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.
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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

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Figure 6

State-dependent flecainide block.

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State-dependent flecainide block. (A) Representative steady-state curren...
(A) Representative steady-state current traces of WT and E1784K before and after flecainide (10 and 100 μmol/l). Cells were depolarized by –20 mV from a holding potential of –150 mV. Currents were normalized by the peak current before flecainide and were superimposed. Calibration bars indicate 1 nA and 1 ms. (B) Concentration-response curve for flecainide-induced tonic block in WT (n = 5) and E1784K (n = 5). The normalized peak currents were fit to the Hill equation B(%) = 100/(1 + (D / IC50)nH), where B is the percentage block at drug concentration D, and nH is the Hill coefficient. The IC50 values, representing dissociation constants for resting state (KR) were WT, 150.3 μmol/l and E1784K, 20.4 μmol/l. Thus the mutant channel was far more sensitive to tonic block by flecainide. (C) Dissociation constant for inactivated channels. Cells were depolarized by prepulses ranging from –150 mV to –60 mV for 500 ms from a holding potential of –150 mV to ensure steady-state inactivation, followed by a –20-mV test pulse in the presence or absence of 30 μmol/l flecainide. The pulse protocol cycle time was 60 s. Peak Na currents were normalized to the maximum Na current in the absence or presence of flecainide and were fit to the Boltzmann equation. The dissociation constant for the inactivated state (KI) was calculated using Bean’s equation (27): V1/2 – V1/2c = k × ln([1 + D / KR] / [1 + D / KI]), where V1/2 and V1/2c are the midpoints of steady-state inactivation for flecainide and control, respectively, D is the flecainide concentration, and KR is the dissociation constant for the resting state. The KR values are equivalent to the IC50 values measured at a holding potential of –150 mV (WT, 150.3 μmol/l; E1784K, 20.4 μmol/l) in B.