Referenced in: none

Automatically associated channels: Kv12.1 , Kv7.1 , Nav1.5

Title: A novel mutation in SCN5A, delQKP 1507-1509, causing long QT syndrome: role of Q1507 residue in sodium channel inactivation.

Authors: Dagmar I Keller, Said Acharfi, Etienne Delacrétaz, Nawal Benammar, Martin Rotter, Jean Pierre Pfammatter, Véronique Fressart, Pascale Guicheney, Mohamed Chahine

Journal, date & volume: J. Mol. Cell. Cardiol., 2003 Dec , 35, 1513-21

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/14654377

Abstract
Inherited long QT syndrome (LQTS) is caused by mutations in six genes including SCN5A, encoding the alpha-subunit of the human cardiac voltage-dependent sodium channel hNa(v)1.5. In LQT3, various mutations in SCN5A were identified, which produce a gain of channel function. The aim of this study was to screen SCN5A for mutations in a family with the LQT3 phenotype and to analyze the consequences of the mutation on the channel function. By polymerase chain reaction-denaturating high performance liquid chromatography-sequencing, we identified a novel deletion in SCN5A, delQKP 1507-1509, in the DIII-DIV linker of the sodium channel. The hNa(v)1.5/delQKP1507-1509, hNa(v)1.5/delQ1507 and hNa(v)1.5/Q1507A mutants were constructed in vitro, mutant channels were expressed in the tsA201 human cell line and studied using the whole-cell configuration of the patch clamp technique. A persistent inward sodium current of 1-1.5% of maximum currents measured at -30 mV in all mutant sodium channels was recorded, which was nearly completely blocked by the sodium-channel blockers tetrodotoxin and lidocaine. The deletion mutants resulted in a significant shift of steady-state activation to more depolarized voltages. The delQ1507 showed a small shift of steady-state inactivation towards more negative potentials, whereas no significant shifts were observed in both steady-state activation and inactivation in Q1507A compared to the wild-type Na(v)1.5 sodium channels. The novel SCN5A mutation, delQKP, induces a residual current as previously shown for other SCN5A mutations causing LQTS. DelQKP shares the deletion of Q1507 with the formerly known delKPQ 1505-1507. Our data suggest that Q1507 plays an important role in fast sodium channel inactivation.