title: Pitx2, an atrial fibrillation predisposition gene, directly regulates ion transport and intercalated disc genes.
abstract: BACKGROUND
  Pitx2 is the homeobox gene located in proximity to the human 4q25 familial atrial fibrillation (AF) locus. When deleted in the mouse germline, Pitx2 haploinsufficiency predisposes to pacing-induced AF, indicating that reduced Pitx2 promotes an arrhythmogenic substrate. Previous work focused on Pitx2 developmental functions that predispose to AF. Although Pitx2 is expressed in postnatal left atrium, it is unknown whether Pitx2 has distinct postnatal and developmental functions.
  
  
  RESULTS
  To investigate Pitx2 postnatal function, we conditionally inactivated Pitx2 in the postnatal atrium while leaving its developmental function intact. Unstressed adult Pitx2 homozygous mutant mice display variable R-R interval with diminished P-wave amplitude characteristic of sinus node dysfunction, an AF risk factor in human patients. An integrated genomics approach in the adult heart revealed Pitx2 target genes encoding cell junction proteins, ion channels, and critical transcriptional regulators. Importantly, many Pitx2 target genes have been implicated in human AF by genome-wide association studies. Immunofluorescence and transmission electron microscopy studies in adult Pitx2 mutant mice revealed structural remodeling of the intercalated disc characteristic of human patients with AF.
  
  
  CONCLUSIONS
  Our findings, revealing that Pitx2 has genetically separable postnatal and developmental functions, unveil direct Pitx2 target genes that include channel and calcium handling genes, as well as genes that stabilize the intercalated disc in postnatal atrium.
authors.affiliation: Department of Molecular Physiology and Biophysics.
authors.forename: Ye
authors.initials: Y
authors.lastname: Tao
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.forename: Lele
authors.initials: L
authors.lastname: Li
authors.forename: Yan
authors.initials: Y
authors.lastname: Bai
authors.forename: Yuefang
authors.initials: Y
authors.lastname: Zhou
authors.forename: Anne M
authors.initials: AM
authors.lastname: Moon
authors.forename: Henry J
authors.initials: HJ
authors.lastname: Kaminski
authors.forename: James F
authors.initials: JF
authors.lastname: Martin
mesh_terms: D000818:Animals; D001281:Atrial Fibrillation / Q000235:genetics* / Q000473:pathology; D004562:Electrocardiography; D020869:Gene Expression Profiling; D055106:Genome-Wide Association Study; D006325:Heart Atria / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006720:Homozygote; D006801:Humans; D007365:Intercellular Junctions / Q000378:metabolism; D017136:Ion Transport / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D012307:Risk Factors; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D000097577:Homeobox Protein PITX2
chemical_list: D018398:Homeodomain Proteins; D014157:Transcription Factors; D000097577:Homeobox Protein PITX2
keywords: atrial fibrillation; genetics; genome-wide association analysis