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Gene 2012 Dec 10;5111:26-33. doi: 10.1016/j.gene.2012.09.041.
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Impaired ion channel function related to a common KCNQ1 mutation - implications for risk stratification in long QT syndrome 1.

Aidery P , Kisselbach J , Schweizer PA , Becker R , Katus HA , Thomas D .

Long QT syndrome (LQTS) 1 is the most common type of inherited LQTS and is linked to mutations in the KCNQ1 gene. We identified a KCNQ1 missense mutation, KCNQ1 G325R, in an asymptomatic patient presenting with significant QT prolongation (QTc, 448-600ms). Prior clinical reports revealed phenotypic variability ranging from the absence of symptoms to syncope among KCNQ1 G325R mutation carriers. The present study was designed to determine the G325R ion channel phenotype and its association with the clinical LQTS presentation. Electrophysiological testing was performed using the Xenopus oocyte expression system. KCNQ1 G325R channels were non-functional and suppressed wild type (WT) currents by 71.1%. In the presence of the native cardiac regulatory ß-subunit, KCNE1, currents conducted by G325R and WT KCNQ1 were reduced by 52.9%. Co-expression of G325R and WT KCNQ1 with KCNE1 shifted the voltage-dependence of I(Ks) activation by 12.0mV, indicating co-assembly of mutant and WT subunits. The dysfunctional biophysical phenotype validates the pathogenicity of the KCNQ1 G325R mutation and corresponds well with the severe clinical presentation revealed in some reports. However, the index patient and other mutation carriers were asymptomatic, highlighting potential limitations of risk assessment schemes based on ion channel data.

PubMed ID: 23000022
Article link: Gene

Species referenced: Xenopus laevis
Genes referenced: kcna2 kcna5 kcnb1 kcnc1 kcnd2 kcne1 kcnh1 kcnh2 kcnq1 kcnq2 kcnq3 kcnq4 kcnq5
GO keywords: ion channel activity

Disease Ontology terms: long QT syndrome 1

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