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

KCNQ1通过与调控亚基KCNE蛋白组装形成K^+通道，在多种组织中K^+稳态中起关键作用。在心脏中，KCNQ1与KCNE1共同组装以产生心脏延迟整流器K^+电流。在内耳，KCNQ1/KNCE1复合体在内淋巴维持高浓度的K^+。在胃中，KCNQ1与KCNE2共同组装形成对胃酸分泌至关重要的K^+外排通道。在结肠和小肠中，KCNQ1与KCNE3共同组装，在经上皮camp刺激的Cl^-分泌中发挥重要作用。为了进一步了解Kcnq1在体内的功能，需要建立动物模型。在这里，我们报道了一种共等位Kcnq1突变大鼠的鉴定，命名为deafness Kyoto (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，表现出体重增加受损、内淋巴明显减少、心电图QT间期延长、胃粘膜肥厚导致的耳聋和失衡。令人惊讶的是，WTC-dfk大鼠出现了高血压，这表明Kcnq1可能参与了血压的调节。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。

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.