A novel SCN5A mutation associated with long QT-3: altered inactivation kinetics and channel dysfunction.
Mutations in the gene (SCN5A) encoding the alpha-subunit of the cardiac Na+ channel cause congenital long QT syndrome (LQT-3). Here we describe a novel LQT-3 mutation I1768V (I1768V) located in the sixth transmembrane spanning segment of domain IV. This mutation is unusual in that it is located within a transmembrane spanning domain and does not promote the typically observed sustained inward current corresponding to a gain of channel function (bursting). Rather, I1768V increases the rate of recovery from inactivation and increases the channel availability, observed as a positive shift of the steady-state inactivation curve (+7.6 mV). Using a Markovian model of the cardiac Na+ channel, we simulated these changes in gating behavior and demonstrated that a small increase in the rate of recovery from inactivation is sufficient to explain all of the experimentally observed current changes. The effect of these alterations in channel gating results in an increase in window current that may act to disrupt cardiac repolarization.
Department of Pharmacology, College of Physicians and Surgeons of Columbia University, New York, New York 10032, USA.
Ilaria
I
Rivolta
Colleen E
CE
Clancy
Michihiro
M
Tateyama
Huajun
H
Liu
Silvia G
SG
Priori
Robert S
RS
Kass
D000293:Adolescent; D002460:Cell Line; D004247:DNA / Q000737:chemistry / Q000235:genetics; D004252:DNA Mutational Analysis; D005838:Genotype; D006801:Humans; D007700:Kinetics; D008133:Long QT Syndrome / Q000150:complications / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D009154:Mutation; D062554:NAV1.5 Voltage-Gated Sodium Channel; D018408:Patch-Clamp Techniques; D010957:Plasmids / Q000235:genetics; D015222:Sodium Channels / Q000235:genetics* / Q000502:physiology; D013575:Syncope / Q000209:etiology / Q000503:physiopathology; D017180:Tachycardia, Ventricular / Q000209:etiology / Q000503:physiopathology; D013779:Tetrodotoxin / Q000494:pharmacology; D014162:Transfection
D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D015222:Sodium Channels; D013779:Tetrodotoxin; D004247:DNA