title: A novel LQT-3 mutation disrupts an inactivation gate complex with distinct rate-dependent phenotypic consequences.
abstract: Inherited mutations of SCN5A, the gene that encodes Na(V)1.5, the alpha subunit of the principle voltage-gated Na(+) channel in the heart, cause congenital Long QT Syndrome variant 3 (LQT-3) by perturbation of channel inactivation. LQT-3 mutations induce small, but aberrant, inward current that prolongs the ventricular action potential and subjects mutation carriers to arrhythmia risk dictated in part by the biophysical consequences of the mutations. Most previously investigated LQT-3 mutations are associated with increased arrhythmia risk during rest or sleep. Here we report a novel LQT-3 mutation discovered in a pediatric proband diagnosed with LQTS but who experienced cardiac events during periods of mild exercise as well as rest. The mutation, which changes a single amino acid (S1904L) in the Na(V)1.5 carboxy terminal domain, disrupts the channel inactivation gate complex and promotes late Na(+) channel currents, not by promoting a bursting mode of gating, but by increasing the propensity of the channel to reopen during prolonged depolarization. Incorporating a modified version of the Markov model of the Na(V)1.5 channel into a mathematical model of the human ventricular action potential predicts that the biophysical consequences of the S1904L mutation result in action potential prolongation that is seen for all heart rates but, in contrast to other previously-investigated LQT-3 mutant channels, is most pronounced at fast rates resulting in a drastic reduction in the cells ability to adapt APD to heart rate.
authors: Department of Pharmacology, College of Physicians and Surgeons of Columbia University, New York, New York 10032, USA.
authors: John R
authors: JR
authors: Bankston
authors: Kevin J
authors: KJ
authors: Sampson
authors: Suneel
authors: S
authors: Kateriya
authors: Ian W
authors: IW
authors: Glaaser
authors: David L
authors: DL
authors: Malito
authors: Wendy K
authors: WK
authors: Chung
authors: Robert S
authors: RS
authors: Kass
mesh_terms: D000200:Action Potentials; D019943:Amino Acid Substitution; D001145:Arrhythmias, Cardiac / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D002648:Child; D004562:Electrocardiography; D020022:Genetic Predisposition to Disease; D006329:Heart Conduction System / Q000378:metabolism* / Q000503:physiopathology; D006339:Heart Rate; D006801:Humans; D015640:Ion Channel Gating / Q000235:genetics*; D007700:Kinetics; D008133:Long QT Syndrome / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D008390:Markov Chains; D008955:Models, Cardiovascular; D009124:Muscle Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D062554:NAV1.5 Voltage-Gated Sodium Channel; D010375:Pedigree; D010641:Phenotype; D011487:Protein Conformation; D012964:Sodium / Q000378:metabolism*; D015222:Sodium Channels / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
chemical_list: D009124:Muscle Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D015222:Sodium Channels; D012964:Sodium