||To identify genes involved in cardiac arrhythmia, families with autosomal dominant long QT syndrome (LQT) were investigated. LQT is a disorder that predisposes otherwise healthy individuals to syncope, seizures and sudden death from a ventricular tachyarrhythmia, torsade de pointes. In 1991, our laboratory identified linkage of LQT1 to chromosome 11p15.5. The identification of novel chromosome 11p15.5 polymorphic markers facilitated construction of a refined genetic map and confined LQT1 to a ~3 centimorgan region. Physical mapping studies identified an NruI restriction fragment of ~700 kilobases in which the LQT1 gene is located. Genetic analyses of additional LQT families demonstrated that LQT is a heterogeneous disorder. Two of these loci have been mapped to chromosomes 7 (LQT2) and 3 (LQT3). The myocellular hypothesis of LQT suggests that cardiac ion channels and regulators of ion channels are candidates for this disorder. To investigate this hypothesis, several K+ channel genes were isolated and mapped to chromosomes 1, 12 and 19. Genetic and physical mapping of a putative K+ channel, the human ether-a-go-go related gene (HERG), localized this gene to chromosome 7q35-36 near LQT2. Heterologous expression studies defined HERG as the alpha-subunit of the rapidly activating, delayed rectifier K+ current (IKr) in cardiac myocytes. HERG mutations were identified in six LQT families including two intragenic deletions, one splice-donor mutation, and three missense mutations. Northern analyses demonstrated that HERG was strongly expressed in cardiac tissue. To determine the effect of these mutations on HERG function, mutant constructs were expressed singly and in combination with wild-type HERG (WT-HERG). The deletion mutants failed to express functional channels and did not interact with WT-HERG. By contrast, the point mutants interact with WT-HERG and suppress IKr]by a dominant-negative mechanism. These data demonstrate that LQT2 results from mutations in HERG, define HERG as the major component of IKr and provide a mechanistic link between inherited and acquired forms of LQT.