title: Tbx20 controls the expression of the KCNH2 gene and of hERG channels.
abstract: 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 (IhERG) 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 IhERGand 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.
authors.affiliation: Department of Pharmacology, School of Medicine, Instituto de Investigación Sanitaria Gregorio Marañón, Universidad Complutense, 28040 Madrid, Spain.|Centro de Investigación Biomédica en Red (CIBER), Spain.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Caballero
authors.affiliation: Department of Pharmacology, School of Medicine, Instituto de Investigación Sanitaria Gregorio Marañón, Universidad Complutense, 28040 Madrid, Spain.|Centro de Investigación Biomédica en Red (CIBER), Spain.
authors.forename: Raquel G
authors.initials: RG
authors.lastname: Utrilla
authors.affiliation: Department of Pharmacology, School of Medicine, Instituto de Investigación Sanitaria Gregorio Marañón, Universidad Complutense, 28040 Madrid, Spain.|Centro de Investigación Biomédica en Red (CIBER), Spain.
authors.forename: Irene
authors.initials: I
authors.lastname: Amorós
authors.affiliation: Department of Pharmacology, School of Medicine, Instituto de Investigación Sanitaria Gregorio Marañón, Universidad Complutense, 28040 Madrid, Spain.|Centro de Investigación Biomédica en Red (CIBER), Spain.
authors.forename: Marcos
authors.initials: M
authors.lastname: Matamoros
authors.affiliation: Department of Pharmacology, School of Medicine, Instituto de Investigación Sanitaria Gregorio Marañón, Universidad Complutense, 28040 Madrid, Spain.|Centro de Investigación Biomédica en Red (CIBER), Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Pérez-Hernández
authors.affiliation: Department of Pharmacology, School of Medicine, Instituto de Investigación Sanitaria Gregorio Marañón, Universidad Complutense, 28040 Madrid, Spain.|Centro de Investigación Biomédica en Red (CIBER), Spain.
authors.forename: David
authors.initials: D
authors.lastname: Tinaquero
authors.affiliation: Department of Pharmacology, School of Medicine, Instituto de Investigación Sanitaria Gregorio Marañón, Universidad Complutense, 28040 Madrid, Spain.|Centro de Investigación Biomédica en Red (CIBER), Spain.
authors.forename: Silvia
authors.initials: S
authors.lastname: Alfayate
authors.affiliation: Department of Pharmacology, School of Medicine, Instituto de Investigación Sanitaria Gregorio Marañón, Universidad Complutense, 28040 Madrid, Spain.|Centro de Investigación Biomédica en Red (CIBER), Spain.
authors.forename: Paloma
authors.initials: P
authors.lastname: Nieto-Marín
authors.affiliation: Department of Internal Medicine, Center for Arrhythmia Research, University of Michigan, Ann Arbor, MI 48109.|Department of Molecular and Integrative Physiology, Center for Arrhythmia Research, University of Michigan, Ann Arbor, MI 48109.
authors.forename: Guadalupe
authors.initials: G
authors.lastname: Guerrero-Serna
authors.affiliation: Department of Internal Medicine, Center for Arrhythmia Research, University of Michigan, Ann Arbor, MI 48109.|Department of Molecular and Integrative Physiology, Center for Arrhythmia Research, University of Michigan, Ann Arbor, MI 48109.
authors.forename: Qing-Hua
authors.initials: QH
authors.lastname: Liu
authors.affiliation: Department of Internal Medicine, Center for Arrhythmia Research, University of Michigan, Ann Arbor, MI 48109.|Department of Molecular and Integrative Physiology, Center for Arrhythmia Research, University of Michigan, Ann Arbor, MI 48109.
authors.forename: Roberto
authors.initials: R
authors.lastname: Ramos-Mondragón
authors.affiliation: Department of Internal Medicine, Center for Arrhythmia Research, University of Michigan, Ann Arbor, MI 48109.|Department of Molecular and Integrative Physiology, Center for Arrhythmia Research, University of Michigan, Ann Arbor, MI 48109.
authors.forename: Daniela
authors.initials: D
authors.lastname: Ponce-Balbuena
authors.affiliation: Department of Internal Medicine, Center for Arrhythmia Research, University of Michigan, Ann Arbor, MI 48109.|Department of Molecular and Integrative Physiology, Center for Arrhythmia Research, University of Michigan, Ann Arbor, MI 48109.
authors.forename: Todd
authors.initials: T
authors.lastname: Herron
authors.affiliation: Department of Internal Medicine, Center for Arrhythmia Research, University of Michigan, Ann Arbor, MI 48109.|Department of Molecular and Integrative Physiology, Center for Arrhythmia Research, University of Michigan, Ann Arbor, MI 48109.
authors.forename: Katherine F
authors.initials: KF
authors.lastname: Campbell
authors.affiliation: Department of Cardiology, Hospital Universitario La Paz, Instituto de Investigación Sanitaria La Paz (IdiPaz), 28046 Madrid, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Filgueiras-Rama
authors.affiliation: Centro de Investigación Biomédica en Red (CIBER), Spain.|Department of Cardiology, Hospital Universitario La Paz, Instituto de Investigación Sanitaria La Paz (IdiPaz), 28046 Madrid, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Peinado
authors.affiliation: Centro de Investigación Biomédica en Red (CIBER), Spain.|Department of Cardiology, Hospital Universitario La Paz, Instituto de Investigación Sanitaria La Paz (IdiPaz), 28046 Madrid, Spain.
authors.forename: José L
authors.initials: JL
authors.lastname: López-Sendón
authors.affiliation: Department of Internal Medicine, Center for Arrhythmia Research, University of Michigan, Ann Arbor, MI 48109.|Department of Molecular and Integrative Physiology, Center for Arrhythmia Research, University of Michigan, Ann Arbor, MI 48109.|Cardiac Arrhythmia Department, Fundación Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain.
authors.forename: José
authors.identifier: 0000-0003-0080-3500
authors.initials: J
authors.lastname: Jalife
authors.affiliation: Department of Pharmacology, School of Medicine, Instituto de Investigación Sanitaria Gregorio Marañón, Universidad Complutense, 28040 Madrid, Spain; edelpon@med.ucm.es.|Centro de Investigación Biomédica en Red (CIBER), Spain.
authors.forename: Eva
authors.initials: E
authors.lastname: Delpón
authors.affiliation: Department of Pharmacology, School of Medicine, Instituto de Investigación Sanitaria Gregorio Marañón, Universidad Complutense, 28040 Madrid, Spain.|Centro de Investigación Biomédica en Red (CIBER), Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Tamargo
mesh_terms: D000200:Action Potentials / Q000235:genetics; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000235:genetics / Q000378:metabolism; D016466:CHO Cells; D002460:Cell Line; D003412:Cricetulus; D000072237:ERG1 Potassium Channel / Q000235:genetics* / Q000378:metabolism*; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics* / Q000378:metabolism*; D006579:Heterozygote; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism; D008133:Long QT Syndrome / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D009154:Mutation / Q000235:genetics; D032383:Myocytes, Cardiac / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020825:T-Box Domain Proteins / Q000235:genetics* / Q000378:metabolism*
chemical_list: D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D020825:T-Box Domain Proteins; C420984:TBX20 protein, human
keywords: Tbx20; cardiomyocytes; hERG channels; human induced pluripotent stem cells; long QT syndrome