on April 30, 2008
Published online before print April 30, 2008, doi: 10.1161/CIRCEP.107.750752
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Original Article |
Molecular and Clinical Characterization of a Novel SCN5A Mutation Associated with Atrioventricular Block and Dilated Cardiomyopathy
1 Shanghai Institute of Cardiovascular Diseases and Institutes of Biomedical Sciences;
2 University of Tennessee Health Science Center;
3 Jinxiang County Hospital;
4 Jining Medical College;
5 Affiliated Hospital of Jining Medical College
Correspondence: 6 E-mail: zfan{at}physio1.utmem.edu
Background—Increased susceptibility to dilated cardiomyopathy (DCM) 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 (AVB) of adult onset and DCM in a Chinese family.
Methods and Results—Among 32 family members 5 were initially diagnosed with AVB after age 30; 4 were studied, 3 of whom later developed DCM. 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 the 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 while QRS duration decreased with increasing heart rate in non-carrier family members, this change was blunted in unaffected carriers whose electrocardiograms and heart function were normal. Resting QTc interval of unaffected carriers was significantly longer than that of non-carriers, 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 DCM with preceding AVB.
Key Words: dilated cardiomyopathy • late current • mutation • rate-dependence • sodium channel
Author contributions: Junbo Ge, MD, Aijun Sun, MD, PhD, and Vesa Paajanen, PhD contributed equally to this work.
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