Differential expression of KCNQ4 in inner hair cells and sensory neurons is the basis of progressive high-frequency hearing loss
Differential expression of KCNQ4 in inner hair cells and sensory neurons is the basis of progressive high-frequency hearing loss
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DOI：
10.1523/jneurosci.2110-05.2005
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发表时间：
2005-10-05
影响因子：
5.3
通讯作者：
Fritzsch, B
中科院分区：
文献类型：
--
作者：
Beisel, KW;Rocha-Sanchez, SM;Fritzsch, B
人类KCNQ 4突变（称为DFNA 2）可导致非综合征性、常染色体显性、进行性高频听力损失，其中细胞和分子基础尚不清楚。我们提供的免疫荧光数据显示，Kcnq 4在成年人耳蜗的表达具有纵向（基部到顶端）和径向（内毛细胞到外毛细胞）梯度。最强烈的标记是在顶端的外毛细胞和内毛细胞以及螺旋神经节神经元在基部。时空表达研究表明，从出生后第21天（P21）到P120小鼠，KCNQ 4蛋白标记的强度增加，这在中间圈的内毛细胞中最为明显。我们已经确定了四个选择性剪接变异的Kcnq 4在小鼠中。外显子9-11的交替使用产生三种转录变体（v1-v3），而第四种变体（v4）跳过所有三个外显子;所有变体在C末端具有相同的氨基酸序列。逆转录-PCR和定量PCR分析表明，这些变体具有差异表达模式沿沿着的长度的小鼠器官的Corti和螺旋神经节神经元。我们的表达数据表明，导致DFNA 2患者高频丢失的原发性缺陷可能归因于螺旋神经节和基底钩区内毛细胞中功能失调的Kcnq4_v3变体的高水平。与衰老相关的进行性听力损失可能是由于内毛细胞和螺旋神经节神经元中朝向顶点的突变负荷扩展增加所致。
Human KCNQ4 mutations known as DFNA2 cause non-syndromic, autosomal-dominant, progressive high-frequency hearing loss in which the cellular and molecular basis is unclear. We provide immunofluorescence data showing that Kcnq4 expression in the adult cochlea has both longitudinal ( base to apex) and radial ( inner to outer hair cells) gradients. The most intense labeling is in outer hair cells at the apex and in inner hair cells as well as spiral ganglion neurons at the base. Spatiotemporal expression studies show increasing intensity of KCNQ4 protein labeling from postnatal day 21 (P21) to P120 mice that is most apparent in inner hair cells of the middle turn. We have identified four alternative splice variants of Kcnq4 in mice. The alternative use of exons 9-11 produces three transcript variants (v1-v3), whereas the fourth variant (v4) skips all three exons; all variants have the same amino acid sequence at the C termini. Both reverse transcription-PCR and quantitative PCR analyses demonstrate that these variants have differential expression patterns along the length of the mouse organ of Corti and spiral ganglion neurons. Our expression data suggest that the primary defect leading to high-frequency loss DFNA2 patients may be attributable to high levels of the dysfunctional Kcnq4_v3 variant in the spiral ganglion and inner hair cells in the basal hook region. Progressive hearing loss associated with aging may result from an increasing mutational load expansion toward the apex in inner hair cells and spiral ganglion neurons.