A novel SCN5A arrhythmia mutation, M1766L, with expression defect rescued by mexiletine.
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 beta1 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.
Valdivia
Carmen R
CR
Departments of Medicine and Physiology, University of Wisconsin, Madison, WI, USA.
Ackerman
Michael J
MJ
Tester
David J
DJ
Wada
Tomoyuki
T
McCormack
Jorge
J
Ye
Bin
B
Makielski
Jonathan C
JC
D000889:Anti-Arrhythmia Agents / Q000627:therapeutic use*; D004252:DNA Mutational Analysis; D004562:Electrocardiography; D017809:Fatal Outcome; D005500:Follow-Up Studies; D006801:Humans; D007231:Infant, Newborn; D008133:Long QT Syndrome / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D008801:Mexiletine / Q000627:therapeutic use*; D020125:Mutation, Missense; D062554:NAV1.5 Voltage-Gated Sodium Channel; D015222:Sodium Channels / Q000235:genetics*
D000889:Anti-Arrhythmia Agents; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D015222:Sodium Channels; D008801:Mexiletine