High frequency of the IVS2-2A>G DNA sequence variation in SLC26A5, encoding the cochlear motor protein prestin, precludes its involvement in hereditary hearing loss.
High frequency of the IVS2-2A>G DNA sequence variation in SLC26A5, encoding the cochlear motor protein prestin, precludes its involvement in hereditary hearing loss.
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DOI：
10.1186/1471-2350-6-30
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发表时间：
2005-08-08
影响因子：
--
通讯作者：
Alford RL
中科院分区：
文献类型：
--
作者：
Tang HY;Xia A;Oghalai JS;Pereira FA;Alford RL
耳蜗外毛细胞的长度随着膜电位的变化而改变。这种被称为电动的能力被认为能够使哺乳动物耳蜗具有敏感度和频率选择性。Prestin是电动运动所需的跨膜蛋白。纯合子prestin基因敲除小鼠听力严重受损。在人类中，编码prestin的SLC26A5基因的单核苷酸变化已被报道与听力损失有关。这种DNA序列变异IVS2-2A和GT；G发生在外显子3的剪接受体位置，有望取消外显子3的剪接。为了进一步探讨听力损失与IVS2-2A和GT；G转换的关系，并评估等位基因频率，对听力障碍患者和对照组的基因组DNA进行了DNA测序分析。对人、黑猩猩、大鼠、小鼠、斑马鱼和果蝇的SLC26A5基因组DNA序列进行了比对，并比较了外显子3剪接受体位点的进化保守性。使用伯克利果蝇基因组计划的剪接位点预测程序寻找人类SLC26A5内含子2内的选择性剪接受体位点。在74名西班牙裔、白人或不确定种族的听力受损受试者中，有4名发现IVS2-2A>；G变异处于杂合状态，而在150名西班牙裔或白人对照组中，有4名受试者处于杂合状态(p=0.45)。在106名亚裔或非裔美国人中未发现IVS2-2A和G变异。没有发现纯合子受试者(n=330)。对SLC26A5同源序列的比对表明，IVS2-2位置的A核苷酸在几个真核物种中是不变的。序列分析还发现了人SLC26A5内含子2中五个潜在的选择性剪接受体位点。这些数据表明，IVS2-2A>；G变异在听力受损的受试者中可能不会比对照组更频繁。人类SLC26A5内含子2中5个可能的选择性剪接受体位点的鉴定表明，在携带SLC26A5 IVS2-2A和GT；G DNA序列变异的细胞中，Prestin的表达可能是一种潜在的机制。还需要进一步的研究来评估IVS2-2A>；G转换对SLC26A5转录本剪接的影响，并表征IVS2-2A>；G变异体纯合个体的听力状况。
Cochlear outer hair cells change their length in response to variations in membrane potential. This capability, called electromotility, is believed to enable the sensitivity and frequency selectivity of the mammalian cochlea. Prestin is a transmembrane protein required for electromotility. Homozygous prestin knockout mice are profoundly hearing impaired. In humans, a single nucleotide change in SLC26A5, encoding prestin, has been reported in association with hearing loss. This DNA sequence variation, IVS2-2A>G, occurs in the exon 3 splice acceptor site and is expected to abolish splicing of exon 3. To further explore the relationship between hearing loss and the IVS2-2A>G transition, and assess allele frequency, genomic DNA from hearing impaired and control subjects was analyzed by DNA sequencing. SLC26A5 genomic DNA sequences from human, chimp, rat, mouse, zebrafish and fruit fly were aligned and compared for evolutionary conservation of the exon 3 splice acceptor site. Alternative splice acceptor sites within intron 2 of human SLC26A5 were sought using a splice site prediction program from the Berkeley Drosophila Genome Project. The IVS2-2A>G variant was found in a heterozygous state in 4 of 74 hearing impaired subjects of Hispanic, Caucasian or uncertain ethnicity and 4 of 150 Hispanic or Caucasian controls (p = 0.45). The IVS2-2A>G variant was not found in 106 subjects of Asian or African American descent. No homozygous subjects were identified (n = 330). Sequence alignment of SLC26A5 orthologs demonstrated that the A nucleotide at position IVS2-2 is invariant among several eukaryotic species. Sequence analysis also revealed five potential alternative splice acceptor sites in intron 2 of human SLC26A5. These data suggest that the IVS2-2A>G variant may not occur more frequently in hearing impaired subjects than in controls. The identification of five potential alternative splice acceptor sites in intron 2 of human SLC26A5 suggests a potential mechanism by which expression of prestin might be maintained in cells carrying the SLC26A5 IVS2-2A>G DNA sequence variation. Additional studies are needed to evaluate the effect of the IVS2-2A>G transition on splicing of SLC26A5 transcripts and characterize the hearing status of individuals homozygous for the IVS2-2A>G variant.