Sodium channelopathy underlying familial sick sinus syndrome with early onset and predominantly male characteristics.
BACKGROUND
Sick sinus syndrome (SSS) is a common arrhythmia often associated with aging or organic heart diseases but may also occur in a familial form with a variable mode of inheritance. Despite the identification of causative genes, including cardiac Na channel (SCN5A), the pathogenesis and molecular epidemiology of familial SSS remain undetermined primarily because of its rarity.


RESULTS
We genetically screened 48 members of 15 SSS families for mutations in several candidate genes and determined the functional properties of mutant Na channels using whole-cell patch clamping. We identified 6 SCN5A mutations including a compound heterozygous mutation. Heterologously expressed mutant Na channels showed loss-of-function properties of reduced or no Na current density in conjunction with gating modulations. Among 19 family members with SCN5A mutations, QT prolongation and Brugada syndrome were associated in 4 and 2 individuals, respectively. Age of onset in probands carrying SCN5A mutations was significantly less (mean±SE, 12.4±4.6 years; n=5) than in SCN5A-negative probands (47.0±4.6 years; n=10; P<0.001) or nonfamilial SSS (74.3±0.4 years; n=538; P<0.001). Meta-analysis of SSS probands carrying SCN5A mutations (n=29) indicated profound male predominance (79.3%) resembling Brugada syndrome but with a considerably earlier age of onset (20.9±3.4 years).


CONCLUSIONS
The notable pathophysiological overlap between familial SSS and Na channelopathy indicates that familial SSS with SCN5A mutations may represent a subset of cardiac Na channelopathy with strong male predominance and early clinical manifestations.
From the Departments of Molecular Physiology (K.A., T.M., D.T.H., T.I., Y.T., N.M.), Pediatrics (H.Y., H.M.), and Cardiovascular Medicine (S.F., M.K., K.M.), Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Departments of Pediatrics (N.S.) and Cardiovascular Medicine (K.O., I.W.), Nihon University Graduate School of Medicine, Tokyo, Japan; Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan (T.M.); Division of Heart Rhythm Management, Yokohama Rosai Hospital, Yokohama, Japan (A.N.); and The Second Department of Internal Medicine (T.W., Y.O.) and Department of Heart Rhythm Management (H.A.), University of Occupational and Environmental Health, Kitakyushu, Japan.
Keisuke
K
Abe
From the Departments of Molecular Physiology (K.A., T.M., D.T.H., T.I., Y.T., N.M.), Pediatrics (H.Y., H.M.), and Cardiovascular Medicine (S.F., M.K., K.M.), Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Departments of Pediatrics (N.S.) and Cardiovascular Medicine (K.O., I.W.), Nihon University Graduate School of Medicine, Tokyo, Japan; Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan (T.M.); Division of Heart Rhythm Management, Yokohama Rosai Hospital, Yokohama, Japan (A.N.); and The Second Department of Internal Medicine (T.W., Y.O.) and Department of Heart Rhythm Management (H.A.), University of Occupational and Environmental Health, Kitakyushu, Japan.
Taku
T
Machida
From the Departments of Molecular Physiology (K.A., T.M., D.T.H., T.I., Y.T., N.M.), Pediatrics (H.Y., H.M.), and Cardiovascular Medicine (S.F., M.K., K.M.), Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Departments of Pediatrics (N.S.) and Cardiovascular Medicine (K.O., I.W.), Nihon University Graduate School of Medicine, Tokyo, Japan; Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan (T.M.); Division of Heart Rhythm Management, Yokohama Rosai Hospital, Yokohama, Japan (A.N.); and The Second Department of Internal Medicine (T.W., Y.O.) and Department of Heart Rhythm Management (H.A.), University of Occupational and Environmental Health, Kitakyushu, Japan.
Naokata
N
Sumitomo
From the Departments of Molecular Physiology (K.A., T.M., D.T.H., T.I., Y.T., N.M.), Pediatrics (H.Y., H.M.), and Cardiovascular Medicine (S.F., M.K., K.M.), Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Departments of Pediatrics (N.S.) and Cardiovascular Medicine (K.O., I.W.), Nihon University Graduate School of Medicine, Tokyo, Japan; Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan (T.M.); Division of Heart Rhythm Management, Yokohama Rosai Hospital, Yokohama, Japan (A.N.); and The Second Department of Internal Medicine (T.W., Y.O.) and Department of Heart Rhythm Management (H.A.), University of Occupational and Environmental Health, Kitakyushu, Japan.
Hirokazu
H
Yamamoto
From the Departments of Molecular Physiology (K.A., T.M., D.T.H., T.I., Y.T., N.M.), Pediatrics (H.Y., H.M.), and Cardiovascular Medicine (S.F., M.K., K.M.), Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Departments of Pediatrics (N.S.) and Cardiovascular Medicine (K.O., I.W.), Nihon University Graduate School of Medicine, Tokyo, Japan; Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan (T.M.); Division of Heart Rhythm Management, Yokohama Rosai Hospital, Yokohama, Japan (A.N.); and The Second Department of Internal Medicine (T.W., Y.O.) and Department of Heart Rhythm Management (H.A.), University of Occupational and Environmental Health, Kitakyushu, Japan.
Kimie
K
Ohkubo
From the Departments of Molecular Physiology (K.A., T.M., D.T.H., T.I., Y.T., N.M.), Pediatrics (H.Y., H.M.), and Cardiovascular Medicine (S.F., M.K., K.M.), Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Departments of Pediatrics (N.S.) and Cardiovascular Medicine (K.O., I.W.), Nihon University Graduate School of Medicine, Tokyo, Japan; Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan (T.M.); Division of Heart Rhythm Management, Yokohama Rosai Hospital, Yokohama, Japan (A.N.); and The Second Department of Internal Medicine (T.W., Y.O.) and Department of Heart Rhythm Management (H.A.), University of Occupational and Environmental Health, Kitakyushu, Japan.
Ichiro
I
Watanabe
From the Departments of Molecular Physiology (K.A., T.M., D.T.H., T.I., Y.T., N.M.), Pediatrics (H.Y., H.M.), and Cardiovascular Medicine (S.F., M.K., K.M.), Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Departments of Pediatrics (N.S.) and Cardiovascular Medicine (K.O., I.W.), Nihon University Graduate School of Medicine, Tokyo, Japan; Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan (T.M.); Division of Heart Rhythm Management, Yokohama Rosai Hospital, Yokohama, Japan (A.N.); and The Second Department of Internal Medicine (T.W., Y.O.) and Department of Heart Rhythm Management (H.A.), University of Occupational and Environmental Health, Kitakyushu, Japan.
Takeru
T
Makiyama
From the Departments of Molecular Physiology (K.A., T.M., D.T.H., T.I., Y.T., N.M.), Pediatrics (H.Y., H.M.), and Cardiovascular Medicine (S.F., M.K., K.M.), Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Departments of Pediatrics (N.S.) and Cardiovascular Medicine (K.O., I.W.), Nihon University Graduate School of Medicine, Tokyo, Japan; Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan (T.M.); Division of Heart Rhythm Management, Yokohama Rosai Hospital, Yokohama, Japan (A.N.); and The Second Department of Internal Medicine (T.W., Y.O.) and Department of Heart Rhythm Management (H.A.), University of Occupational and Environmental Health, Kitakyushu, Japan.
Satoki
S
Fukae
From the Departments of Molecular Physiology (K.A., T.M., D.T.H., T.I., Y.T., N.M.), Pediatrics (H.Y., H.M.), and Cardiovascular Medicine (S.F., M.K., K.M.), Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Departments of Pediatrics (N.S.) and Cardiovascular Medicine (K.O., I.W.), Nihon University Graduate School of Medicine, Tokyo, Japan; Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan (T.M.); Division of Heart Rhythm Management, Yokohama Rosai Hospital, Yokohama, Japan (A.N.); and The Second Department of Internal Medicine (T.W., Y.O.) and Department of Heart Rhythm Management (H.A.), University of Occupational and Environmental Health, Kitakyushu, Japan.
Masaki
M
Kohno
From the Departments of Molecular Physiology (K.A., T.M., D.T.H., T.I., Y.T., N.M.), Pediatrics (H.Y., H.M.), and Cardiovascular Medicine (S.F., M.K., K.M.), Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Departments of Pediatrics (N.S.) and Cardiovascular Medicine (K.O., I.W.), Nihon University Graduate School of Medicine, Tokyo, Japan; Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan (T.M.); Division of Heart Rhythm Management, Yokohama Rosai Hospital, Yokohama, Japan (A.N.); and The Second Department of Internal Medicine (T.W., Y.O.) and Department of Heart Rhythm Management (H.A.), University of Occupational and Environmental Health, Kitakyushu, Japan.
Daniel T
DT
Harrell
From the Departments of Molecular Physiology (K.A., T.M., D.T.H., T.I., Y.T., N.M.), Pediatrics (H.Y., H.M.), and Cardiovascular Medicine (S.F., M.K., K.M.), Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Departments of Pediatrics (N.S.) and Cardiovascular Medicine (K.O., I.W.), Nihon University Graduate School of Medicine, Tokyo, Japan; Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan (T.M.); Division of Heart Rhythm Management, Yokohama Rosai Hospital, Yokohama, Japan (A.N.); and The Second Department of Internal Medicine (T.W., Y.O.) and Department of Heart Rhythm Management (H.A.), University of Occupational and Environmental Health, Kitakyushu, Japan.
Taisuke
T
Ishikawa
From the Departments of Molecular Physiology (K.A., T.M., D.T.H., T.I., Y.T., N.M.), Pediatrics (H.Y., H.M.), and Cardiovascular Medicine (S.F., M.K., K.M.), Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Departments of Pediatrics (N.S.) and Cardiovascular Medicine (K.O., I.W.), Nihon University Graduate School of Medicine, Tokyo, Japan; Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan (T.M.); Division of Heart Rhythm Management, Yokohama Rosai Hospital, Yokohama, Japan (A.N.); and The Second Department of Internal Medicine (T.W., Y.O.) and Department of Heart Rhythm Management (H.A.), University of Occupational and Environmental Health, Kitakyushu, Japan.
Yukiomi
Y
Tsuji
From the Departments of Molecular Physiology (K.A., T.M., D.T.H., T.I., Y.T., N.M.), Pediatrics (H.Y., H.M.), and Cardiovascular Medicine (S.F., M.K., K.M.), Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Departments of Pediatrics (N.S.) and Cardiovascular Medicine (K.O., I.W.), Nihon University Graduate School of Medicine, Tokyo, Japan; Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan (T.M.); Division of Heart Rhythm Management, Yokohama Rosai Hospital, Yokohama, Japan (A.N.); and The Second Department of Internal Medicine (T.W., Y.O.) and Department of Heart Rhythm Management (H.A.), University of Occupational and Environmental Health, Kitakyushu, Japan.
Akihiko
A
Nogami
From the Departments of Molecular Physiology (K.A., T.M., D.T.H., T.I., Y.T., N.M.), Pediatrics (H.Y., H.M.), and Cardiovascular Medicine (S.F., M.K., K.M.), Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Departments of Pediatrics (N.S.) and Cardiovascular Medicine (K.O., I.W.), Nihon University Graduate School of Medicine, Tokyo, Japan; Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan (T.M.); Division of Heart Rhythm Management, Yokohama Rosai Hospital, Yokohama, Japan (A.N.); and The Second Department of Internal Medicine (T.W., Y.O.) and Department of Heart Rhythm Management (H.A.), University of Occupational and Environmental Health, Kitakyushu, Japan.
Taichi
T
Watabe
From the Departments of Molecular Physiology (K.A., T.M., D.T.H., T.I., Y.T., N.M.), Pediatrics (H.Y., H.M.), and Cardiovascular Medicine (S.F., M.K., K.M.), Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Departments of Pediatrics (N.S.) and Cardiovascular Medicine (K.O., I.W.), Nihon University Graduate School of Medicine, Tokyo, Japan; Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan (T.M.); Division of Heart Rhythm Management, Yokohama Rosai Hospital, Yokohama, Japan (A.N.); and The Second Department of Internal Medicine (T.W., Y.O.) and Department of Heart Rhythm Management (H.A.), University of Occupational and Environmental Health, Kitakyushu, Japan.
Yasushi
Y
Oginosawa
From the Departments of Molecular Physiology (K.A., T.M., D.T.H., T.I., Y.T., N.M.), Pediatrics (H.Y., H.M.), and Cardiovascular Medicine (S.F., M.K., K.M.), Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Departments of Pediatrics (N.S.) and Cardiovascular Medicine (K.O., I.W.), Nihon University Graduate School of Medicine, Tokyo, Japan; Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan (T.M.); Division of Heart Rhythm Management, Yokohama Rosai Hospital, Yokohama, Japan (A.N.); and The Second Department of Internal Medicine (T.W., Y.O.) and Department of Heart Rhythm Management (H.A.), University of Occupational and Environmental Health, Kitakyushu, Japan.
Haruhiko
H
Abe
From the Departments of Molecular Physiology (K.A., T.M., D.T.H., T.I., Y.T., N.M.), Pediatrics (H.Y., H.M.), and Cardiovascular Medicine (S.F., M.K., K.M.), Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Departments of Pediatrics (N.S.) and Cardiovascular Medicine (K.O., I.W.), Nihon University Graduate School of Medicine, Tokyo, Japan; Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan (T.M.); Division of Heart Rhythm Management, Yokohama Rosai Hospital, Yokohama, Japan (A.N.); and The Second Department of Internal Medicine (T.W., Y.O.) and Department of Heart Rhythm Management (H.A.), University of Occupational and Environmental Health, Kitakyushu, Japan.
Koji
K
Maemura
From the Departments of Molecular Physiology (K.A., T.M., D.T.H., T.I., Y.T., N.M.), Pediatrics (H.Y., H.M.), and Cardiovascular Medicine (S.F., M.K., K.M.), Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Departments of Pediatrics (N.S.) and Cardiovascular Medicine (K.O., I.W.), Nihon University Graduate School of Medicine, Tokyo, Japan; Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan (T.M.); Division of Heart Rhythm Management, Yokohama Rosai Hospital, Yokohama, Japan (A.N.); and The Second Department of Internal Medicine (T.W., Y.O.) and Department of Heart Rhythm Management (H.A.), University of Occupational and Environmental Health, Kitakyushu, Japan.
Hideki
H
Motomura
From the Departments of Molecular Physiology (K.A., T.M., D.T.H., T.I., Y.T., N.M.), Pediatrics (H.Y., H.M.), and Cardiovascular Medicine (S.F., M.K., K.M.), Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Departments of Pediatrics (N.S.) and Cardiovascular Medicine (K.O., I.W.), Nihon University Graduate School of Medicine, Tokyo, Japan; Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan (T.M.); Division of Heart Rhythm Management, Yokohama Rosai Hospital, Yokohama, Japan (A.N.); and The Second Department of Internal Medicine (T.W., Y.O.) and Department of Heart Rhythm Management (H.A.), University of Occupational and Environmental Health, Kitakyushu, Japan. makitan@nagasaki-u.ac.jp.
Naomasa
N
Makita
D000293:Adolescent; D017677:Age Distribution; D017668:Age of Onset; D053447:Channelopathies / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology*; D005820:Genetic Testing / Q000379:methods; D006801:Humans; D015994:Incidence; D007564:Japan; D008297:Male; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics*; D010375:Pedigree; D035583:Rare Diseases; D017678:Sex Distribution; D012804:Sick Sinus Syndrome / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D055815:Young Adult
D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human
Nav1.5 voltage-gated sodium channel; mutation; sex; sick sinus syndrome