Atrial fibrillation (AF) carries a significant risk of stroke and heart failure and is associated with substantial morbidity and mortality

332 INTRODUCTION Atrial fibrillation (AF) carries a significant risk of stroke and heart failure and is associated with substantial morbidity and mortality (Feinberg et al., 1995; Stewart et al., 2002). Up to 30% of patients with AF have a family history of the condition, suggesting that the disease has a broad genetic basis (Darbar, 2008; Lubitz et al., 2010; Miyasaka et al., 2006). Cases of ‘lone’ AF, defined by the presence of sustained arrhythmia in the absence of structural heart disease or other identifiable causes in patients younger than 65 years of age, further underscore the contribution of genetic variation to the development of AF (Parvez and Darbar, 2010). Recent studies have identified both common and rare genetic variants contributing to AF susceptibility. Positional cloning and candidate gene approaches have implicated mutations in genes encoding ion channels, gap junctions and signaling molecules in isolated cases and small kindreds (Abraham et al., 2010; Gollob et al., 2006; Hodgson-Zingman et al., 2008). Genome-wide association studies (GWAS) have also recognized AF susceptibility loci (Ellinor et al., 2012) on chromosomes 4q25 near PITX2 (Gudbjartsson et al., 2007; Ritchie et al., 2012), 1q21 in KCNN3 (Ellinor et al., 2010) and 16q22 in ZFHX3 (Gudbjartsson et al., 2009). Even so, most cases of lone AF remain of unknown etiology, are poorly penetrant, and segregate in isolated cases or small families, rendering the identification of causative genes and the design of new therapeutic strategies particularly challenging (Darbar et al., 2012). Moreover, there is a paucity of functional modeling of known variants that could be used to draw putative molecular and cellular pathways contributing to AF symptoms. In many cases of AF, electrical signals initiate in ectopic atrial locations, often close to the muscle sleeves of the pulmonary veins (Haïssaguerre et al., 1998; Levin et al., 2009). Pulmonary veins and pulmonary myocardium develop from pharyngeal mesoderm, a process that depends on transcription factor PITX2 (Liu et al., 2002; Mommersteeg et al., 2007). Recent evidence suggests that aberrant activation of embryonic mechanisms of atrial and pulmonary myocardium development can lead to AF (Mommersteeg et al., 2009) and genetic studies have linked PITX2 to AF patients (Gudbjartsson et al., 2007; Ritchie et al., 2012). Heterozygote Pitx2 knockout mice, which have only 40% lower Pitx2 expression than wild types, are also prone to arrhythmias, indicating that even modest changes in Pitx2 protein levels might promote AF (Kirchhof et al., 2011). During development, Pitx2 expression is regulated by BMP signaling (Furtado et al., 2008; Monteiro et al., 2008; Schlange et Disease Models & Mechanisms 6, 332-341 (2013) doi:10.1242/dmm.010488