A novel LQT3 mutation implicates the human cardiac sodium channel domain IVS6 in inactivation kinetics.
The Long QT3 syndrome is associated with mutations in the cardiac sodium channel gene SCN5A.


OBJECTIVE
The aim of the present study was the identification and functional characterization of a mutation in a family with the long QT3 syndrome.


METHODS
The human cardiac sodium channel gene SCN5A was screened for mutations by single-stranded conformation polymorphism. The functional consequences of mutant sodium channels were characterized after expressing mutant and wild-type cRNAs in Xenopus oocytes by two-electrode voltage clamp measurements.


RESULTS
SCN5A screening revealed an A-->G substitution at codon 1768, close to the C-terminal end of domain IVS6, which changes an isoleucine to a valine. Functional expression of mutant I1768V-channels in Xenopus oocytes showed that the voltage-dependence and slope factors of activation and inactivation were unchanged compared to wild-type channels. No difference in persistent TTX-sensitive current could be detected between wild-type and I1768V channels, a channel feature often increased in LQT3 mutants. However, I1768V mutant channels recovered faster from inactivation (2.4 times) than wild-type channels and displayed less slow inactivation.


CONCLUSIONS
We postulate that severe destabilization of the inactivated state leads to increased arrhythmogenesis and QT prolongation in I1768V mutation carriers in the absence of a persistent inward sodium current.
Groenewegen
W Antoinette
WA
Department of Medical Physiology, University Medical Center Utrecht, P.O. Box 85060, 3508 AB, Utrecht, The Netherlands. groenewegen@med.uu.nl <groenewegen@med.uu.nl>
Bezzina
Connie R
CR
van Tintelen
J Peter
JP
Hoorntje
Theo M
TM
Mannens
Marcel M A M
MM
Wilde
Arthur A M
AA
Jongsma
Habo J
HJ
Rook
Martin B
MB
D000293:Adolescent; D000328:Adult; D002648:Child; D004252:DNA Mutational Analysis; D016757:Death, Sudden, Cardiac / Q000209:etiology; D004562:Electrocardiography; D005260:Female; D006801:Humans; D008133:Long QT Syndrome / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D009154:Mutation; D062554:NAV1.5 Voltage-Gated Sodium Channel; D010375:Pedigree; D015222:Sodium Channels / Q000235:genetics* / Q000502:physiology
D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D015222:Sodium Channels