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

描述（由申请人提供）：每年，心源性猝死声称多达25，000人没有结构性心脏病。这些心脏性猝死病例的遗传和后天原因越来越多地被寻找，数百种突变与促心律失常疾病长QT（LQT）综合征有关。大多数先天性LQT综合征患者在KCNQ 1或KCNH 2（人类乙醚a-go-go相关）基因中存在突变，这些基因编码电压门控K+通道1亚基Kv7.1和Kv11.1，这些亚基是心脏延迟整流K+电流的基础。研究表明，KCNQ 1（LQT 1）突变和KCNH 2（LQT 2）突变通常会导致功能丧失。许多LQT 1和大多数LQT 2突变导致Kv7.1和Kv11.1保留在内质网（ER）中，从而减少了在细胞表面表达的功能通道的数量。到目前为止，增加ER输出和功能表达的机制仅被鉴定为运输缺陷型LQT 2突变，并且不幸的是，这些机制中的大多数不具有治疗潜力。为了合理地开发用于治疗具有运输缺陷LQT 1或LQT 2突变的患者的治疗策略，我们建议研究指导LQT 1和LQT 2突变的ER保留以及野生型（WT）Kv7.1和Kv11.1的ER输出和运输的细胞特性。我们将测试这个假设：LQT 1和LQT 2突变的ER滞留受细胞质量控制的不同组分以及不同囊泡转运途径中的Kv7.1和Kv11.1交通的调节。我们预期，调节分子伴侣、辅助分子伴侣和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LQT 1和LQT 2突变的功能表达，并且可以操纵Kv7.1和Kv11.1的囊泡运输特性以增加其功能表达。公共卫生相关性：每年心源性猝死声称多达25，000人没有结构性心脏病。这些心脏性猝死病例的遗传和后天原因越来越多地被确定，数百种突变与促心律失常疾病长QT（LQT）综合征有关。大约每7,000人中就有一人患有LQT 1或LQT 2，这分别是由KCNQ 1或KCNH 2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，它们是心脏中延迟整流K+电流的基础。研究表明，LQT 1和LQT 2突变通常会导致功能丧失。导致功能丧失的机制各不相同，但现在认识到，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，增加这些突变的功能表达的机制仅在LQT 2中被鉴定，并且不具有治疗潜力。为了合理地开发治疗策略，用于治疗具有运输缺陷LQT 1或LQT 2突变的患者，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。我们将测试这一假设，即LQT 1和LQT 2突变的ER保留是由不同的细胞质量控制的组成部分，和Kv7.1和Kv11.1交通在不同的囊泡运输途径。我们预计，我们将确定新的方法来增加运输缺陷LQT 1和LQT 2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.