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蛋白组装而形成K^+通道，并在各种组织中的K^+稳态中起关键作用。在心脏中，KCNQ1与KCNE1共组装，以产生心脏脱落的整流器K^+电流。在内耳中，KCNQ1/CNCE1复合物在内淋巴中保持高浓度的K^+。在胃中，KCNQ1与KCNE2共组装，形成对胃酸分泌至关重要的K^+ Exflux通道。在结肠和小肠中，KCNQ1与KCNE3共同组装，在transepithelial Camp刺激的Cl^ - 分泌中发挥重要作用。为了进一步了解体内KCNQ1功能，需要动物模型。在这里，我们报道了鉴定共生kcnq1突变大鼠，称为“京都（DFK）”及其表型的表征。 WTC-DFK大鼠在KCNQ1基因处携带内部缺失，并显示出因在ECG中显着减少内淋巴，延长QT间隔的体重，耳聋和失衡而受损，以及与胃痛性胃mucosa相关的胃肠道。令人惊讶的是，WTC-DFK大鼠显示高血压，这表明KCNQ1可能参与了血压调节。这些发现表明，WTC-DFK大鼠可以代表研究KCNQ1的生理功能以及为KCNQ1相关疾病的新治疗程序的生理功能的强大工具。