Delayed Rectifier K Channel Biogenesis is Unveiled in Models of Long QT Syndrome

描述(申请人提供)：每年，多达25,000名没有结构性心脏病的人因心脏性猝死而死亡。人们越来越多地寻找这些心脏性猝死的遗传和后天原因，数百种突变与心律失常疾病长QT间期(LQT)综合征有关。大多数先天性LQT综合征患者都有KCNQ1或KCNH2(人醚A-GO-GO相关)基因突变，这两个基因编码电压门控K+通道1亚单位Kv7.1和Kv11.1，它们是心脏延迟整流钾电流的基础。研究表明，KCNQ1(LQT1)突变和KCNH2(LQT2)突变通常会导致功能丧失。许多LQT1和大多数LQT2突变导致Kv7.1和Kv11.1保留在内质网(ER)中，从而减少了细胞表面表达的功能通道的数量。到目前为止，增加内质网输出和功能表达的机制只被确定为贩运缺陷的LQT2突变，不幸的是，这些机制中的大多数没有治疗潜力。为了合理地制定治疗LQT1或LQT2突变患者的治疗策略，我们建议研究指导LQT1和LQT2突变的ER保留以及野生型(WT)Kv7.1和Kv11.1的ER输出和贩运的细胞特性。我们将检验这一假设：LQT1和LQT2突变的内质网保留受到细胞质量控制的不同组成部分的调节，以及Kv7.1和Kv11.1在不同的囊泡运输途径中的运输。我们预计，调节伴侣、辅助伴侣与Kv7.1或Kv11.1之间的相互作用将选择性地增加不同运输缺陷LQT1和LQT2突变的功能表达，并且可以通过操纵Kv7.1和Kv11.1的囊泡运输属性来提高它们的功能表达。公共卫生相关性：每年多达25,000名没有结构性心脏病的人死于心脏性猝死。这些心脏性猝死的遗传和后天原因越来越多地被发现，数百个突变与心律失常疾病长QT间期(LQT)综合征有关。大约每7,000人中就有一人患有LQT1或LQT2，这分别是由KCNQ1或KCNH2基因突变引起的。这些基因编码电压门控K+通道1亚基Kv7.1和Kv11.1，它们是心脏延迟整流钾电流的基础。研究表明，LQT1和LQT2突变通常会导致功能丧失。功能丧失的机制各不相同，但现在人们认识到，许多这些突变减少了细胞表面表达的功能通道的数量，因为它们保留在细胞内的内质网(ER)中。到目前为止，增加这些突变功能表达的机制只被确定为LQT2，没有治疗潜力。为了合理开发治疗运输缺陷LQT1或LQT2突变患者的治疗策略，我们建议研究Kv7.1和Kv11.1的细胞质量控制和囊泡运输特性。我们将检验这一假设，即LQT1和LQT2突变的内质网保留受到细胞质量控制的不同组成部分的调节，以及Kv7.1和Kv11.1在不同的囊泡运输途径中的运输。我们预计，我们将找到新的方法来增加贩运缺陷的LQT1和LQT2突变的功能表达。

DESCRIPTION (provided by applicant): Every year, sudden cardiac death claims up to 25,000 people that do not have structural heart disease. Genetic and acquired causes for these cases of sudden cardiac death are increasingly being sought, and hundreds of mutations have been linked to the pro-arrhythmia disease Long QT (LQT) syndrome. Most congenital LQT syndrome patients have mutations in either the KCNQ1 or KCNH2 (human ether a-go-go- related) genes, which encode the voltage-gated K+ channel 1-subunits Kv7.1 and Kv11.1 that underlie the delayed rectifier K+ current in the heart. Studies suggest that KCNQ1 (LQT1) mutations and KCNH2 (LQT2) mutations typically result in a loss of function. Many LQT1 and most LQT2 mutations cause Kv7.1 and Kv11.1 to be retained in Endoplasmic Reticulum (ER), thereby decreasing the number of functional channels expressed at the cell surface. Thus far, mechanisms that increase the ER export and functional expression have only been identified for trafficking deficient LQT2 mutations, and, unfortunately, most of these mechanisms do not have therapeutic potential. In order to rationally develop therapeutic strategies for treating patients with trafficking deficient LQT1 or LQT2 mutations, we propose to study cellular properties that direct the ER retention for LQT1 and LQT2 mutations, and the ER export and trafficking for wild type (WT) Kv7.1 and Kv11.1. We will test that hypothesis: The ER retention of LQT1 and LQT2 mutations is regulated by different components of cellular quality control, and Kv7.1 and Kv11.1 traffic in distinct vesicular transport pathways. We anticipate that modulating interactions between chaperones, co-chaperones, and Kv7.1 or Kv11.1 will selectively increase the functional expression for different trafficking deficient LQT1 and LQT2 mutations, and that the vesicular transport properties for Kv7.1 and Kv11.1 can be manipulated to increase their functional expression. PUBLIC HEALTH RELEVANCE: Every year sudden cardiac death claims up to 25,000 people that do not have structural heart disease. Genetic and acquired causes for these cases of sudden cardiac death are increasingly being identified, and hundreds of mutations have been linked to the pro-arrhythmia disease Long QT (LQT) syndrome. About one in 7,000 people have LQT1 or LQT2, which is caused by mutations in either the KCNQ1 or KCNH2 genes, respectively. These genes encode the voltage-gated K+ channel 1-subunits Kv7.1 and Kv11.1 that underlie the delayed rectifier K+ current in the heart. Studies suggest that LQT1 and LQT2 mutations typically result in a loss of function. The mechanisms that underlie the loss of function varies, but it is now recognized that many of these mutations decrease the number of functional channels expressed at the cell surface, because they are retained inside the cell in the Endoplasmic Reticulum (ER). Thus far, mechanisms that increase the functional expression for these mutations have only been identified for LQT2 and do not have therapeutic potential. In order to rationally develop therapeutic strategies for treating patients with trafficking deficient LQT1 or LQT2 mutations, we propose to study the cellular quality control and vesicular transport properties for Kv7.1 and Kv11.1. We will test the hypothesis that the ER retention of LQT1 and LQT2 mutations is regulated by different components of cellular quality control, and Kv7.1 and Kv11.1 traffic in distinct vesicular transport pathways. We anticipate that we will identify novel ways to increase the functional expression for trafficking deficient LQT1 and LQT2 mutations.