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A new C-terminal hERG mutation A915fs+47X associated with symptomatic LQT2 and auditory-trigger syncope.. A new C-terminal hERG mutation A915fs+47X associated with symptomatic LQT2 and auditory-trigger syncope.: New LQT2-related hERG mutation A915fs+47X
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Expected publication in November issue of Heart Rhythm. Now after proof correction.. International audience. BACKGROUND: A novel mutation of hERG (A915fs+47X) was discovered in a 32-year-old woman with torsades de pointes, long QTc interval (515 ms), and syncope upon auditory trigger. OBJECTIVE: We explored whether the properties of this mutation could explain the pathology. METHODS: Whole-cell A915fs+47X (del) and wild-type (WT) currents were recorded in transiently transfected COS7 cells or Xenopus oocytes. Western blots and sedimentation analysis of del/WT hERG were used to analyze protein expression, assembly, and trafficking. RESULTS: The tail current density at -40 mV after a 2-s depolarization to +40 mV in COS7 cells expressing del was 36% of that for WT. Inactivation was 1.9-fold to 2.8-fold faster in del versus WT between -60 and +60 mV. In the range -60 to -10 mV, we found that a nondeactivating fraction of current was increased in del at the expense of a rapidly deactivating fraction, with a slowly deactivating fraction being unchanged. In Xenopus oocytes, expression of del alone produced 38% of WT currents, whereas coexpression of 1/2 WT + 1/2 del produced 49.8%. Furthermore, the expression of del protein at the cell surface was reduced by about 50%. This suggests that a partial trafficking defect of del contributes to the reduction in del current densities and to the dominant negative effect when coexpressed with WT. In model simulations, the mutation causes a 10% prolongation of action potential duration. CONCLUSION: Decreased current levels caused by a trafficking defect may explain the long QT syndrome observed in our patient.
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