Abstract 1471: Novel Mutation in the KCNQ1 Associated with Brugada Syndrome
INTRODUCTION: Brugada syndrome (BrS) is an inherited sudden death syndrome, characterized by ST segment elevation in the right precordial ECG leads and the development of polymorphic ventricular tachycardia. The disorder has been associated with mutations in SCN5A, SCN1B, GPD1L, CACNA1C, CACNB2B genes, causing a loss-of-function in sodium and calcium channel currents and mutations in KCNE3, resulting in a gain of function in the transient outward current. Despite this progress, a genetic link cannot be identified in approximately 70% of BrS probands, indicating the involvement of others genes. KCNQ1 is a gene encoding the α-subunit of the slowly activating delayed rectifier K+ current (IKs). We report on the identification and characterization of a KCNQ1 mutation associated with BrS.
METHODS AND RESULTS: A 64-year-old male, with no previous history of heart disease, experienced multiple episodes of ventricular tachycardia associated with syncope. Coved-type ST segment elevation in two of the right precordial ECG leads suggested a BrS phenotype. Family history revealed that his father and aunt died of heart disease, the aunt had died suddenly. All exons and introns borders of 14 candidate genes were screened by direct sequencing. A novel KCNQ1 mutation (V162M) in a conserved residue was identified in the proband and two asymptomatic daughters. He also has a common polymorphism in CACNB2b-D601E (23% allele frequency in control population). Wild-type (WT)-KCNQ1 or V162M-KCNQ1 channels were co-expressed with WT-KCNE1 in TSA201 cells. Channel function was studied using whole-cell patch clamp technique. At +20 mV, current amplitude at 20 ms into the pulse was significantly greater in mutant vs. WT channels (47.42±1.10 vs. 15.02±1.75 pA/pF; n=6; p <0.001). In contrast, IKs current at 2 s was similar (134.96±30.30 vs. 106.88±34.38 pA/pF; n=6; p = 0.55). Activation time constant was faster in mutant vs. WT (τ = 335.35 ± 0.67 vs. 1268.31 ± 2.94 ms; n=6, p=0.001). Expression of CACNB2b-D601E revealed no difference in calcium channel current compared to WT.
CONCLUSIONS: Our results suggest that a mutation in KCNQ1 can precipitate BrS by accelerating activation of IKs, and thus accentuating phase 1 repolarization in right the ventricular epicardium.