Abstract Body (Do not enter title and authors here): Background: Cardiac arrhythmias afflict tens of millions of people, causing one-fifth of all deaths. Although mouse models have aided understanding of some pacemaker genes and arrhythmias, mice are not known to naturally acquire arrhythmias, and the substantial differences between mouse and human cardiac anatomy and physiology have limited their utility in preclinical studies and pharmacological testing. Our lab has been investigating the mouse lemur – the smallest, easiest to maintain, and one of the most abundant non-human primates – as a new primate genetic model organism.

Methods and Results: We carried out an ECG screen of over 350 mouse lemurs. Twenty-two lemurs (6.2%) were identified with eight different naturally-occurring arrhythmias resembling human ECG pathologies (sick sinus syndrome, PACs, Afib, PVCs, NSVT, ST-depression, inverted T-waves, ST-elevation). Pedigree construction showed two were familial, atrial fibrillation and sick sinus syndrome (SSS), an episodic bradycardia resembling human SSS which has been mapped to two causative genes, the pacemaker channel HCN4 and the cardiac sodium channel SCN5A. Genome sequencing of the lemur SSS pedigree mapped the disease locus to a 1.5 Mb interval on chromosome 7 and supported autosomal recessive Mendelian inheritance. The most appealing candidate gene in the interval was SLC41A2, a little studied magnesium transporter. Although mouse SLC41A2 knockouts do not show a cardiac pacemaker phenotype, we found that CRISPR-mediated knockout of SLC41A2 in human iPSC-derived cardiac pacemaker cells (sinoatrial nodal cells, SANCs) altered human SANC magnesium dynamics and slowed their firing rate and calcium transients. The results indicate that SLC41A2 functions cell autonomously and primate-specifically in cardiac pacemaker cells, and that intracellular magnesium dynamics have a crucial but previously unappreciated role in setting pacemaker rate.

Conclusion: Our work characterizes a critical new component of the human cardiac pacemaker and introduces an important, dynamic role for magnesium. It identifies a potential new cause of human sick sinus syndrome, and a route to new arrythmia diagnostics and therapeutics. It establishes the mouse lemur as a tractable genetic model organism for discovering new genes, molecules, and mechanisms of the primate pacemaker, and for identifying novel candidate genes and therapeutic targets for human arrhythmias which can be generalized to other tissues and diseases.