Mutation detection of cardiac ion channel genes in sudden death cases

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In the sudden death of a young adult, which is unexplained by a morphorogical examination and is unexpected by past history, we contructed a working theory that ion channels expressed in cardiac conducting system may be involved in the sudden death because long QT syndrome (LQT) has been shown to be caused by mutations in various ion channel genes.HERG, KVLQT, and SCN5A of which mutations cause LQT, and Kir6.2, GIRK1, GIRK4, and MAXIK were analyzed for mutations in eight sudden death cases and 100 healthy controls. A C to T transition in an intron of GIRK4 was found to be the only candidate mutation for sudden death on the basis of the function of the GIRK4 associated channel (I_<KACh>). The transition was assumed to change the splice donor site, leading to premature introduction of stop codon in the following exon. The mRNA was expected to be 5 bp longer than usual one. RT-PCR of ectopically expressed mRNA in leucocytes recovered from a healthy individual homozygous for the mutation failed to show the longer mRNA but this result does not mean that the presumed splice variant is not produced in impulse' conducting system. Only a small fraction of the truncated GIRK4 must decrease the I_<KACh> channel by dominant negative effect, thus resulting in functional impairment of the I_<KACh> channel.In addition to the GIRK4 mutation, several polymorphic mutations were identified in the other channel genes but all of them were found to be neutral variants. In this study, mutation has not been searched for along the total length of the genes. Further screening for mutation of the genes will be required.