The cardiac Na current macromolecular complex and role in arrhythmia mechanism

心脏Na电流大分子复合物及其在心律失常中的作用机制

• 批准号: 8903545
• 负责人: JONATHAN C MAKIELSKI
• 金额: $ 37.63万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8903545
• 关键词: Accounting; Address; Affect; Arrhythmia; Atrial Fibrillation; Basic Science; Candidate Disease Gene; Cardiac; Cardiac Myocytes; Caveolae; Cell physiology; Clinic; Clinical; Clinical Sciences; Complex; Cysteine; DLG1 gene; Diagnosis; Diagnostic; Disease; Electrophysiology (science); Family; Functional disorder; Funding; Gene Mutation; Genes; Genetic; Genetic Variation; Genotype; Goals; Health; Heart; Heart Diseases; Heart failure; Human; Inherited; Intercalated disc; Ion Channel; Ischemia; Lateral; Lead; Link; Location; Long QT Syndrome; Macromolecular Complexes; Membrane; Modeling; Molecular; Mus; Muscle Cells; Mutation; Myocardial Ischemia; Nature; Participant; Pathogenesis; Patients; Phenotype; Phosphorylation; Physiological; Protein Subunits; Proteins; Proteomics; Regulation; Relative (related person); Reporting; Role; Scaffolding Protein; Sick Sinus Syndrome; Sodium; Specificity; Sudden infant death syndrome; Syndrome; System; Techniques; Transgenic Mice; Ubiquitination; Ventricular Fibrillation; Work; adapter protein; base; bench to bedside; caveolin-3; clinically relevant; cohort; enzyme substrate; gain of function; gene discovery; genetic regulatory protein; immunocytochemistry; improved; induced pluripotent stem cell; insight; loss of function; novel; preference; research study; screening; syntrophin

DESCRIPTION (provided by applicant): Dysfunction of the Na current (INa) flowing through the α subunit of the cardiac Na channel encoded by SCN5A participates in pathogenic mechanisms for arrhythmia, heart failure, and ischemia. Over the past 9 years we have been an active participant and contributor as the field progressed from discovery of arrhythmia mutations in α subunits of ion channels to discovery of mutations in other subunits and associated proteins that form ion channel macromolecular complexes (MMCs). The MMC for INa now has at least 21 associated components that we will call MMCCs. These include subunits, ChIPs, scaffolding, and adapter and regulatory proteins. In the past 4-year period we identified ten new clinical syndromes involving "arrhythmia genes" encoding INa- MMCCs: CAV3 in LQT9 and SIDS, SCN4B in LQT10 and SIDS, SNTA1 in LQT12 and SIDS, GPD1L in SIDS, and SCNB3 in IVF and SIDS; all of these we showed to cause dysfunction of INa. We also made progress on mechanism showing that GPD1L mutations decrease INa through a mechanism of direct SCN5A phosphorylation and that SNTA1 mutations increase late INa through a mechanism of direct nitrosylation of SCN5A. In the next project period we propose to more thoroughly investigate mechanisms of CAV3 and SNTA1 action on INa involving nitrosylation of SCN5A and the MMCC Nedd4.2L. In Aim 1 we will elucidate mechanisms for INa dysfunction (gain of function or late INa) involving direct nitrosylation of SCN5A. In Aim 2 we will elucidate mechanisms for INa dysfunction (loss of function or INa) involving nitrosylation of Nedd4.2L. In Aim 3 we will determine compositions and locations of different types of INa-MMCs in mouse and human heart with a focus on CAV3-MMCCs. And we will continue the gene discovery efforts under Aim 4 where we will characterize INa from novel mutations in INa-MMCCs identified in screens of arrhythmia patients who are not linked to known genotypes and determine the mechanism of action that affect INa. We already have two novel candidate genes with two mutations in SAP97 and three mutations in Nedd4.2L from patients with Brugada syndrome. The progress on this project on arrhythmia gene discovery will have impact on increasing the diagnostic yield for patients with inherited arrhythmias. The elucidation of mechanisms by which these gene products affect INa will produce insights into both physiological regulation of INa, and pathophysiological causes of INa dysfunction for both inherited arrhythmia and commonly acquired cardiac diseases such as heart failure and ischemia.

描述（由申请人提供）：流经由SCN 5A编码的心脏Na通道α亚基的Na电流（INa）功能障碍参与心律失常、心力衰竭和缺血的致病机制。在过去的9年里，我们一直是该领域的积极参与者和贡献者，从发现离子通道α亚基中的心律失常突变到发现形成离子通道大分子复合物（MMC）的其他亚基和相关蛋白质中的突变。INa的MMC现在至少有21个相关组件，我们称之为MMCC。这些包括亚基，ChIP，支架，适配器和调节蛋白。在过去的4年中，我们确定了10个新的临床综合征，涉及编码INa-MMCCs的"心律失常基因"：LQT9和SIDS中的CAV 3，LQT10和SIDS中的SCN 4B，LQT12和SIDS中的SNTA 1，SIDS中的GPD 1L，IVF和SIDS中的SCNB 3;所有这些我们都显示出导致INa功能障碍。我们还在机制方面取得了进展，表明GPD1L突变通过直接SCN 5A磷酸化机制降低INa，SNTA 1突变通过SCN 5A直接亚硝基化机制增加晚期INa。在下一个项目期间，我们建议更彻底地研究CAV 3和SNTA 1对INa的作用机制，包括SCN 5A和MMCC Nedd4.2L的亚硝基化。在目标1中，我们将阐明涉及SCN 5A直接亚硝基化的INa功能障碍（功能获得或晚期INa）的机制。在目标2中，我们将阐明涉及Nedd4.2L亚硝基化的INa功能障碍（功能丧失或INa）的机制。在目标3中，我们将确定小鼠和人心脏中不同类型的INa-MMCs的组成和位置，重点是CAV3-MMCs。我们将继续目标4下的基因发现工作，我们将从与已知基因型无关的心律失常患者筛选中发现的INa-MMCCs中的新突变中表征INa，并确定影响INa的作用机制。我们已经从Brugada综合征患者中获得了两个新的候选基因，其中SAP97有两个突变，Nedd4.2L有三个突变。心律失常基因发现项目的进展将对提高遗传性心律失常患者的诊断率产生影响。阐明这些基因产物影响INa的机制将使我们深入了解INa的生理调节和INa功能障碍的病理生理原因，包括遗传性心律失常和常见的获得性心脏病，如心力衰竭和缺血。

项目成果

Molecular pathological study on LRRC10 in sudden unexplained nocturnal death syndrome in the Chinese Han population.

中国汉族人群夜间不明原因猝死综合征LRRC10的分子病理学研究

• DOI: 10.1007/s00414-016-1516-z
• 发表时间: 2017-05
• 期刊: International journal of legal medicine
• 影响因子: 2.1
• 作者: Huang L;Tang S;Chen Y;Zhang L;Yin K;Wu Y;Zheng J;Wu Q;Makielski JC;Cheng J
• 通讯作者: Cheng J

Vinculin variant M94I identified in sudden unexplained nocturnal death syndrome decreases cardiac sodium current.

在不明原因的夜间死亡综合征中发现的纽蛋白变异体 M94I 会降低心脏钠电流。

• DOI: 10.1038/srep42953
• 发表时间: 2017-02-20
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Cheng J;Kyle JW;Wiedmeyer B;Lang D;Vaidyanathan R;Makielski JC
• 通讯作者: Makielski JC

The biophysical characterization of the first SCN5A mutation R1512W identified in Chinese sudden unexplained nocturnal death syndrome.

中国不明原因夜间死亡综合征中首次发现的 SCN5A 突变 R1512W 的生物物理特征

• DOI: 10.1097/md.0000000000003836
• 发表时间: 2016-06
• 期刊: Medicine
• 影响因子: 1.6
• 作者: Zheng J;Zhou F;Su T;Huang L;Wu Y;Yin K;Wu Q;Tang S;Makielski JC;Cheng J
• 通讯作者: Cheng J

Identification of rare variants of DSP gene in sudden unexplained nocturnal death syndrome in the southern Chinese Han population.

中国南方汉族人群不明原因夜间死亡综合征中 DSP 基因罕见变异的鉴定。

• DOI: 10.1007/s00414-015-1275-2
• 发表时间: 2016-03
• 期刊: International journal of legal medicine
• 影响因子: 2.1
• 作者: Zhao Q;Chen Y;Peng L;Gao R;Liu N;Jiang P;Liu C;Tang S;Quan L;Makielski JC;Cheng J
• 通讯作者: Cheng J