Cardiac Channel Mutations in Sudden Infant Death Syndrome (SIDS)

婴儿猝死综合症 (SIDS) 中的心脏通道突变

• 批准号: 7317600
• 负责人: MICHAEL JOHN ACKERMAN
• 金额: $ 51.73万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-06-07 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7317600
• 关键词: A kinase anchoring protein; Accounting; Age-Years; Ankyrins; Appendix; Autonomic nervous system; Back to Sleep; Calcium; Candidate Disease Gene; Cardiac; Carrier Proteins; Cause of Death; Cessation of life; DNA; DNA Sequence; Disease; Exons; Functional disorder; Gender; Gene Mutation; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genomics; Genotype; Glycerol-3-Phosphate Dehydrogenase; Heteroduplex Analysis; High Pressure Liquid Chromatography; Homeodomain Proteins; Inborn Errors of Metabolism; Infant; Introns; Investigation; Laboratories; Long QT Syndrome; Macromolecular Complexes; Methods; Minisatellite Repeats; Molecular; Mutation; Mutation Analysis; Mutation Detection; Open Reading Frames; Pathogenesis; Patients; Phenotype; Polymerase Chain Reaction; Population; Positioning Attribute; Principal Investigator; Properdin; Proteins; RNA Splicing; Research Personnel; Risk; RyR2; Ryanodine Receptor Calcium Release Channel; Sampling; Scanning; Signal Pathway; Signal Transduction; Site; Sodium; Sodium Channel; Sudden Death; Sudden infant death syndrome; Susceptibility Gene; Syndrome; System; Temperature; Transfection; Translating; United States; Variant; Ventricular Tachycardia; Work; base; case control; caveolin-3; cohort; gain of function; insertion/deletion mutation; instrumentation; novel; phosphodiesterase 4D; programs; promoter; research study; serotonin transporter; sorcin; stem; success; syntrophin alpha1; vesicular monoamine transporter 2

DESCRIPTION (provided by applicant): With over 2000 deaths each year in the United States, Sudden Infant Death Syndrome (SIDS) remains the leading cause of death in infants 1 month to 1 year of age. The fundamental causes of SIDS remain poorly understood. Current etiologic studies for SIDS have focused on the central/autonomic nervous system, inborn errors of metabolism, and genetic cardiac channelopathies as possible substrates for the "vulnerable infant" in accordance with the SIDS triple risk hypothesis. Our prior work investigating Cardiac Channel Mutations in SIDS (HD42569) has established that the pathogenic mechanism for approximately 10% of SIDS may stem from the most common cardiac channelopathy known as long QT syndrome (LOTS). Recently, our Sudden Death Genomics Laboratory has discovered and functionally characterized two novel LQTS-susceptibility genes: CAV3 (LQT9) and SCN4B (LQT10) involving mutations in Channel Interacting Proteins (ChlPs) of the cardiac sodium channel macromolecular complex yielding LQTS-phenotypes. Most recently, mutation scanning of a limited region of the encoded calcium release channel revealed pathogenic mutations in approximately 2% of white infants. Functional studies indicate an arrhythmogenic mechanism consistent with type 1 catecholaminergic polymorphic ventricular tachycardia (CPVT1). In addition, polymorphisms that might predispose infants to sudden death in critical situations have been identified in various signaling pathways of the autonomic nervous system (ANS). However, these initial observations, derived from small cohorts of SIDS, have not been confirmed. Given the relationship between prolongation of the QT interval and dysregulation of the ANS, this proposal will seek to confirm the associations between SIDS and genetic variation in critical components of the ANS. These discoveries frame the experiments outlined in this renewal and support the applicant's hypothesis that an additional 5 - 10% of SIDS may stem from mutations in the ChlPs that comprise the sodium channel macromolecular complex and the calcium release channel macromolecular complex. If correct, this proposal will provide molecular and functional evidence implicating mutations in either the cardiac channel pore-forming subunits or ChlPs as the probable cause for 20% of SIDS (an estimated 400 cases each year). Furthermore, it will explore the involvement of genetic variations in genes encoding key proteins of the ANS- related serotonergic signaling pathways in the pathogenesis of this disease. Specifically, using polymerase chain reaction, denaturing high performance liquid chromatography, and DNA sequencing on one of the world's largest DNA cohorts of SIDS cases (N = 600), the applicant proposes to i) conduct comprehensive open reading frame/splice site mutational analysis of 12 genes that encode key ChlPs within the sodium channel and calcium release channel macromolecular complexes as candidate genes for SIDS and ii) conduct confirmatory case-control association studies involving polymorphisms/genetic variations in the ANS as well as novel candidate gene mutation analysis of VMAT2, a gene that encodes a key determinant of ANS-related serotonergic signaling.

描述（由申请人提供）：美国每年有超过 2000 人死亡，婴儿猝死综合症 (SIDS) 仍然是 1 个月至 1 岁婴儿死亡的主要原因。 SIDS 的根本原因仍然知之甚少。目前针对 SIDS 的病因学研究主要集中在中枢/自主神经系统、先天性代谢缺陷和遗传性心脏离子通道病上，根据 SIDS 三重风险假说，这些因素可能是“脆弱婴儿”的基础。我们之前研究 SIDS 心脏通道突变 (HD42569) 的工作已经确定，大约 10% SIDS 的致病机制可能源于最常见的心脏通道病变，即长 QT 综合征 (LOTS)。最近，我们的猝死基因组学实验室发现了两个新的 LQTS 易感基因并进行了功能表征：CAV3 (LQT9) 和 SCN4B (LQT10)，涉及产生 LQTS 表型的心脏钠通道大分子复合物的通道相互作用蛋白 (ChlP) 突变。最近，对编码的钙释放通道的有限区域进行突变扫描，发现大约 2% 的白人婴儿存在致病性突变。功能研究表明，其致心律失常机制与 1 型儿茶酚胺能多形性室性心动过速 (CPVT1) 一致。此外，在自主神经系统（ANS）的各种信号通路中还发现了可能导致婴儿在危急情况下猝死的多态性。然而，这些源自小规模 SIDS 群体的初步观察结果尚未得到证实。鉴于 QT 间期延长与 ANS 失调之间的关系，该提案将寻求确认 SIDS 与 ANS 关键组成部分的遗传变异之间的关联。这些发现构成了本次更新中概述的实验，并支持申请人的假设，即另外 5-10% 的 SIDS 可能源于包含钠通道大分子复合物和钙释放通道大分子复合物的 ChLP 中的突变。如果正确，该提议将提供分子和功能证据，表明心脏通道成孔亚基或 ChlP 的突变是 20% SIDS（每年估计有 400 例）的可能原因。此外，还将探讨编码 ANS 相关血清素信号通路关键蛋白的基因的遗传变异在该疾病的发病机制中的作用。具体而言，利用聚合酶链式反应、变性高效液相色谱和DNA测序对世界上最大的SIDS病例DNA队列之一（N = 600）进行DNA测序，申请人建议i）对编码钠通道和钙释放通道大分子复合物内关键ChLP的12个基因进行全面的开放阅读框/剪接位点突变分析，作为SIDS的候选基因；ii）进行验证性分析 病例对照关联研究涉及 ANS 中的多态性/遗传变异以及 VMAT2 的新候选基因突变分析，VMAT2 是编码 ANS 相关血清素信号的关键决定因素的基因。