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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 Xander H.T.,
Rossenbacker Tom,
Jongbloed Roselie J.,
Gewillig Marc,
Heidbüchel Hein,
Doevendans Pieter A.,
Vos Marc A.,
Wellens Hein J.J.,
Kass Robert S.
Publication year - 2003
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.9136
Subject(s) - missense mutation , long qt syndrome , gating , mutation , biology , linker , hek 293 cells , biophysics , depolarization , microbiology and biotechnology , short qt syndrome , mutant , genetics , medicine , qt interval , gene , computer science , operating system
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, 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. © 2003 Wiley‐Liss, Inc.