Abstract 2821: Novel KCNE5 Mutations Are Associated With Brugada Syndrome and Idiopathic Ventricular Fibrillation
Introduction: In Brugada syndrome (BrS), male patients are significantly prevalent. Among genes coding ion channels and their modulatory proteins, KCNE5 is located in the X chromosome and encodes an auxiliary subunit for K channels. Combined with KCND3, KCNE5 has been shown to modify the transient outward current (Ito). Ito plays a key role in determining the repolarization process in the myocardium; therefore KCNE5 can be an attractive candidate for gene responsible for BrS and other idiopathic ventricular fibrillation (IVF).
Methods and Results: In consecutive 190 Japanese patients with BrS or IVF that were introduced to our institution and negative for SCN5A mutation, we conducted a further extensive genetic screening for KCNE5 using DHPLC-WAVE system and direct sequencing. We identified two novel KCNE5 mutations, Y81H in 3 probands and D92E-E93X in one proband from 4 unrelated families. One of the probands with the Y81H mutation was a male showing typical Brugada ECG. He was rescued from VF attacks and implanted ICD. Another two were female patients and did not show Brugada ECG. Both experienced VF and underwent ICD implantation. The D92E-E93X mutation was identified in a 59-year-old man who lost his consciousness when he was in high fever. His ECG recorded at rest displayed coved type ST elevations in right precordial leads at the third costal position. In 250 normal volunteers, Y81H mutation was identified in 2 females, and D92E-E93X was not identified. To see the effect of the KCNE5 mutations, we conducted biophysical assay using co-transfection with KCND3 or KCNQ1. In the experiments with KCND3 which encodes Kv4.3, the transient outward currents (Ito) were significantly increased in both of the mutations compared to WT: mean current densities at +50 mV were 93.8±15.4 pA/pF in WT, 161.0±19.8 pA/pF in Y81H and 174.2±27.2 pA/pF in D92E-E93X (P<0.001). In contrast, there were no significant changes in current properties reconstructed by KCNQ1 plus WT and two KCNE5 mutants.
Conclusion: KCNE5, an auxiliary subunit for cardiac K channels, modulates Ito and its novel mutations appeared to cause IVF especially BrS in male patients through the gain-of-function effects on Ito currents. The screening for KCNE5 mutation is therefore of clinical importance for BrS or IVF.