TY - JOUR
T1 - A novel SCN5A arrhythmia mutation, M1766L, with expression defect rescued by mexiletine
AU - Valdivia, Carmen R.
AU - Ackerman, Michael J.
AU - Tester, David J.
AU - Wada, Tomoyuki
AU - McCormack, Jorge
AU - Ye, Bin
AU - Makielski, Jonathan C.
PY - 2002
Y1 - 2002
N2 - Objective: Mutations in the cardiac sodium channel gene, SCN5A, cause congenital long QT syndrome (LQT3), Brugada syndrome, idiopathic ventricular fibrillation, and conduction disease by distinct cellular and clinical electrophysiological phenotypes. Methods: Postmortem molecular analysis of SCN5A was conducted on an infant who presented shortly after birth with self-terminating torsades de pointes. The infant was treated with lidocaine, propranolol, and mexiletine and was stable for 16 months manifesting only a prolonged QT interval. The infant collapsed suddenly following presumed viral gastroenteritis, was found in 2:1 AV block, and was subsequently declared brain dead. Genomic DNA was subjected to SCN5A mutational analyses and DNA sequencing revealing a novel, spontaneous germline missense mutation, M1766L. The M1766L mutation was engineered into the hH1a clone by site-directed mutagenesis, transfected into embryonic kidney cells (HEK-293), and studied by voltage clamp. Results: The M1766L mutation caused a significant decrease in the sodium channel expression. Co-expression with β1 subunit, incubation at low temperature, and most effectively incubation with mexiletine partially 'rescued' the defective expression. In addition to this pronounced loss of function, M1766L also showed a 10-fold increase in the persistent late sodium current. Conclusions: These findings suggest that M1766L-SCN5A channel dysfunction may contribute to the basis of lethal arrhythmias, displays an overlapping electrophysiological phenotype, and represents the first sodium channelopathy rescued by drug.
AB - Objective: Mutations in the cardiac sodium channel gene, SCN5A, cause congenital long QT syndrome (LQT3), Brugada syndrome, idiopathic ventricular fibrillation, and conduction disease by distinct cellular and clinical electrophysiological phenotypes. Methods: Postmortem molecular analysis of SCN5A was conducted on an infant who presented shortly after birth with self-terminating torsades de pointes. The infant was treated with lidocaine, propranolol, and mexiletine and was stable for 16 months manifesting only a prolonged QT interval. The infant collapsed suddenly following presumed viral gastroenteritis, was found in 2:1 AV block, and was subsequently declared brain dead. Genomic DNA was subjected to SCN5A mutational analyses and DNA sequencing revealing a novel, spontaneous germline missense mutation, M1766L. The M1766L mutation was engineered into the hH1a clone by site-directed mutagenesis, transfected into embryonic kidney cells (HEK-293), and studied by voltage clamp. Results: The M1766L mutation caused a significant decrease in the sodium channel expression. Co-expression with β1 subunit, incubation at low temperature, and most effectively incubation with mexiletine partially 'rescued' the defective expression. In addition to this pronounced loss of function, M1766L also showed a 10-fold increase in the persistent late sodium current. Conclusions: These findings suggest that M1766L-SCN5A channel dysfunction may contribute to the basis of lethal arrhythmias, displays an overlapping electrophysiological phenotype, and represents the first sodium channelopathy rescued by drug.
KW - Long QT syndrome
KW - Na-channel
KW - Sudden death
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U2 - 10.1016/S0008-6363(02)00445-5
DO - 10.1016/S0008-6363(02)00445-5
M3 - Article
C2 - 12123767
AN - SCOPUS:0036063688
SN - 0008-6363
VL - 55
SP - 279
EP - 289
JO - Cardiovascular research
JF - Cardiovascular research
IS - 2
ER -