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Congenital long QT syndrome type 3 (LQT3) is caused by mutations in the gene SCN5A encoding the &agr;-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. © 2003 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

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. © 2003 Wiley‐Liss, Inc. [ABSTRACT FROM AUTHOR]