Published online before print April 30, 2008, doi: 10.1161/CIRCEP.107.750752
Original Articles |
Molecular and Clinical Characterization of a Novel SCN5A Mutation Associated With Atrioventricular Block and Dilated Cardiomyopathy
From the Shanghai Institute of Cardiovascular Diseases (J.G., A.S., S.W., Y.L., J.J., K.W., Y.Z.), Zhongshan Hospital, Fudan University, Shanghai, China; Institutes of Biomedical Sciences (J.G., Y.Z.), Fudan University, Shanghai, China; Department of Emergency (C.S.), Jinxiang County Hospital, Jining, Shandong, China; Jining Medical College (Z.Y.), Jining, Shandong, China; Department of Medical Ultrasound (S.W.), Affiliated Hospital of Jining Medical College, Jining, Shandong, China; Department of Physiology (V.P., L.G., K.W., Z.F.), The University of Tennessee Health Science Center, Memphis, Tenn.
Correspondence: Correspondence to Junbo Ge, MD, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, People’s Republic of China (e-mail gejunbo{at}zshospital.net); and Zheng Fan, PhD, Department of Physiology, The University of Tennessee Health Science Center, Memphis, TN 38163 (e-mail zfan@physio1.utmem.edu).
Received November 6, 2007; accepted March 21, 2008.
Background— Increased susceptibility to dilated cardiomyopathy has been observed in patients carrying mutations in the SCN5A gene, but the underlying mechanism remains unclear. In this study, we identified and characterized, both in vitro and clinically, an SCN5A mutation associated with familial progressive atrioventricular block of adult onset and dilated cardiomyopathy in a Chinese family.
Methods and Results— Among 32 family members, 5 were initially diagnosed with atrioventricular block after age 30; 4 were studied, 3 of whom later developed dilated cardiomyopathy. We found a heterozygous single-nucleotide mutation resulting in an amino acid substitution (A1180V) in all studied patients and in 6 other younger unaffected members but not in 200 control chromosomes. When expressed with the β1 subunit, the mutated channels exhibited a –4.5-mV shift of inactivation with slower recovery leading to a rate-dependent Na+ current reduction and a moderate increase in late Na+ current. Clinical study revealed that although QRS duration decreased with increasing heart rate in noncarrier family members, this change was blunted in unaffected carriers whose ECG and heart function were normal. Resting corrected QT interval of unaffected carriers was significantly longer than that of noncarriers, even though it was still within the normal range.
Conclusions— A1180V expresses a mild Na+ channel phenotype in vitro and a corresponding clinical phenotype in unaffected mutation carriers, implying that A1180V caused structural heart disease in affected carriers by disturbing Na+ influx and, hence, cellular Na+ homeostasis. The high penetrance of A1180V suggests this phenotype as a high risk factor for dilated cardiomyopathy with preceding atrioventricular block.
Key Words: dilated cardiomyopathy • late current • mutation • rate dependence • sodium channel
CLINICAL PERSPECTIVE
*Drs Junbo Ge, Aijun Sun, and Vesa Paajanen contributed equally to this work.The online-only Data Supplement is available with this article at http://circep.ahajournals.org/cgi/content/full/CIRCEP.107.750752/DC1.
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