Functional Implications of non-coding data in HERG-mRNA

描述（由申请人提供）：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。它的生物医学意义突出了它与遗传性（LQT 2位点）和获得性长QT综合征的联系。在hERG中已报告了超过600种有害突变（>440种错义）。为什么这个通道如此容易受到错义突变的影响还不清楚。大多数LQT 2 hERG突变被认为导致组装缺陷和向细胞表面的运输-推测是由于新生hERG通道的错误折叠。有证据表明，即使是野生型通道的折叠和贩运也是脆弱的。hERG加工受到各种药物和环境应激的影响。大多数研究从逻辑上来说都集中在氨基酸变化如何影响通道蛋白质加工上。对通道加工中的mRNA依赖因子知之甚少。我们的初步研究分析了hERG mRNA中不改变氨基酸序列的非编码（或更恰当地称为编码外信息）的影响。我们发现hERG mRNA的独立区域包含的信息极大地影响了通道翻译和运输效率，这是一种不寻常的现象。我们推测，hERG固有的脆弱的生物合成和LQT 2错义突变之间发生协同作用，导致遗传性LQT 2的发病机制。对hERG通道mRNA依赖性加工机制的研究可能会使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。本研究的目的是：1）确定影响hERG通道翻译和转运效率的mRNA元件的特定位置和性质。2)确定hERG通道蛋白翻译和转运的mRNA序列特异性调控的共翻译和翻译后机制。3)研究hERG mRNA序列特异性元件如何影响LQT 2的发病机制。

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.