Loss-of-Function Mutations in the PRPS1 Gene Cause a Type of Nonsyndromic X-linked Sensorineural Deafness, DFN2
Loss-of-Function Mutations in the PRPS1 Gene Cause a Type of Nonsyndromic X-linked Sensorineural Deafness, DFN2
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PRPS1 基因的功能丧失突变会导致一种非综合征性 X 连锁感音神经性耳聋 (DFN2)。
DOI：
10.1016/j.ajhg.2009.11.015
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发表时间：
2010-01-08
影响因子：
9.8
通讯作者：
Yuan, Huijun
中科院分区：
文献类型：
--
作者：
Liu, Xuezhong;Han, Dongyi;Yuan, Huijun
我们报告了一个X连锁的非综合征性语后听力障碍的中国大家庭，其中的关键连锁区间跨越5.41 cM的遗传距离和15.1 Mb的物理距离重叠DFN2位点。突变筛查PRPS1基因在这个家庭和在三个以前报道的DFN2家庭确定了四个不同的错义突变PRPS1。这些突变导致磷酸核糖焦磷酸（PRPP）合成酶I活性丧失，如通过结构分析计算机模拟显示的，以及通过患者红细胞和成纤维细胞中的体外酶活性测定显示的。通过原位杂交，我们证明了Prps1在小鼠前庭和耳蜗毛细胞中的表达，在毛细胞中持续表达，在螺旋神经节中表达。PRPS1是第二个被发现的与X连锁非综合征性耳聋相关的基因，是X连锁非综合征性耳聋基因检测的一个很好的候选基因。
We report a large Chinese family with X-linked postlingual nonsyndromic hearing impairment in which the critical linkage interval spans a genetic distance of 5.41 cM and a physical distance of 15.1 Mb that overlaps the DFN2 locus. Mutation screening of the PRPS1 gene in this family and in the three previously reported DFN2 families identified four different missense mutations in PRPS1. These Mutations result in a loss of phosphoribosyl pyrophosphate (PRPP) synthetase I activity, as was shown in silico by structural analysis and was shown in vitro by enzymatic activity assays in erythrocytes and fibroblasts from patients. By ill Situ hybridization, we demonstrate expression of Prps1 in murine vestibular and cochlea hair cells, with Continuous expression in hair cells and postnatal expression in the spiral ganglion. Being the second identified gene associated with X-linked nonsyndromic deafness, PRPS1 will be a good candidate gene for genetic testing for X-linked nonsyndromic hearing loss.