Prestin, a cochlear motor protein, is defective in non-syndromic hearing loss
Prestin, a cochlear motor protein, is defective in non-syndromic hearing loss
复制标题
DOI：
10.1093/hmg/ddg127
复制
发表时间：
2003-05-15
影响因子：
3.5
通讯作者：
Chen, ZY
中科院分区：
文献类型：
--
作者：
Liu, XZ;Ouyang, XM;Chen, ZY
普雷斯廷是一种膜蛋白，其高度且几乎仅在耳蜗的外毛细胞（OHC）中表达，是感知膜电位并驱动OHC中的快速长度变化的运动蛋白。令人惊讶的是，普雷斯廷是一个基因家族，溶质载体（SLC）家族26，编码阴离子转运蛋白和相关蛋白质的成员。在这个家族中已知的9个人类基因中，有3个（SLC 26 A2、SLC 26 A3和SLC 26 A4）与不同的人类遗传性疾病相关。普雷斯廷在OHC中的有限表达，以及其作为机械放大器的功能，使其成为人类耳聋的强有力的候选基因。本文报道了人普雷斯廷基因的四种剪接异构体（SLC 26 A5 a、B、c和d）的克隆和鉴定。SLC 26 A5 a是普雷斯廷的主要形式，而其他的表现出与某些发育阶段相关的有限分布。基于普雷斯廷的功能重要性，我们筛选了一组耳聋先证者中可能涉及普雷斯廷基因的突变。我们在普雷斯廷基因的第3外显子发现了一个5 '-UTR剪接受体突变（IVS 2 -2A>G），该突变导致两个不相关家族的隐性非综合征性耳聋。此外，在这些受试者中观察到相同突变的高频率杂合性，表明该突变在引起听力损失中的半显性影响的可能性。最后，仅在高加索先证者中观察到这种突变表明与特定种族背景相关。本研究揭示了普雷斯廷在人类听觉加工中的重要功能。
Prestin, a membrane protein that is highly and almost exclusively expressed in the outer hair cells (OHCs) of the cochlea, is a motor protein which senses membrane potential and drives rapid length changes in OHCs. Surprisingly, prestin is a member of a gene family, solute carrier (SLC) family 26, that encodes anion transporters and related proteins. Of nine known human genes in this family, three (SLC26A2, SLC26A3 and SLC26A4) are associated with different human hereditary diseases. The restricted expression of prestin in OHCs, and its proposed function as a mechanical amplifier, make it a strong candidate gene for human deafness. Here we report the cloning and characterization of four splicing isoforms for the human prestin gene (SLC26A5a, b, c and d). SLC26A5a is the predominant form of prestin whereas the others showed limited distribution associated with certain developmental stages. Based on the functional importance of prestin we screened for possible mutations involving the prestin gene in a group of deaf probands. We have identified a 5'-UTR splice acceptor mutation (IVS2-2A>G) in exon 3 of the prestin gene, which is responsible for recessive non-syndromic deafness in two unrelated families. In addition, a high frequency of heterozygosity for the same mutation was observed in these subjects, suggesting the possibility of semi-dominant influence of the mutation in causing hearing loss. Finally, the observation of this mutation only in the Caucasian probands indicated an association with a specific ethnic background. This study thereby reveals an essential function of prestin in human auditory processing.