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Mesquita, Fernanda C P; Arantes, Paulo C; Kasai-Brunswick, Tais H; Araujo, Dayana S; Gubert, Fernanda; Monnerat, Gustavo; Silva Dos Santos, Danúbia; Neiman, Gabriel; Leitão, Isabela C; Barbosa, Raiana A Q; Coutinho, Jorge L; Vaz, Isadora M; Dos Santos, Marcus N; Borgonovo, Tamara; Cruz, Fernando E S; Miriuka, Santiago; Medei, Emiliano H; Campos de Carvalho, Antonio C; Carvalho, Adriana B
Scientific reports, 12/2019, Volume: 9, Issue: 1Journal Article
Patient-specific cardiomyocytes obtained from induced pluripotent stem cells (CM-iPSC) offer unprecedented mechanistic insights in the study of inherited cardiac diseases. The objective of this work was to study a type 2 long QT syndrome (LQTS2)-associated mutation (c.1600C > T in KCNH2, p.R534C in hERG) in CM-iPSC. Peripheral blood mononuclear cells were isolated from two patients with the R534C mutation and iPSCs were generated. In addition, the same mutation was inserted in a control iPSC line by genome editing using CRISPR/Cas9. Cells expressed pluripotency markers and showed spontaneous differentiation into the three embryonic germ layers. Electrophysiology demonstrated that action potential duration (APD) of LQTS2 CM-iPSC was significantly longer than that of the control line, as well as the triangulation of the action potentials (AP), implying a longer duration of phase 3. Treatment with the I inhibitor E4031 only caused APD prolongation in the control line. Patch clamp showed a reduction of I on LQTS2 CM-iPSC compared to control, but channel activation was not significantly affected. Immunofluorescence for hERG demonstrated perinuclear staining in LQTS2 CM-iPSC. In conclusion, CM-iPSC recapitulated the LQTS2 phenotype and our findings suggest that the R534C mutation in KCNH2 leads to a channel trafficking defect to the plasma membrane.
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