PMID- 32392813
OWN - NLM
STAT- MEDLINE
DCOM- 20210225
LR  - 20210225
IS  - 2073-4409 (Electronic)
IS  - 2073-4409 (Linking)
VI  - 9
IP  - 5
DP  - 2020 May 7
TI  - hiPSC-Derived Cardiomyocyte Model of LQT2 Syndrome Derived from Asymptomatic and 
      Symptomatic Mutation Carriers Reproduces Clinical Differences in Aggregates but 
      Not in Single Cells.
LID - 10.3390/cells9051153 [doi]
LID - 1153
AB  - Mutations in the HERG gene encoding the potassium ion channel HERG, represent one 
      of the most frequent causes of long QT syndrome type-2 (LQT2). The same genetic 
      mutation frequently presents different clinical phenotypes in the family. Our 
      study aimed to model LQT2 and study functional differences between the mutation 
      carriers of variable clinical phenotypes. We derived human-induced pluripotent 
      stem cell-derived cardiomyocytes (hiPSC-CM) from asymptomatic and symptomatic 
      HERG mutation carriers from the same family. When comparing asymptomatic and 
      symptomatic single LQT2 hiPSC-CMs, results from allelic imbalance, potassium 
      current density, and arrhythmicity on adrenaline exposure were similar, but a 
      difference in Ca2+ transients was observed. The major differences were, however, 
      observed at aggregate level with increased susceptibility to arrhythmias on 
      exposure to adrenaline or potassium channel blockers on CM aggregates derived 
      from the symptomatic individual. The effect of this mutation was modeled 
      in-silico which indicated the reactivation of an inward calcium current as one of 
      the main causes of arrhythmia. Our in-vitro hiPSC-CM model recapitulated major 
      phenotype characteristics observed in LQT2 mutation carriers and strong phenotype 
      differences between LQT2 asymptomatic vs. symptomatic were revealed at 
      CM-aggregate level.
FAU - Shah, Disheet
AU  - Shah D
AUID- ORCID: 0000-0002-8229-0835
AD  - Faculty of Medicine and Health Technology and BioMediTech Institute, Tampere 
      University, Tampere 33520, Finland.
FAU - Prajapati, Chandra
AU  - Prajapati C
AD  - Faculty of Medicine and Health Technology and BioMediTech Institute, Tampere 
      University, Tampere 33520, Finland.
FAU - Penttinen, Kirsi
AU  - Penttinen K
AD  - Faculty of Medicine and Health Technology and BioMediTech Institute, Tampere 
      University, Tampere 33520, Finland.
FAU - Cherian, Reeja Maria
AU  - Cherian RM
AD  - Faculty of Medicine and Health Technology and BioMediTech Institute, Tampere 
      University, Tampere 33520, Finland.
FAU - Koivumaki, Jussi T
AU  - Koivumaki JT
AD  - Faculty of Medicine and Health Technology and BioMediTech Institute, Tampere 
      University, Tampere 33520, Finland.
FAU - Alexanova, Anna
AU  - Alexanova A
AD  - Faculty of Medicine and Health Technology and BioMediTech Institute, Tampere 
      University, Tampere 33520, Finland.
FAU - Hyttinen, Jari
AU  - Hyttinen J
AD  - Faculty of Medicine and Health Technology and BioMediTech Institute, Tampere 
      University, Tampere 33520, Finland.
FAU - Aalto-Setala, Katriina
AU  - Aalto-Setala K
AD  - Faculty of Medicine and Health Technology and BioMediTech Institute, Tampere 
      University, Tampere 33520, Finland.
AD  - Heart Hospital, Tampere University Hospital, Tampere 33520, Finland.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200507
PL  - Switzerland
TA  - Cells
JT  - Cells
JID - 101600052
SB  - IM
MH  - Adult
MH  - Alleles
MH  - Case-Control Studies
MH  - Cell Aggregation
MH  - Female
MH  - Humans
MH  - Induced Pluripotent Stem Cells/metabolism/*pathology
MH  - Ion Channel Gating
MH  - Long QT Syndrome/*genetics/*pathology
MH  - Male
MH  - Middle Aged
MH  - *Models, Biological
MH  - Mutation/*genetics
MH  - Myocytes, Cardiac/metabolism/*pathology
PMC - PMC7290503
OTO - NOTNLM
OT  - HERG
OT  - LQT2
OT  - arrhythmia
OT  - channelopathies
OT  - in vitro electrophysiology
OT  - in-silico modeling
OT  - induced pluripotent stem cells
COIS- The abstract for this project was presented at BioMediTech Research day, 
      University of Tampere, Finland, at the Ion Channel Symposium, Cardiac Arrhythmia 
      meeting, Copenhagen and at the Euro-physiology conference, in London, England. 
      The authors declare no competing or financial interests.
EDAT- 2020/05/13 06:00
MHDA- 2021/02/26 06:00
PMCR- 2020/05/01
CRDT- 2020/05/13 06:00
PHST- 2020/02/26 00:00 [received]
PHST- 2020/04/29 00:00 [revised]
PHST- 2020/05/02 00:00 [accepted]
PHST- 2020/05/13 06:00 [entrez]
PHST- 2020/05/13 06:00 [pubmed]
PHST- 2021/02/26 06:00 [medline]
PHST- 2020/05/01 00:00 [pmc-release]
AID - cells9051153 [pii]
AID - cells-09-01153 [pii]
AID - 10.3390/cells9051153 [doi]
PST - epublish
SO  - Cells. 2020 May 7;9(5):1153. doi: 10.3390/cells9051153.