title: A novel mutation L619F in the cardiac Na+ channel SCN5A associated with long-QT syndrome (LQT3): a role for the I-II linker in inactivation gating.
abstract: Congenital long QT syndrome type 3 (LQT3) is caused by mutations in the gene SCN5A encoding the alpha-subunit of the cardiac Na(+) channel (Nav1.5). Functional studies of SCN5A mutations in the linker between domains III and IV, and more recently the C-terminus, have been shown to alter inactivation gating. Here we report a novel LQT3 mutation, L619F (LF), located in the domain I-II linker. In an infant with prolonged QTc intervals, mutational analysis identified a heterozygous missense mutation (L619F) in the domain I-II linker of the cardiac Na(+) channel. Wild-type (WT) and mutant channels were studied by whole-cell patch-clamp analysis in transiently expressed HEK cells. LF channels increase maintained Na(+) current (0.79 pA/pF for LF; 0.26 pA/pF for WT) during prolonged depolarization. We found a +5.8mV shift in steady state inactivation in LF channels compared to WT (WT, V(1/2)=-64.0 mV; LF, V(1/2)=-58.2 mV). The positive shift of inactivation, without a corresponding shift in activation, increases the overlap window current in LF relative to WT (1.09 vs. 0.58 pA/pF), as measured using a positive voltage ramp protocol (-100 to +50 mV in 2s). The increase in window current, combined with an increase in non-inactivating Na(+) current, may act to prolong the AP plateau and is consistent with the disease phenotype observed in patients. Moreover, the defective inactivation imposed by the L619F mutation implies a role for the I-II linker in the Na(+) channel inactivation process.
authors.affiliation: Department of Cardiology, Cardiovascular Research Institute Maastricht, The Netherlands.
authors.forename: Xander H T
authors.initials: XH
authors.lastname: Wehrens
authors.forename: Tom
authors.initials: T
authors.lastname: Rossenbacker
authors.forename: Roselie J
authors.initials: RJ
authors.lastname: Jongbloed
authors.forename: Marc
authors.initials: M
authors.lastname: Gewillig
authors.forename: Hein
authors.initials: H
authors.lastname: Heidbüchel
authors.forename: Pieter A
authors.initials: PA
authors.lastname: Doevendans
authors.forename: Marc A
authors.initials: MA
authors.lastname: Vos
authors.forename: Hein J J
authors.initials: HJ
authors.lastname: Wellens
authors.forename: Robert S
authors.initials: RS
authors.lastname: Kass
mesh_terms: D001665:Binding Sites / Q000235:genetics / Q000502:physiology; D002460:Cell Line; D004247:DNA / Q000737:chemistry / Q000235:genetics; D004252:DNA Mutational Analysis; D006801:Humans; D015640:Ion Channel Gating / Q000235:genetics / Q000502:physiology; D008133:Long QT Syndrome / Q000235:genetics*; D008564:Membrane Potentials / Q000502:physiology; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D020125:Mutation, Missense; D062554:NAV1.5 Voltage-Gated Sodium Channel; D018408:Patch-Clamp Techniques; D015222:Sodium Channels / Q000235:genetics* / Q000502:physiology; D014162:Transfection
chemical_list: D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D015222:Sodium Channels; D004247:DNA