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—The N629D mutation, adjacent to the GFG signature sequence of the HERG1 A K+ channel, causes long-QT syndrome (LQTS). Expression of N629D inXenopus oocytes produces a rapidly activating, noninactivating current. N629D is nonselective among monovalent cations; permeation of K+ was similar to that of Na+ or Cs+ . During repolarization to potentials between −30 and −70 mV, N629D manifested an inward tail current, which was abolished by replacement of extracellular Na+ (Na+ e ) with extracellularN -methyl-d -glucamine (NMGe ). Because LQTS occurs in heterozygous patients, we coexpressed N629D and wild type (WT) at equimolar concentrations. Heteromultimer formation was demonstrated by analyzing the response to 0 [K+ ]e . The outward time-dependent current was nearly eliminated for WT at 0 [K+ ]e , whereas no reduction was observed for homomultimeric N629D or for the equimolar coexpressed current. To assess physiological significance, dofetilide-sensitive currents were recorded during application of simulated action potential clamps. During phase 3 repolarization, WT manifested outward currents, whereas homomultimeric N629D manifested inward depolarizing currents. During coexpression studies, variable phenotypes were observed ranging from a reduction in outward repolarizing current to net inward depolarizing current during phase 3. In summary, N629D replaces the WT outward repolarizing tail current with an inward depolarizing sodium current, which is expected to delay later stages of repolarization and contribute to arrhythmogenesis. Thus, the consequences of N629D resemble the pathophysiology seen in LQT3 Na+ channel mutations and may be considered the first LQTS K+ channel mutation that exhibits gain of function.

Novel Gain-of-Function Mechanism in K + Channel–Related Long-QT Syndrome:

Novel Gain-of-Function Mechanism in K ⁺ Channel–Related Long-QT Syndrome: