The E1784K mutation in SCN5A is associated with mixed clinical phenotype of type 3 long QT syndrome
Naomasa Makita, … , Alfred L. George Jr., Dan M. Roden
Naomasa Makita, … , Alfred L. George Jr., Dan M. Roden
Published May 1, 2008
Citation Information: J Clin Invest. 2008;118(6):2219-2229. https://doi.org/10.1172/JCI34057.
View: Text | PDF
Research Article Cardiology

The E1784K mutation in SCN5A is associated with mixed clinical phenotype of type 3 long QT syndrome

Abstract

Phenotypic overlap of type 3 long QT syndrome (LQT3) with Brugada syndrome (BrS) is observed in some carriers of mutations in the Na channel SCN5A. While this overlap is important for patient management, the clinical features, prevalence, and mechanisms underlying such overlap have not been fully elucidated. To investigate the basis for this overlap, we genotyped a cohort of 44 LQT3 families of multiple ethnicities from 7 referral centers and found a high prevalence of the E1784K mutation in SCN5A. Of 41 E1784K carriers, 93% had LQT3, 22% had BrS, and 39% had sinus node dysfunction. Heterologously expressed E1784K channels showed a 15.0-mV negative shift in the voltage dependence of Na channel inactivation and a 7.5-fold increase in flecainide affinity for resting-state channels, properties also seen with other LQT3 mutations associated with a mixed clinical phenotype. Furthermore, these properties were absent in Na channels harboring the T1304M mutation, which is associated with LQT3 without a mixed clinical phenotype. These results suggest that a negative shift of steady-state Na channel inactivation and enhanced tonic block by class IC drugs represent common biophysical mechanisms underlying the phenotypic overlap of LQT3 and BrS and further indicate that class IC drugs should be avoided in patients with Na channels displaying these behaviors.

Authors

Naomasa Makita, Elijah Behr, Wataru Shimizu, Minoru Horie, Akihiko Sunami, Lia Crotti, Eric Schulze-Bahr, Shigetomo Fukuhara, Naoki Mochizuki, Takeru Makiyama, Hideki Itoh, Michael Christiansen, Pascal McKeown, Koji Miyamoto, Shiro Kamakura, Hiroyuki Tsutsui, Peter J. Schwartz, Alfred L. George Jr., Dan M. Roden

×

Figure 5

Tonic block and UDB by flecainide.

Options: View larger image (or click on image) Download as PowerPoint
Tonic block and UDB by flecainide. (A) Representative current traces of ...
(A) Representative current traces of WT, E1784K, and T1304M before and after 10 μmol/l flecainide. A train of 100 pulses (to –20 mV for 20 ms) was applied at 2 Hz from a holding potential of –120 mV. Numbers indicate the first, 30th, and 100th pulse of the 2-Hz train. Zero current levels are indicated by dotted lines. (B) Time course of the peak current levels after application of 10 μmol/l flecainide. Peak current levels recorded with each pulse were normalized to the baseline prior to flecainide treatment. (C) Tonic block, determined by the first test pulse after application of flecainide, was weak in WT (4.5% ± 4.0%, n = 5) and T1304M (7.1% ± 2.7%, n = 5; P = NS) but was remarkably enhanced in E1784K (43.7% ± 8.0%, n = 5; **P < 0.001). Conversely, UDB, determined by the difference between first and 100th pulses relative to the first pulse, was slightly attenuated in E1784K (WT, 43.4% ± 3.0%; E1784K, 32.0% ± 2.2%; *P < 0.05), but not in T1304M (36.9% ± 2.7%; P = NS). Net flecainide block at the 100th train was significantly enhanced in E1784K (WT, 45.5% ± 5.0%; E1784K, 61.8% ± 2.5%; P < 0.01) but not in T1304M (41.2% ± 3.2%; P = NS). (D) Recovery from flecainide block. Cells were held at a potential of –150 mV and superfused with 30 μmol/l flecainide, and a train of 50 pulses (to –20 mV for 20 ms) at 10 Hz was applied to block Na channels. The pulse protocol cycle time was 60 s. Recovery from block was then assessed by a –20-mV test pulse applied after varying the duration of a –150-mV repolarization period (Δt). Peak current was normalized, and the data were fit to a double exponential function.