Mutations in the KCNH2 gene; encoding Potassium ion channel IKr, represents one of the most frequent causes of Long QT 2 syndrome. This study is focused on a heterozygous missense mutation L552S in the S5 subunit of the ion channel KCNH2, which has been identified as founder mutation in Finland. The same genetic mutation in a family often shows different phenotype. Current treatment is directed towards symptom relief and prevention of sudden cardiac death and no specific therapy or treatment for LQT2 exists. Studying the disease mechanism with a human iPSC-CM model would be necessary for better treatment and making improved drugs. Aim of this study was to model LQT2 with iPSC-CM from asymptomatic and symptomatic mutation carriers from the same family and gain insight into the disease causing mechanism induced by the genetic mutation L552S. The results from this study is proof that a functional iPSC derived LQT2 model from both asymptomatic and symptomatic patients can be made and it shows differences. Electrophysiological differences on HERG block, and adrenergic stimulation were of found. HERG current was measured with Voltage clamp and the calcium kinetics was studied with calcium imaging. The allelic imbalance was studied by quantitative polymerase chain reaction. To uncover the mechanism of the disease causing mutation, and the HERG protein was expressed in HEK cells and their expression and localization was analyzed using confocal imaging. This is the first study till date which has analyzed at cellular level with an aim to understand similarities or differences at genetic, protein and electrophysiological level between cardiomyocytes from asymptomatic and symptomatic LQT2 patient cell lines. Our model does not only recapitulate major phenotype characteristics as observed in LQT2 patients but also is a proof of concept that this model can be used to study the disease mechanisms further and can serve as a platform for pharmacological screenings. The results would potentially help in personalized treatment of LQT2.
Europhysiology 2018 (London, UK) (2018) Proc Physiol Soc 41, C001
Oral Communications: Asymptomatic and symptomatic long QT 2 syndrome disease model using iPSC-CM from patients with L552S mutation
D. A. Shah1, C. Prajapati1, R. Cherian1, K. Penttinen1, A. Alexanova1, K. Aalto-Setälä1,3,2
1. Medicine and Life Sciences, Heart Group, BioMediTech, University of Tampere, Tampere, Finland. 2. Heart Center, Tampere University Hospital, Tampere, Finland, Tampere, Finland. 3. School of Medicine, University of Tampere, Tampere, Finland, Tampere, Finland.
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Where applicable, experiments conform with Society ethical requirements.