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.