otolith, along with reduced Hair cells and supporting cells. Based on these phenomena, we deduce TRRAP is likely a new kind of hereditary deafness gene, the mutation of which leads to hair cell dysfunction and hearing loss through affecting c-MYC、β-catenin and related genes. We want to complete the researches in this project as follows: (1) To determine the type and frequency of TRRAP mutation in 500 patients with sensorineural deafness; (2) To prepare two kinds of TRRAP mutant transgenic mice with point mutation and shift mutation respectively, determine the pathogenicity of these mutations. (3) To find and determine the target proteins and target genes of TRRAP, clarify the pathogenic mechanism of mutate TRRAP through changes of target molecules. We hope the program will provide new basis and method for the prevention and treatment of hereditary hearing loss.