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: 7676123
• 负责人: MICHAEL JOHN ACKERMAN
• 金额: $ 52.82万
• 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/7676123
• 关键词: 1 year old; A kinase anchoring protein; Accounting; Ankyrins; 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; 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; case control; caveolin-3; cohort; gain of function; high risk infant; infant death; insertion/deletion mutation; instrumentation; novel; phosphodiesterase 4D; population based; 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(申请人提供)：在美国，每年有超过2000例死亡，婴儿猝死综合症(SID)仍然是导致1个月至1岁婴儿死亡的主要原因。小岛屿发展中国家的根本原因仍然知之甚少。根据小岛屿发展中国家三重风险假说，目前对小岛屿发展中国家的病因学研究主要集中在中枢/自主神经系统、先天代谢障碍和遗传性心脏通道病作为“脆弱婴儿”的可能底物。我们先前对SID(HD42569)心脏通道突变的研究已经确定，大约10%的SID的致病机制可能源于最常见的心脏通道病，即长QT综合征(LOTS)。最近，我们的猝死基因组实验室发现了两个新的LQTS易感基因：CAV3(LQT9)和SCN4B(LQT10)，涉及产生LQTS表型的心脏钠通道大分子复合体的通道相互作用蛋白(ChLP)突变。最近，对编码的钙释放通道有限区域的突变扫描发现，大约2%的白人婴儿存在致病突变。功能研究表明，导致心律失常的机制与1型儿茶酚胺能多形性室性心动过速(CPVT1)一致。此外，已在自主神经系统(ANS)的各种信号通路中发现了可能使婴儿在危急情况下猝死的基因多态性。然而，这些从小岛屿发展中国家小群体中得出的初步观察结果尚未得到证实。鉴于QT间期延长与ANS调节失调之间的关系，这项建议将寻求证实SID与ANS关键组成部分的遗传变异之间的关联。这些发现框定了本次更新中概述的实验，并支持申请人的假设，即额外5%-10%的SID可能源于组成钠通道大分子复合体和钙释放通道大分子复合体的ChLP突变。如果正确，这一建议将提供分子和功能证据，表明心脏通道孔洞形成亚单位或ChLP的突变可能是20%的SID(估计每年400例)的原因。此外，还将探讨ANS相关5-羟色胺能信号通路关键蛋白编码基因的遗传变异在本病发病机制中的作用。具体地说，申请人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小岛屿发展中国家病例之一(N=600)进行了全面的开放阅读框架/剪接点突变分析，对编码钠通道和钙释放通道高分子复合体中的关键ChLP的12个基因进行了突变分析，以及ii)进行了涉及ANS多态/遗传变异的验证性病例对照关联研究，以及VMAT2的新的候选基因突变分析，VMAT2是编码ANS相关5-羟色胺信号的关键决定基因。