The E1784K mutation in SCN5A is associated with mixed clinical phenotype of type 3 long QT syndrome.
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.
Makita
Naomasa
N
Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Behr
Elijah
E
Shimizu
Wataru
W
Horie
Minoru
M
Sunami
Akihiko
A
Crotti
Lia
L
Schulze-Bahr
Eric
E
Fukuhara
Shigetomo
S
Mochizuki
Naoki
N
Makiyama
Takeru
T
Itoh
Hideki
H
Christiansen
Michael
M
McKeown
Pascal
P
Miyamoto
Koji
K
Kamakura
Shiro
S
Tsutsui
Hiroyuki
H
Schwartz
Peter J
PJ
George
Alfred L
AL
Roden
Dan M
DM
D000293:Adolescent; D000328:Adult; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D001703:Biophysics / Q000379:methods; D002648:Child; D004252:DNA Mutational Analysis; D004562:Electrocardiography; D005260:Female; D005424:Flecainide / Q000494:pharmacology; D006801:Humans; D008133:Long QT Syndrome / Q000235:genetics* / Q000473:pathology; D008297:Male; D009124:Muscle Proteins / Q000235:genetics* / Q000502:physiology*; D009154:Mutation; D062554:NAV1.5 Voltage-Gated Sodium Channel; D010641:Phenotype; D015222:Sodium Channels / Q000235:genetics* / Q000502:physiology*
D000889:Anti-Arrhythmia Agents; D009124:Muscle Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D015222:Sodium Channels; D005424:Flecainide