耳聋是严重高发的致残性疾病，新致聋基因的发现及其致聋机制的诠释在耳聋防治研究领域一直占据着重要的源头创新地位。2010年本课题组在Am J Hum Genet杂志（影响因子11.68，申请人为并列第一作者）首次报道了DFNX1型耳聋的致病基因PRPS1，发现PRPS1基因突变后PRS-1酶活性的部分下降导致了内耳能量代谢障碍，从而引发了DFNX1型耳聋的发生和进行性加重。在此工作基础上，本申请课题拟模拟我们发现的人类DFNX1型耳聋基因突变构建knock-in小鼠模型，利用模式动物深入研究PRPS1基因突变致聋机制，验证S-腺苷甲硫氨酸（SAM）对PRS-1经典代谢途径的代偿作用，在实体动物模型上评估SAM对DFNX1型耳聋症状前预防作用的有效性和安全性，为DFNX1型耳聋药物干预的临床可行性提供可靠的依据。

Hearing Loss is a common disease causes human disability. The identification of the genes underlying hereditary hearing loss and to decipher its mechanism will be important to prevent the recurrence of hearing loss. This research field has always had originally innovative achievements.In the previous study, our research group found that mutations in PRPS1 causing DFNX1 nonsyndromic hearing impairment. These mutations result in a loss of phosphoribosyl pyrophosphate (PRPP) synthetase 1 activity, as was shown in silico by structural analysis and was shown in vitro by enzymatic activity assays in erythrocytes and fibroblasts from patients.These results were published in Am.J.Hum.Genet.,2010 (IF=11.68, the applicant was the joint first anthors).In this proposal, we are going to establish a knock-in mouse model mimicing human DFNX1 hearing loss. With these mouse model, we are going to decipher the deep mechanism of DFNX1 hearing loss. This study will evaluate the effectiveness and the security of utilizing SAM supplementation in the diet alleviate some of the symptoms of patients with PRPS1 spectrum diseases by replenishing purine nucleotides and attenuate the progression of hearing loss in DFNX1 individuals. This project will provide the evidence to evaluate the clinical feasibility of presymptomatic prevention of DFNX1 hearing loss.