Identification of a causative gene responsible for deafness, imbalance, and abnormal EEG in the WTC-dfk rat

鉴定导致 WTC-dfk 大鼠耳聋、失衡和脑电图异常的致病基因

基本信息

批准号：
15300141
负责人：
KURAMOTO Takashi
金额：
$ 10.75万
依托单位：
Kyoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2005
项目状态：
已结题

项目摘要

KCNQ1 forms K^+ channels by assembly with regulatory subunit KCNE proteins and plays a key role in the K^+ homeostasis in a variety of tissues. In the heart, KCNQ1 is co-assembled with the KCNE1 to produce a cardiac-delayed rectifier K^+ current. In the inner ear, KCNQ1/KNCE1 complex maintains the high concentration of K^+ in the endolymph. In the stomach, KCNQ1 is co-assembled with KCNE2 to form the K^+ exflux channel that is essential for gastric acid secretion. In the colon and small intestine, KCNQ1 is co-assembled with KCNE3 to play an important role in transepithelial cAMP-stimulated Cl^- secretion. For further understanding of Kcnq1 function in vivo, an animal model has been required. Here we reported the identification of a coisogenic Kcnq1 mutant rat, named deafness Kyoto (dfk), and the characterization of its phenotypes. WTC-dfk rats carried intragenic deletion at the Kcnq1 gene, and showed impaired gain of weight, deafness and imbalance resulting from the marked reduction of endolymph, prolonged QT interval in the ECG, and gastric achlorhydria associated with hypertrophic gastric mucosa. Surprisingly, WTC-dfk rats showed hypertension, which suggested that Kcnq1 might be involved in the regulation of blood pressure. These findings suggest that WTC-dfk rats could represent a powerful tool for studying the physiological functions of KCNQ1 and for the establishment of new therapeutic procedures for Kcnq1-related diseases.

KCNQ1 通过与调节亚基 KCNE 蛋白组装形成 K^+ 通道，在多种组织的 K^+ 稳态中发挥关键作用。在心脏中，KCNQ1 与 KCNE1 共同组装，产生心脏延迟整流器 K^+ 电流。在内耳中，KCNQ1/KNCE1 复合物维持内淋巴中 K^+ 的高浓度。在胃中，KCNQ1 与 KCNE2 共同组装，形成对胃酸分泌至关重要的 K^+ 外流通道。在结肠和小肠中，KCNQ1 与 KCNE3 共同组装，在跨上皮 cAMP 刺激的 Cl^- 分泌中发挥重要作用。为了进一步了解 Kcnq1 体内功能，需要动物模型。在这里，我们报告了同基因 Kcnq1 突变大鼠的鉴定，命名为京都聋 (dfk)，并对其表型进行了表征。 WTC-dfk 大鼠携带 Kcnq1 基因基因内缺失，由于内淋巴显着减少、心电图 QT 间期延长以及与胃粘膜肥厚相关的胃酸缺乏，导致体重增加受损、耳聋和失衡。令人惊讶的是，WTC-dfk 大鼠表现出高血压，这表明 Kcnq1 可能参与血压调节。这些发现表明，WTC-dfk 大鼠可以成为研究 KCNQ1 生理功能和建立 Kcnq1 相关疾病新治疗方法的有力工具。