Missense mutations in POU4F3 cause autosomal dominant hearing impairment DFNA15 and affect subcellular localization and DNA binding
Missense mutations in POU4F3 cause autosomal dominant hearing impairment DFNA15 and affect subcellular localization and DNA binding
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DOI：
10.1002/humu.20693
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发表时间：
2008-04-01
期刊：
影响因子：
3.9
通讯作者：
Kremer, Hannie
中科院分区：
文献类型：
--
作者：
Collin, Rob W. J.;Chellappa, Ramesh;Kremer, Hannie
在一个患有常染色体显性遗传性非综合征性听力障碍（ADNSHI）的荷兰家系中，发现与DFNA 15位点存在连锁关系，其两点对数比值（LOD）评分为5.1。对DFNA 15的POU4F3基因进行序列分析，发现存在错义突变（c.865C > T），与该家系的耳聋分离。预测该突变导致转录因子POU4F3的POU同源结构域中苯丙氨酸残基取代亮氨酸残基（p.L289F）。对30名显性遗传性听力障碍患者的POU4F3基因进行突变分析，发现了第二个新的错义突变（c.668T > C），导致POU特异性DNA（蛋白质的结合结构域）内的亮氨酸残基（p.L223P）被脯氨酸取代。在描述两个DNA结合结构域的结构的计算机模型中，预测改变会影响这些结构域的三级结构。瞬时转染研究表明，而野生型POU4F3几乎完全位于细胞核中，部分突变蛋白也存在于细胞质中。此外，这两种突变蛋白质显示出与DNA结合以及转录激活报告基因表达的能力大大降低。总之，我们的结果描述了POU4F3中导致DFNA 15的第一个错义突变的鉴定。此外，该基因的突变似乎并不是荷兰人群中听力障碍的罕见原因，因此POU4F3基因可能适合在诊断测试中实施。
In a Dutch pedigree suffering from autosomal dominant nonsyndromic hearing impairment (ADNSHI), linkage was found to the locus for DFNA15, with a two-point logarithm of the odds (LOD) score of 5.1. Sequence analysis of the POU4F3 gene that is involved in DFNA15 revealed the presence of a missense mutation (c.865C > T), segregating with the deafness in this family. The mutation is predicted to result in the substitution of a phenylalanine residue for a leucine residue (p.L289F) in the POU homeodomain of the transcription factor POU4F3. Mutation analysis of the POU4F3 gene in 30 patients suffering from dominantly inherited hearing impairment revealed a second novel missense mutation (c.668T > C), resulting in the substitution of a proline for a leucine residue (p.L223P) within the POU-specific DNA,binding domain of the protein. In a computer model describing the structure of the two DNA,binding domains, the alterations are predicted to affect the tertiary structure of these domains. Transient transfection studies showed that whereas the wild-type POU4F3 is located almost exclusively in the nucleus, part of the mutant proteins was also present in the cytoplasm. In addition, both mutant proteins showed greatly reduced capability for binding to DNA as well as transcriptionally activating reporter gene expression. Together, our results describe the identification of the first missense mutations in POU4F3 causing DFNA15. Furthermore, mutations in this gene do not seem to be a rare cause of hearing impairment in the Dutch population, and the POU4F3 gene may thus be suitable for implementation in diagnostic testing.