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 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.

SCN4B -Encoded Sodium Channel β4 Subunit in Congenital Long-QT Syndrome

“…Until now 3 genes have been associated with 2:1 AV block: SCN5A, KCNH2, and CACNA1. 17,[27][28][29][30][31][32][33][34][35][36][37][38] Our data suggest that perturbations in the SCN4B-encoded ␤4 subunit constitute another pathogenic mechanism for 2:1 AV block in patients with LQTS.…”

An international compendium of mutations in the SCN5A-encoded cardiac sodium channel in patients referred for Brugada syndrome genetic testing

“…Five of the 10 have been functionally characterized previously, with L619F,21 P1332L,22 R1623Q,23 and E1784K24 producing channel abnormalities consistent with an LQT3 phenotype and G615E25 producing a wild-type-like SCN5A channel 10…”

A common SCN5A polymorphism modulates the biophysical defects of SCN5A mutations

“…It is interesting to note that previous studies demonstrated that LQT3 mutations located in the cytoplasmic linker between domains I and II (A572D, A572F, delAL586–587, G615E, L619F, and R680H) can either increase the persistent Na + current or shorten recovery times from inactivation 10,23,24. This suggests that the domain I–II linker, in addition to the domain III–IV linker and the C-terminus region25,26–29, might also be involved in stabilizing the channels’ fast inactivation.…”