Cardiac sodium channel mutation associated with epinephrine-induced QT prolongation and sinus node dysfunction.
BACKGROUND
Long-QT syndrome (LQTS) is an inherited arrhythmia characterized by prolonged ventricular repolarization and malignant tachyarrhythmias. LQT1, LQT2, and LQT3 are caused by mutations in KCNQ1 (LQT1), KCNH2 (LQT2), and SCN5A (LQT3), which account for approximately 90% of genotyped LQTS patients. Most cardiac events in LQT1 patients occur during exercise, whereas patients with LQT3 tend to have arrhythmic events during rest or asleep.


OBJECTIVE
The study aimed to identify a genetic mutation in a Japanese man who presented with sinus node dysfunction and prolonged QT interval on exercise and epinephrine stress tests, as well as to clarify the electrophysiological properties of mutant channels.


METHODS
LQTS-related genes were screened in this patient. Electrophysiological functional assays were conducted with a heterologous expression system.


RESULTS
We identified a heterozygous missense SCN5A mutation, V2016M, which changes the last amino acid of the cardiac sodium channel. Electrophysiological analyses revealed that the mutant channels exhibited a loss-of-function feature, decreased peak sodium current densities (wild type 175.2 ± 17.6 pA/pF; V2016M 97.2 ± 16.0 pA/pF; P < .01). In addition, the mutant channels showed gain-of-function features: increased late sodium currents by protein kinase A activation (wild type 0.07 ± 0.01%; V2016M 0.17 ± 0.03%; P < .05) and impaired inactivation of sodium channels by protein kinase A or C activation.


CONCLUSIONS
We identified an SCN5A mutation in a patient with sinus node dysfunction and epinephrine-induced QT prolongation, which was an atypical phenotype for LQT3. The electrophysiological properties of the mutant channels might be associated with the overlapping clinical features of the patient.
Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Jiarong
J
Chen
Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan. Electronic address: makiyama@kuhp.kyoto-u.ac.jp.
Takeru
T
Makiyama
Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan; Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Otsu, Japan.
Yimin
Y
Wuriyanghai
Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan; Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Otsu, Japan; Center for Epidemiologic Research in Asia, Shiga University of Medical Science, Otsu, Japan.
Seiko
S
Ohno
Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Kenichi
K
Sasaki
Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Mamoru
M
Hayano
Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Takeshi
T
Harita
Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Suguru
S
Nishiuchi
Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Yuta Yamamoto
Department of Medicine and Clinical Science, Yamaguchi University Graduate School of Medicine, Ube, Japan.
Takeshi
T
Ueyama
Department of Medicine and Clinical Science, Yamaguchi University Graduate School of Medicine, Ube, Japan.
Akihiko
A
Shimizu
Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Otsu, Japan.
Minoru
M
Horie
Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Takeshi
T
Kimura
D004837:Epinephrine / Q000494:pharmacology*; D005080:Exercise Test / Q000009:adverse effects / Q000379:methods; D020022:Genetic Predisposition to Disease; D006801:Humans; D008133:Long QT Syndrome / Q000150:complications / Q000175:diagnosis / Q000235:genetics / Q000503:physiopathology; D008297:Male; D020125:Mutation, Missense; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics*; D012804:Sick Sinus Syndrome / Q000175:diagnosis / Q000209:etiology; D013566:Sympathomimetics / Q000494:pharmacology; D013575:Syncope / Q000175:diagnosis / Q000209:etiology; D055815:Young Adult
D062554:NAV1.5 Voltage-Gated Sodium Channel; D013566:Sympathomimetics; D004837:Epinephrine
Adrenergic stimulation; Epinephrine; Long-QT syndrome; Protein kinase A; Protein kinase C; SCN5A