Mutation location and I-Ks requlation in the arrhythmic risk of long QT syndrome type 1: the importance of the KCNQ1 S6 region

Peter J Schwartz*, Cristina Moreno, Maria-Christina Kotta, Matteo Pedrazzini, Lia Crotti, Federica Dagradi, Silvia Castelletti, Kristina H Haugaa, Isabelle Denjoy, Maria A Shkolnikova, Paul A Brink, Marshall J Heradien, Sandrine R M Seyen, Roel L. H. Spätjens, Carla Spazzolini, Paul G A Volders

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


Aims Mutation type, location, dominant-negative I-Ks reduction, and possibly loss of cyclic adenosine monophosphate (cAMP)-dependent I-Ks stimulation via protein kinase A (PKA) influence the clinical severity of long QT syndrome type 1 (LQT1). Given the malignancy of KCNQ1-p.A341V, we assessed whether mutations neighbouring p.A341V in the S6 channel segment could also increase arrhythmic risk.

Methods and results Clinical and genetic data were obtained from 1316 LQT1 patients [450 families, 166 unique KCNQ1 mutations, including 277 p.A341V-positive subjects, 139 patients with p.A341-neighbouring mutations (91 missense, 48 non-missense), and 900 other LQT1 subjects]. A first cardiac event represented the primary endpoint. S6 segment missense variant characteristics, particularly cAMP stimulation responses, were analysed by cellular electrophysiology. p.A341neighbouring mutation carriers had a QTc shorter than p.A341V carriers (477 +/- 33 vs. 490 +/- 44 ms) but longer than the remaining LQT1 patient population (467 +/- 41 ms) (P < 0.05 for both). Similarly, the frequency of symptomatic subjects in the p.A341-neighbouring subgroup was intermediate between the other two groups (43% vs. 73% vs. 20%; P< 0.001). These differences in clinical severity can be explained, for p.A341V vs. p.A341-neighbouring mutations, by the p.A341V-specific impairment of IKs regulation. The differences between the p.A341-neighbouring subgroup and the rest of LQT1 mutations may be explained by the functional importance of the S6 segment for channel activation.

Conclusion KCNQ1 S6 segment mutations surrounding p.A341 increase arrhythmic risk. p.A341V-specific loss of PKA-dependent I-Ks enhancement correlates with its phenotypic severity. Cellular studies providing further insights into I-Ks-channel regulation and knowledge of structure-function relationships could improve risk stratification. These findings impact on clinical management.



Original languageEnglish
Pages (from-to)4743-4755
Number of pages14
JournalEuropean Heart Journal
Issue number46
Early online date10 Sept 2021
Publication statusPublished - 7 Dec 2021


  • Long QT syndrome
  • Genetics
  • Sudden cardiac death
  • KVLQT1


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