Disease characterization using LQTS-specific induced pluripotent stem cells.
OBJECTIVE
Long QT syndrome (LQTS) is an inheritable and life-threatening disease; however, it is often difficult to determine disease characteristics in sporadic cases with novel mutations, and more precise analysis is necessary for the successful development of evidence-based clinical therapies. This study thus sought to better characterize ion channel cardiac disorders using induced pluripotent stem cells (iPSCs).


RESULTS
We reprogrammed somatic cells from a patient with sporadic LQTS and from controls, and differentiated them into cardiomyocytes through embryoid body (EB) formation. Electrophysiological analysis of the LQTS-iPSC-derived EBs using a multi-electrode array (MEA) system revealed a markedly prolonged field potential duration (FPD). The IKr blocker E4031 significantly prolonged FPD in control- and LQTS-iPSC-derived EBs and induced frequent severe arrhythmia only in LQTS-iPSC-derived EBs. The IKs blocker chromanol 293B did not prolong FPD in the LQTS-iPSC-derived EBs, but significantly prolonged FPD in the control EBs, suggesting the involvement of IKs disturbance in the patient. Patch-clamp analysis and immunostaining confirmed a dominant-negative role for 1893delC in IKs channels due to a trafficking deficiency in iPSC-derived cardiomyocytes and human embryonic kidney (HEK) cells.


CONCLUSIONS
This study demonstrated that iPSCs could be useful to characterize LQTS disease as well as drug responses in the LQTS patient with a novel mutation. Such analyses may in turn lead to future progress in personalized medicine.
Department of Cardiology,  Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582,  Japan.
Toru
T
Egashira
Shinsuke
S
Yuasa
Tomoyuki
T
Suzuki
Yoshiyasu
Y
Aizawa
Hiroyuki
H
Yamakawa
Tomohiro
T
Matsuhashi
Yohei
Y
Ohno
Shugo
S
Tohyama
Shinichiro
S
Okata
Tomohisa
T
Seki
Yusuke
Y
Kuroda
Kojiro
K
Yae
Hisayuki
H
Hashimoto
Tomofumi
T
Tanaka
Fumiyuki
F
Hattori
Toshiaki
T
Sato
Shunichiro
S
Miyoshi
Seiji
S
Takatsuki
Mitsushige
M
Murata
Junko
J
Kurokawa
Tetsushi
T
Furukawa
Naomasa
N
Makita
Takeshi
T
Aiba
Wataru
W
Shimizu
Minoru
M
Horie
Kaichiro
K
Kamiya
Itsuo
I
Kodama
Satoshi
S
Ogawa
Keiichi
K
Fukuda
D000200:Action Potentials; D000293:Adolescent; D000818:Animals; D002454:Cell Differentiation; D065150:Cellular Reprogramming; D018920:Coculture Techniques; D058732:Embryoid Bodies / Q000378:metabolism / Q000473:pathology; D005455:Fluorescent Antibody Technique; D018507:Gene Expression Regulation, Developmental; D020022:Genetic Predisposition to Disease; D057809:HEK293 Cells; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000637:transplantation; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051657:KCNQ1 Potassium Channel / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000637:transplantation; D018408:Patch-Clamp Techniques; D010641:Phenotype; D026902:Potassium Channel Blockers / Q000494:pharmacology; D024642:Potassium Channels, Voltage-Gated / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D029597:Romano-Ward Syndrome / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D013724:Teratoma / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D014162:Transfection
D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; C489622:KCNE1 protein, human; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D026902:Potassium Channel Blockers; D024642:Potassium Channels, Voltage-Gated