title: PITX2 insufficiency leads to atrial electrical and structural remodeling linked to arrhythmogenesis.
abstract: BACKGROUND
  Pitx2 is a homeobox transcription factor that plays a pivotal role in early left/right determination during embryonic development. Pitx2 loss-of-function mouse mutants display early embryonic lethality with severe cardiac malformations, demonstrating the importance of Pitx2 during cardiogenesis. Recently, independent genome-wide association studies have provided new evidence for a putative role of PITX2 in the adult heart. These studies have independently reported several risk variants close to the PITX2 locus on chromosome 4q25 that are strongly associated with atrial fibrillation in humans.
  
  
  RESULTS
  We show for the first time that PITX2C expression is significantly decreased in human patients with sustained atrial fibrillation, thus providing a molecular link between PITX2 loss of function and atrial fibrillation. In addition, morphological, molecular, and electrophysiological characterization of chamber-specific Pitx2 conditional mouse mutants reveals that atrial but not ventricular chamber-specific deletion of Pitx2 results in differences in the action potential amplitude and resting membrane potential in the adult heart as well as ECG characteristics of atrioventricular block. Lack of Pitx2 in atrial myocardium impairs sodium channel and potassium channel expression, mediated in part by miRNA misexpression.
  
  
  CONCLUSIONS
  This study thus identifies Pitx2 as an upstream transcriptional regulator of atrial electric function, the insufficiency of which results in cellular and molecular changes leading to atrial electric and structural remodeling linked to arrhythmogenesis.
authors.affiliation: Department of Experimental Biology, University of Jaén, Jaén, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Chinchilla
authors.forename: Houria
authors.initials: H
authors.lastname: Daimi
authors.forename: Estefanía
authors.initials: E
authors.lastname: Lozano-Velasco
authors.forename: Jorge N
authors.initials: JN
authors.lastname: Dominguez
authors.forename: Ricardo
authors.initials: R
authors.lastname: Caballero
authors.forename: Eva
authors.initials: E
authors.lastname: Delpón
authors.forename: Juan
authors.initials: J
authors.lastname: Tamargo
authors.forename: Juan
authors.initials: J
authors.lastname: Cinca
authors.forename: Leif
authors.initials: L
authors.lastname: Hove-Madsen
authors.forename: Amelia E
authors.initials: AE
authors.lastname: Aranega
authors.forename: Diego
authors.initials: D
authors.lastname: Franco
mesh_terms: D000818:Animals; D001281:Atrial Fibrillation / Q000503:physiopathology*; D002460:Cell Line; D004562:Electrocardiography; D004594:Electrophysiology; D006325:Heart Atria / Q000166:cytology / Q000378:metabolism* / Q000473:pathology*; D006352:Heart Ventricles / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D015221:Potassium Channels / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics; D000097577:Homeobox Protein PITX2
chemical_list: D018398:Homeodomain Proteins; D035683:MicroRNAs; D015221:Potassium Channels; D015222:Sodium Channels; D014157:Transcription Factors; D000097577:Homeobox Protein PITX2; C544547:MIRN1 microRNA, human; C517731:Mirn1 microRNA, mouse