Abstract 12845: Novel Gain-of-Function N-terminal KCNH2 Mutation Associated with the Short QT Syndrome
AIM: The human ether-a-go-go-related gene (HERG) encodes the α subunit of the rapidly activating delayed rectifier channel responsible for IKr. N588K and T618I mutations in the S5-P loop region and an R1135H mutation in the C-terminal of the KCNH2 gene have previously been shown to underlie the SQT1 form of the short QT syndrome (SQTS), a clinical disorder characterized by abbreviated QT intervals on the electrocardiogram and an increased risk of life-threatening arrhythmia. Here, we describe a novel mutation in KCNH2 associated with tall peaked T waves and abbreviated QTc intervals ranging between 349 and 381 ms.
METHODS and RESULTS: The proband's index event was a loss of consciousness while driving. He received an ICD, but no appropriate shocks were delivered over a 3 year follow-up. Direct DNA sequencing revealed a substitution of thymine for guanine, predicting a substitution of aspartic acid (D) for glutamine acid (E) at position 50 in the N-terminal of KCNH2. The variation was absent in 1300 healthy controls and alignment of the amino acid sequence of HERG showed that residue E50 is highly conserved among species. Functional expression of E50D-KCNH2 in TSA201 cells at 37°C showed a marked gain of function. Whole cell voltage clamp studies demonstrated a significantly increased peak IKr tail current for E50D-KCNH2 compared with WT-KCNH2, in both cases co-expressed with WT-KCNE1. Total charge of IKr tail of E50D-KCNH2 current normalized to cell size capacitive at +10 mV showed a 6-fold increase relative to WT-KCNH2 (n = 10 cells for each, P < 0.01). Kinetic analysis revealed slower deactivation of E50D-KCNH2; voltage dependence of inactivation was shifted in the positive direction (WT: -76.8 ± 4.8 vs. E50D: -65.3 ± 2.7 mV).
CONCLUSION: We report the first pathogenic mutation in the N-terminal of KCNH2 associated with SQT1. The E50D missense mutation causes a gain of function of IKr tail current density, slower deactivation and a positive shift in the voltage dependence of inactivation.
- © 2011 by American Heart Association, Inc.