Combination of cardiac conduction disease and long QT syndrome caused by mutation T1620K in the cardiac sodium channel.
OBJECTIVE
The aim of the present study was to elucidate the molecular mechanism underlying the concomitant occurrence of cardiac conduction disease and long QT syndrome (LQT3), two SCN5A channelopathies that are explained by loss-of-function and gain-of-function, respectively, in the cardiac Na+ channel.


RESULTS
A Caucasian family with prolonged QT interval, intermittent bundle-branch block, sudden cardiac death, and syncope was investigated. Lidocaine (1 mg/kg i.v.) normalized the prolonged QT interval and rescued bundle-branch block. An SCN5A mutation analysis was performed that revealed a C-to-A mutation at position 4859 (exon 28), predicted to change a highly conserved threonine for a lysine at position 1620. Mutant channels were characterized both in Xenopus oocytes and HEK293 cells. The T1620K mutation remarkably altered the properties of Nav1.5 channels. In particular, the voltage-dependence of the current decay time constants was largely lost. As a consequence, mutant channels inactivated faster than wild-type channels at potentials negative to -30 mV, resulting in less Na+ inward current (loss-of-function), but significantly slower at potentials positive to -30 mV, resulting in an increased Na+ inward current (gain-of-function). Moreover, we found a hyperpolarized shift of steady-state activation and an accelerated recovery from inactivation (gain-of-function). At the same time, channel availability was significantly reduced at the resting membrane potential (loss-of-function).


CONCLUSIONS
We conclude that lysine at position 1620 leads to both loss-of-function and gain-of-function properties in hNav1.5 channels, which may consequently cause in the same individuals impaired impulse propagation in the conduction system and prolonged QTc intervals, respectively.
Department of Internal Medicine I, Friedrich Schiller University Jena, Jena, Germany.
Ralf
R
Surber
Sabine
S
Hensellek
Dirk
D
Prochnau
Gerald S
GS
Werner
Klaus
K
Benndorf
Hans R
HR
Figulla
Thomas
T
Zimmer
D000200:Action Potentials; D000293:Adolescent; D000328:Adult; D000404:Ajmaline / Q000627:therapeutic use; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000627:therapeutic use; D002037:Bundle-Branch Block / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D002460:Cell Line; D002648:Child; D004252:DNA Mutational Analysis; D016757:Death, Sudden, Cardiac / Q000209:etiology; D004562:Electrocardiography; D005260:Female; D018014:Gene Transfer Techniques; D020022:Genetic Predisposition to Disease; D006801:Humans; D007700:Kinetics; D008012:Lidocaine / Q000627:therapeutic use; D008133:Long QT Syndrome / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D008239:Lysine; D008297:Male; D009124:Muscle Proteins / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D009206:Myocardium / Q000378:metabolism*; D062554:NAV1.5 Voltage-Gated Sodium Channel; D018408:Patch-Clamp Techniques; D010375:Pedigree; D012964:Sodium / Q000378:metabolism*; D015222:Sodium Channels / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D013575:Syncope / Q000235:genetics / Q000378:metabolism; D013912:Threonine; D014982:Xenopus laevis
D000889:Anti-Arrhythmia Agents; D009124:Muscle Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D015222:Sodium Channels; D000404:Ajmaline; D013912:Threonine; D008012:Lidocaine; D012964:Sodium; D008239:Lysine