Functional Implications of non-coding data in HERG-mRNA

描述(申请人提供)：HERG编码一种钾通道，对正常心脏电生理和节律控制至关重要。它与遗传性长QT间期综合征(LQT2位点)和获得性长QT间期综合征的联系突出了它的生物医学意义。HERG报告了600多个有害突变(&gt；440个错义突变)。为什么该通道如此容易受到错义突变的影响尚不清楚。大多数LQT2 HERG突变被认为导致有缺陷的组装和运输到细胞表面-可能是由于新生的HERG通道的错误折叠。有证据表明，即使是野生河道的折叠和贩运也是脆弱的。HERG加工受到多种药物和环境压力的影响。大多数研究从逻辑上集中在氨基酸的变化如何影响通道蛋白的处理。对通道加工中的信使核糖核酸依赖因子知之甚少。我们的初步研究分析了不改变氨基酸序列的HERG mRNA中非编码(或更恰当地称为额外编码信息)的影响。我们发现，Herg mRNA的独立和独立区域包含的信息极大地影响通道翻译和运输效率-这是一种不寻常的情况。我们假设HERG固有的脆弱生物合成和导致遗传性LQT2发病的LQT2错义突变之间存在协同作用。对HERG通道依赖于mRNA的处理机制的研究可能会引导我们重新考虑遗传性和获得性心律失常综合征的诊断和治疗方法。本项目的目的是：1)确定影响HERG通道翻译和运输效率的mRNA元件的特定地点和性质。2)确定HERG通道蛋白翻译和运输的共翻译和翻译后机制。3)探讨Herg基因序列特异性元件在LQT2发病机制中的作用。

DESCRIPTION (provided by applicant): hERG encodes a potassium channel that is of essential importance to normal cardiac electrophysiology and rhythm control. Its biomedical significance is highlighted by its link to both hereditary (locus LQT2) and acquired Long-QT syndromes. Over 600 deleterious mutations (>440 missense) have been reported in hERG. Why the channel is so susceptible to missense mutations is not known. The majority of LQT2 hERG mutations are believed to result in defective assembly and trafficking to the cell surface-presumably due to misfolding of the nascent hERG channel. There is evidence that folding and trafficking of even wild type channels is tenuous. hERG processing is affected by a wide variety of drugs and environmental stresses. Most investigation has logically focused on how amino acid changes affect channel protein processing. Less is known about mRNA-dependent factors in channel processing. Our preliminary studies analyzed the effects of non-coding (or more appropriately termed, extra-coding information) in hERG mRNA that does not alter amino acid sequence. We found that separate and independent regions of hERG mRNA contain information that greatly affects channel translation and trafficking efficiencies-an unusual occurrence. We postulate that a synergy occurs between the inherently fragile biosynthesis of hERG and the LQT2 missense mutations that contribute to the pathogenesis of hereditary LQT2. Investigation of mechanisms underlying mRNA-dependent processing of hERG channels may lead us to reconsider diagnostic and therapeutic approaches to hereditary and acquired arrhythmia syndromes. The aims of this project are: 1) To determine the specific locale and nature of mRNA elements that affect efficiency of hERG channel translation and trafficking. 2) To determine co- and post-translational mechanisms for mRNA-sequence- specific regulation of hERG channel protein translation and trafficking. 3) To investigate how hERG mRNA- sequence-specific elements impact the pathogenesis of LQT2.