Pitx2, an Atrial Fibrillation Predisposition Gene, Directly Regulates Ion Transport and Intercalated Disc Genes
Background—Pitx2 is the homeobox gene located in proximity to the human 4q25 familial atrial fibrillation locus. When deleted in the mouse germline, Pitx2 haploinsufficiency predisposes to pacing induced atrial fibrillation indicating that reduced Pitx2 promotes an arrhythmogenic substrate. Previous work focused on Pitx2 developmental functions that predispose to atrial fibrillation. Although Pitx2 is expressed in postnatal left atrium, it is unknown whether Pitx2 has distinct postnatal and developmental functions.
Methods and 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 atrial fibrillation 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 atrial fibrillation 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 atrial fibrillation patients.
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.
- Received July 2, 2013.
- Revision received November 14, 2013.
- Accepted November 22, 2013.