Some of these gain-of-function mutations are additionally associated with sinus bradycardia, and paradoxically, some KCNQ1 gain-of-function mutations have been linked to QT prolongation (borderline LQT). To date, eight gain-of-function mutations in KCNQ1 have been identified that underlie persistent familial atrial fibrillation (AF) ( Hancox et al., 2014 Hasegawa et al., 2014), and four have been reported to cause short QT syndrome type 2 (SQT2) ( Bellocq et al., 2004 Hong et al., 2005 Moreno et al., 2015 Wu et al., 2015). Gain-of-function mutations in KCNQ1 associate with complex phenotypes. Loss-of-function mutations in KCNQ1 can reduce I Ks and underlie the inherited form of long QT syndrome (LQT1) ( Wang et al., 1996), while gain-of-function mutations in KCNQ1 can act to increase channel opening, resulting in enhanced I Ks ( Chen et al., 2003 Hong et al., 2005 Lundby et al., 2007 Das et al., 2009 Bartos et al., 2011, 2013 Ki et al., 2014 Moreno et al., 2015). LQT1, which is the most common form of LQTS, is caused by mutations in the KCNQ1 gene, affecting the slow delayed-rectifier repolarizing current ( I Ks) ( Barhanin et al., 1996 Sanguinetti et al., 1996). Long QT Syndrome (LQTS) is a type of cardiac disorder that is often related to syncope and sudden cardiac death.

The mechanisms revealed in the study can potentially inform management and treatment of KCNQ1 gain-of-function mutation carriers. In conclusion, our computational modeling experiments provide novel mechanistic explanations for the observed borderline QT prolongation, and predict that KCNQ1-G229D could underlie SN dysfunction and conduction delays. In a population of human SN cell models, the KCNQ1-G229D mutation results in slow/abnormal sinus rhythm, and we identify that a stronger L-type calcium current enables the SN to be more robust to the mutation. Interestingly, APD prolongations were predominantly seen at slow pacing cycle lengths (CL > 1,000 ms), which suggests a greater arrhythmic risk during bradycardia, and is consistent with the observed sudden death during sleep. However, in a subset of models, KCNQ1-G229D can act to prolong ventricular APD by up to 7% (19 ms) and underlie depolarization abnormalities, which could promote QT prolongation and conduction delays.

In a population of human atrial and ventricular cell models and tissue, the presence of KCNQ1-G229D predominantly shortens atrial action potential duration (APD). We introduce the effect of the mutation in populations of atrial, ventricular and sinus node (SN) cell models to investigate mechanisms underlying phenotypic variability. Using patch-clamp experiments, we confirm that KCNQ1-G229D causes a significant gain in channel function. We report a clinical description of a family that carry this mutation and that a member of the family died suddenly during sleep at 21 years old. Previous studies have shown this mutation to cause AF and borderline QT prolongation. The goal of the study is to investigate the ionic, cellular and tissue mechanisms underlying the complex phenotype of a gain-of-function mutation in KCNQ1, c.686G > A (p.G229D) using computer modeling and simulations informed by in vitro measurements. Paradoxically, gain-of-function mutations in KCNQ1 have been reported to cause borderline QT prolongation, atrial fibrillation (AF), sinus bradycardia, and sudden death, however, the mechanisms are not well understood. LQT1 is a subtype of LQTS caused by mutations in KCNQ1, affecting the slow delayed-rectifier potassium current ( I Ks), which is essential for cardiac repolarization. The congenital long QT syndrome (LQTS) is a cardiac electrophysiological disorder that can cause sudden cardiac death.

6The William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.

5School of Mathematical Sciences, Queensland University of Technology, Brisbane, QLD, Australia.

4Australian Research Council Centre of Excellence for Mathematical and Statistical Frontiers, Queensland University of Technology, Brisbane, QLD, Australia.

3Department of Stem Cell Biology, Centre for Biomolecular Sciences, University of Nottingham, Nottingham, United Kingdom.

2St BartholomewвЂ™s Hospital, London, United Kingdom.

1Department of Computer Science, British Heart Foundation Centre of Research Excellence, University of Oxford, Oxford, United Kingdom.

Schilling 2, Claire Kirkby 2, Chris Denning 3, Divya Rajamohan 3, Kevin Burrage 1,4,5, Andrew Tinker 6, Blanca Rodriguez 1* and Stephen C. Xin Zhou 1, Alfonso Bueno-Orovio 1, Richard J.

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