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Title
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A novel mutation L619F in the cardiac channel SCN5A associated with long-QT syndrome (LQT3) : a role for the I-II linker in inactivation gating
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Author
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Abstract
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| Congenital long QT syndrome type 3 (LQT3) is caused by mutations in the gene SCN5A encoding the α-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, V1/2=−64.0 mV; LF, V1/2=−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. |
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Language
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English
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Source (journal)
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Human mutation : mutation in brief
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Publication
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2003
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DOI
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10.1002/HUMU.9136
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Volume/pages
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(2003)
, p. 1-8
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Article Reference
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607
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Medium
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E-only publicatie
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Full text (Publisher's DOI)
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