Abstract 1425: The Popeye Domain Containing 2 (Popdc2) Gene is Essential for Sinus Node Function
The Popeye domain containing (Popdc) genes encode plasma membrane-localized proteins, which are abundantly expressed in heart and skeletal muscle tissues. Here we show by protein modeling and binding experiments that Popdc proteins constitute a novel class of cyclic nucleotide binding proteins. Sequence comparison of the Popeye domain revealed that the majority of the conserved amino acids were clustered around the putative cyclic nucleotide-binding domain. Mutagenesis of conserved amino acids (charge to alanine) impaired cyclic nucleotide binding. Mice with a null mutation of the Popdc2 gene were engineered and found to survive into adulthood. While Popdc2 is strongly expressed in cardiac myocytes, highest expression was seen in the cardiac conduction tissue. ECG analysis in conscious animals was performed. Under baseline conditions a normal heart rate was observed in null mutants. An age-dependent development of chronotropic incompetence was found when mice were challenged with swimming exercise, mental stress and after beta-adrenergic stimulation. Analysis of individual ECGs revealed severe sinuatrial node (SAN) dysfunction with long pauses interrupting periods of normal sinus rhythm. Stress-induced pauses were neither due to AV nodal block nor due to prolonged AV conduction. PQ intervals were not different between genotypes at different heart rates. The bradycardic phenotype was accompanied by a degeneration of the SAN structure, with a specific loss of tissue in the inferior part. Since the inferior SAN becomes the predominant pacemaker center after sympathetic stimulation, the specific loss of SAN myocytes in this region may explain the observed stress-induced sinus node dysfunction. Cardiac conduction defects were also observed in embryonic zebrafish Popdc2 morphants, suggesting an evolutionary conserved function of Popdc2 as a regulator of sinus node formation and preservation. The striking similarity of sick sinus syndrome in the elderly and the here-described phenotype in Popdc2−/− mice makes this a suitable animal model to study the molecular basis of this disease. Moreover Popdc2 null mutants may also be suitable for the development of therapeutic interventions such as the generation of biological pacemakers.