title: A novel mutation in SCN5A, delQKP 1507-1509, causing long QT syndrome: role of Q1507 residue in sodium channel inactivation.
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.
authors.affiliation: Inserm U582, IFR No. 14, Pitié-Salpêtrière Hospital, Paris, France.
authors.forename: Dagmar I
authors.initials: DI
authors.lastname: Keller
authors.forename: Said
authors.initials: S
authors.lastname: Acharfi
authors.forename: Etienne
authors.initials: E
authors.lastname: Delacrétaz
authors.forename: Nawal
authors.initials: N
authors.lastname: Benammar
authors.forename: Martin
authors.initials: M
authors.lastname: Rotter
authors.forename: Jean Pierre
authors.initials: JP
authors.lastname: Pfammatter
authors.forename: Véronique
authors.initials: V
authors.lastname: Fressart
authors.forename: Pascale
authors.initials: P
authors.lastname: Guicheney
authors.forename: Mohamed
authors.initials: M
authors.lastname: Chahine
mesh_terms: D000328:Adult; D001483:Base Sequence; D002460:Cell Line; D002648:Child; D002851:Chromatography, High Pressure Liquid; D004252:DNA Mutational Analysis; D005260:Female; D005820:Genetic Testing; D006579:Heterozygote; D006801:Humans; D008012:Lidocaine / Q000494:pharmacology; D008133:Long QT Syndrome / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D062554:NAV1.5 Voltage-Gated Sodium Channel; D018408:Patch-Clamp Techniques; D010375:Pedigree; D016133:Polymerase Chain Reaction; D017384:Sequence Deletion; D026941:Sodium Channel Blockers / Q000494:pharmacology; D015222:Sodium Channels / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism*; D013779:Tetrodotoxin / Q000494:pharmacology
chemical_list: D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D013779:Tetrodotoxin; D008012:Lidocaine