Cardiac Channel Mutations in SIDS

简介（由申请人提供）：Michael J. Ackerman, m.d.，博士，是梅奥医学院医学、儿科学、分子药理学和实验治疗学的助理教授。Ackerman博士是一名指导猝死基因组学实验室和长QT综合征诊所的内科科学家。他的长期目标是确定婴儿、儿童、青少年和年轻人心源性猝死的潜在原因。在这份题为“婴儿猝死综合征的心脏通道突变”的提案中，申请人阐述了一个基本问题的答案：在婴儿猝死综合症死亡中，有多少百分比的婴儿在编码心脏离子通道的基因中具有假定的致病突变？目前，在美国，小岛屿发展中国家每年继续声称有近3000名明显健康的婴儿。小岛屿发展中国家的根本原因仍然知之甚少。在具体目标1中，Ackerman博士将使用温度调节异双工分析和变性高效液相色谱法对已经涉及人类心律失常综合征（即先天性长QT综合征）的5个心脏通道基因进行突变分析。在具体目标2中，将通过突变分析研究两个非lqts心律失常综合征离子通道基因作为新的SIDS候选基因。最后，在特定的目标3中，目标1和目标2中鉴定的通道基因可能发生的突变将在功能上进行表征。这些突变将通过定点诱变进入野生型通道，在瞬时和稳定的转染细胞系中表达，并使用单电极膜片钳技术进行表征。如果申请人的假设是正确的，即10%的SIDS婴儿具有心脏通道突变，那么心脏通道基因将解释迄今为止最大的可识别婴儿子集的“潜在脆弱性”。这一发现可能对进一步减少我国和全世界小岛屿发展中国家发病率的努力产生重大影响。

DESCRIPTION (provided by applicant): Michael J. Ackerman, M.D., Ph.D. is a board eligible pediatric cardiologist and an Assistant Professor of Medicine, Pediatrics, and Molecular Pharmacology & Experimental Therapeutics at Mayo Medical School. Dr. Ackerman is a physician-scientist directing a sudden death genomics laboratory and the Long QT Syndrome Clinic. His long-term objectives are to identify the underlying causes of sudden cardiac death in infants, children, adolescents, and young adults. In this proposal entitled Cardiac Channel Mutations in Sudden Infant Death Syndrome, the applicant sets forth to answer the fundamental question: what percentage of infants suffering a SIDS death possessed putative disease-causing mutations in the genes encoding their cardiac ion channels? Presently, SIDS continues to claim nearly 3000 apparently healthy infants each year in the United States. The fundamental causes underlying SIDS remain poorly understood. In specific aim 1, Dr. Ackerman will perform a mutational analysis of the 5 cardiac channel genes already implicated in a human arrhythmia syndrome, namely congenital long QT syndrome using temperature modulated heteroduplex analysis and denaturing high performance liquid chromatography. In specific aim 2, two non-LQTS arrhythmia syndrome ion channel genes will be investigated by mutational analysis as novel candidate SIDS genes. Finally, in specific aim 3, the possible mutations in the channel genes identified in aims 1 and 2 will be characterized functionally. These mutations will be engineered by site-directed mutagenesis into the wild type channel, expressed in transient and stable transfection cell lines, and characterized using single electrode patch clamp technologies. If the applicant's hypothesis is correct that 10% of infants with SIDS possess cardiac channel mutations, then cardiac channel genes would account for the "underlying vulnerability" for the largest identifiable subset of infants to date. Such a discovery could have significant implications on attempts to further reduce the incidence of SIDS in our country and throughout the world.