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R534C mutation in hERG causes a trafficking defect in iPSC-derived cardiomyocytes from patients with type 2 long QT syndrome

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, 2019-12, Vol.9 (1), p.19203-9, Article 19203 [Periódico revisado por pares]

England: Nature Publishing Group

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Título:
R534C mutation in hERG causes a trafficking defect in iPSC-derived cardiomyocytes from patients with type 2 long QT syndrome
Autor: 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
Assuntos: Action Potentials - genetics ; Adolescent ; Adult ; Cardiomyocytes ; Cell Membrane - genetics ; ERG1 Potassium Channel - genetics ; Female ; Gene Editing - methods ; Humans ; Induced Pluripotent Stem Cells - physiology ; Leukocytes, Mononuclear - physiology ; Long QT syndrome ; Long QT Syndrome - genetics ; Male ; Mutation ; Mutation - genetics ; Myocytes, Cardiac - physiology ; Phenotype ; Protein Transport - genetics ; Stem cells ; Young Adult
É parte de: Scientific reports, 2019-12, Vol.9 (1), p.19203-9, Article 19203
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
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Descrição: 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.
Editor: England: Nature Publishing Group
Idioma: Inglês

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R534C mutation in hERG causes a trafficking defect in iPSC-derived cardiomyocytes from patients with type 2 long QT syndrome

England: Nature Publishing Group

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