Department of Medicine, Division of Cardiovascular Medicine, University of Wisconsin-Madison School of Medicine and Public Health, Madison, United States
Stefan R Mazurek
Department of Medicine, University of Chicago, Chicago, United States
Sonja Lazarevic
Departments of Pediatrics, Pathology, and Human Genetics, University of Chicago, Chicago, United States
Margaret Gadek
Departments of Pediatrics, Pathology, and Human Genetics, University of Chicago, Chicago, United States
Yitang Wang
Department of Pathology, University of Chicago, Chicago, United States
Department of Pathology, University of Chicago, Chicago, United States
Hector H Valdivia
Department of Medicine, Division of Cardiovascular Medicine, University of Wisconsin-Madison School of Medicine and Public Health, Madison, United States
Department of Pathology, University of Chicago, Chicago, United States; Section of Neurosurgery, Department of Surgery, University of Chicago, Chicago, United States
Michael T Broman
Department of Medicine, University of Chicago, Chicago, United States
Risk for Atrial Fibrillation (AF), the most common human arrhythmia, has a major genetic component. The T-box transcription factor TBX5 influences human AF risk, and adult-specific Tbx5-mutant mice demonstrate spontaneous AF. We report that TBX5 is critical for cellular Ca2+ homeostasis, providing a molecular mechanism underlying the genetic implication of TBX5 in AF. We show that cardiomyocyte action potential (AP) abnormalities in Tbx5-deficient atrial cardiomyocytes are caused by a decreased sarcoplasmic reticulum (SR) Ca2+ ATPase (SERCA2)-mediated SR calcium uptake which was balanced by enhanced trans-sarcolemmal calcium fluxes (calcium current and sodium/calcium exchanger), providing mechanisms for triggered activity. The AP defects, cardiomyocyte ectopy, and AF caused by TBX5 deficiency were rescued by phospholamban removal, which normalized SERCA function. These results directly link transcriptional control of SERCA2 activity, depressed SR Ca2+ sequestration, enhanced trans-sarcolemmal calcium fluxes, and AF, establishing a mechanism underlying the genetic basis for a Ca2+-dependent pathway for AF risk.
