Investigação de variantes gênicas de canais iônicos em pacientes com síndrome do QT longo

Ernesto, Curty; Cruz, Fernando Eugênio dos Santos; Lima, Fabiane Santos; Coutinho, Jorge Luiz Albuquerque; Silva, Rosane; Ürményi, Turán P.; Carvalho, Antônio Carlos Campos de; Rondinelli, Edson

doi:10.1590/s0066-782x2011005000015

Cited by 2 publications

(3 citation statements)

References 36 publications

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“…Although this mutation has already been described 26,27 , its mechanism of action remains unclear. Itoh and colleagues described a missense mutation in the S4 region of hERG in a Japanese LQTS2 family.…”

Section: Discussionmentioning

confidence: 99%

“…Two patients with a heterozygous mutation in KCNH2 (c.1600C > T, p.R534C) 26 were invited to donate 5 mL of peripheral blood after obtaining written informed consent. This study was approved by the National Institute of Cardiology’s ethics review board under number 27044614.3.0000.5272.…”

Section: Methodsmentioning

confidence: 99%

“…Genomic DNA was extracted from the iPSCs and exons corresponding to the coding region of KCNH2 were amplified as previously published 26 . To amplify exon 7 of KCNH2, the PCRx Enhancer Reagent (Thermo Scientific) was added to the reaction, according to the manufacturer’s instructions.…”

Section: Methodsmentioning

confidence: 99%

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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

Arantes

Kasai-Brunswick

et al. 2019

Sci Rep

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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 IKr inhibitor E4031 only caused APD prolongation in the control line. Patch clamp showed a reduction of IKr 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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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%