| 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. | | Author(s) | Wehrens XH, Rossenbacker T, Jongbloed RJ, Gewillig M, Heidbüchel H, Doevendans PA, Vos MA, Wellens HJ, Kass RS | | Institution | Department of Cardiology, Cardiovascular Research Institute Maastricht, The Netherlands. | | Source | Hum Mutat 2003 May; 21(5):552. | | MeSH | Binding Sites
Cell Line
DNA
DNA Mutational Analysis
Humans
Ion Channel Gating
Long QT Syndrome
Membrane Potentials
Mutagenesis, Site-Directed
Mutation
Mutation, Missense
Patch-Clamp Techniques
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Sodium Channels
Transfection
| | 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. | | Language | eng | | Pub Type(s) | Journal Article
| | PubMed ID | 12673799 |
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