Pitx2c increases in atrial myocytes from chronic atrial fibrillation patients enhancingIKsand decreasingICa,L

Pérez-Hernández, Marta; Matamoros, Marcos; Barana, Adriana; Amorós, Irene; Gómez, Ricardo; Núñez, Mercedes; Sacristán, Silvia; Pinto, Ángel González; Fernández-Avilés, Francisco; Tamargo, Juan; Delpón, Eva; Caballero, Ricardo

doi:10.1093/cvr/cvv280

Cited by 63 publications

(103 citation statements)

References 34 publications

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“…Therefore, Tbx20 effects on the L-type Ca 2+ current (I CaL ) were tested in both HL-1 cells and hiPSC-CMs. In HL-1 cells, I CaL was measured using Ba 2+ as a charge carrier (I Ba ) (15,18). Fig.…”

Section: Resultsmentioning

confidence: 99%

“…HL-1 and Chinese hamster ovary cells were transiently transfected by using Lipofectamine 2000 and FuGENE X-tremeGENE, respectively, and cultured as described (15,17,18,30).…”

Section: Methodsmentioning

confidence: 99%

“…Currents were recorded using the whole-cell patch-clamp technique (15,17,18,30). Series resistance was compensated manually using the compensation unit of the Axopatch amplifier; ≥80% compensation was achieved.…”

Section: Methodsmentioning

confidence: 99%

“…Cav1.2, Kir2.1, Kv7.1, minK, hERG, MiRP1, and Tbx20 proteins were detected in HL-1 cells transfected or not with Tbx20 WT or p.R311C by Western blot following previously described procedures (17,18).…”

Section: Methodsmentioning

confidence: 99%

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Tbx20 controls the expression of the KCNH2 gene and of hERG channels

Caballero

Utrilla

Amorós

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Long QT syndrome (LQTS) exhibits great phenotype variability among family members carrying the same mutation, which can be partially attributed to genetic factors. We functionally analyzed the KCNH2 (encoding for Kv11.1 or hERG channels) and TBX20 (encoding for the transcription factor Tbx20) variants found by next-generation sequencing in two siblings with LQTS in a Spanish family of African ancestry. Affected relatives harbor a heterozygous mutation in KCNH2 that encodes for p.T152HfsX180 Kv11.1 (hERG). This peptide, by itself, failed to generate any current when transfected into Chinese hamster ovary (CHO) cells but, surprisingly, exerted "chaperone-like" effects over native hERG channels in both CHO cells and mouse atrial-derived HL-1 cells. Therefore, heterozygous transfection of native (WT) and p.T152HfsX180 hERG channels generated a current that was indistinguishable from that generated by WT channels alone. Some affected relatives also harbor the p.R311C mutation in Tbx20. In human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), Tbx20 enhanced human KCNH2 gene expression and hERG currents (I hERG ) and shortened action-potential duration (APD). However, Tbx20 did not modify the expression or activity of any other channel involved in ventricular repolarization. Conversely, p.R311C Tbx20 did not increase KCNH2 expression in hiPSC-CMs, which led to decreased I hERG and increased APD. Our results suggest that Tbx20 controls the expression of hERG channels responsible for the rapid component of the delayed rectifier current. On the contrary, p.R311C Tbx20 specifically disables the Tbx20 protranscriptional activity over KCNH2. Therefore, TBX20 can be considered a KCNH2-modifying gene.is characterized by abnormal prolongation of the QT interval of the electrocardiogram (ECG) and is due to delayed ventricular repolarization. LQTS increases the occurrence of ventricular tachyarrhythmias, particularly torsade de pointes, leading to recurrent syncope, seizures, ventricular fibrillation, and sudden cardiac death (SCD) (1). At least 15 genes have been reported in autosomal-dominant forms of LQTS (1). However, mutations in KCNQ1 (LQT1), KCNH2 (LQT2), and SCN5A (LQT3) represent the most frequent forms of LQTS (∼90%) (1, 2).KCNH2 encodes Kv11.1, or hERG, channels, which generate the rapid component of the delayed rectifier current (I Kr ) responsible for ventricular repolarization in humans (3). In a Spanish family of African ancestry suffering LQTS, we identified a frameshift and a missense mutation in KCNH2 that were assumed to be the diseasecausing mutations. However, in some family members, we also identified a missense mutation in TBX20 coding for the transcription factor Tbx20, which is necessary in early stages of heart development (4). Importantly, results in flies and mice demonstrated that Tbx20 is also required for maintaining adult heart function (5, 6).Here we have tested the KCNH2 and TBX20 mutations to establish whether they can account for prolongation of repolarization. Our results dem...

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Section: Resultsmentioning

confidence: 99%

“…HL-1 and Chinese hamster ovary cells were transiently transfected by using Lipofectamine 2000 and FuGENE X-tremeGENE, respectively, and cultured as described (15,17,18,30).…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Tbx20 controls the expression of the KCNH2 gene and of hERG channels

Caballero

Utrilla

Amorós

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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show abstract

“…3,4 We have found that symptomatic response to antiarrhythmic drug therapy is at least partially modulated by common single-nucleotide polymorphisms at the chromosome 4q25 locus. 5 Pérez-Hernández et al 6 showed that patients with chronic AF have a significantly higher expression of Pitx2c messenger RNA vs normal sinus rhythm controls; enhanced Pitx2c expression in HL-1 atrial myocytes results in an increase in slow delayed rectifier potassium current (I Ks ) and decrease in L-type calcium current (I Ca,L ), which are hallmarks of AF. More recently, the AFGen Consortium has identified 12 new genetic loci associated with AF.…”

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confidence: 99%