Functionally Aberrant Mutant KCNQ1 With Intermediate Heterozygous and Homozygous Phenotypes

Deleterious mutations in KCNQ1 may lead to an autosomal dominant form of long QT syndrome (LQTS) (Romano-Ward) or autosomal recessive form (Jervell and Lange-Nielsen). Both are associated with severe ventricular tachyarrhythmias due to the reduction of the slowly activating delayed rectifier K+ current (IKs). Our objective was to investigate the functional consequences of KCNQ1-R562S mutation in an atypical form of KCNQ1-linked LQTS. Mutant KCNQ1-R562S was analyzed via confocal imaging, surface biotinylation assays, co-immunoprecipitation, phosphatidylinositol-4,5-bisphosphate pulldown test, whole-cell patch clamp, and computational intrinsic disorder analyses. Protein expression, assembly with KCNE1, and trafficking to the surface membrane of KCNQ1-R562S were comparable with wild-type channels. The most significant functional effect of the R562S mutation was a depolarizing shift in the voltage dependence of activation that was dependent on association with KCNE1. The biophysical abnormality was only partially dominant over coexpressed wild-type channels. R562S mutation impaired C-terminal association with membrane phosphatidylinositol-4,5-bisphosphate. These changes led to compromised rate-related accumulation of repolarizing current that is an important property of normal IKs. KCNQ1-R562S mutation reduces effective IKs due to channel gating alteration with a mild clinical expression in the heterozygous state due to minimal dominant phenotype. In the homozygous state, it is exhibited with a moderately severe LQTS phenotype due to the incomplete absence of IKs. Les mutations délétères du gène KCNQ1 peuvent aboutir à une forme de syndrome du QT long autosomique dominante (Romano-Ward) ou autosomique récessive (Jervell et Lange-Nielsen). Ces deux formes sont associées à des tachyarythmies ventriculaires sévères causées par la réduction du courant potassique (K+) à rectification retardée et à activation lente (IKs). Notre objectif était d’analyser les conséquences fonctionnelles de la mutation KCNQ1-R562S dans une forme atypique de syndrome du QT long associé au gène KCNQ1. Le gène mutant KCNQ1-R562S a été analysé par les techniques suivantes : imagerie confocale, épreuve de biotinylation de surface, co-immunoprécipitation, test de « pulldown » de phosphatidylinositol-4,5-bisphosphate, par électrophysiologie moléculaire « technique du patch clamp » sur des cellules entières et analyse computationnelle des troubles intrinsèques. L’expression des protéines, l’a