Chang, S.; Karanewsky, C. J.; Pendleton, J. L.; Ren, L.; Anzeraey, A.; Froelicher, V.; Liang, D.; Razafindrakoto, A.; Ravelonjanahary, H. N.; Albertelli, M. A.; Quertermous, T.; Wright, P. C.; Perret, M.; Terrien, J.; Aujard, F.; Wu, J. C.; Krasnow, M. A.

Cardiac arrhythmias afflict tens of millions of people, causing one-fifth of all deaths (1). 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 (2-6). To establish a primate genetic model organism for arrhythmias, we carried out an electrocardiographic (ECG) screen of over 350 lab and wild mouse lemurs (Microcebus spp.), an emerging model organism that is among the smallest, fastest-reproducing, and most abundant primates (7). Twenty-two lemurs (6.2%) were identified with eight different naturally-occurring arrhythmias resembling human ECG pathologies (SSS, PACs, Afib, PVCs, NSVT, STD, iTWs, STE). Pedigree construction showed two were familial, premature atrial contractions (PACs)/atrial fibrillation (Afib) and sick sinus syndrome (SSS), an episodic bradycardia. Genome sequencing of the SSS pedigree mapped the disease locus to a 1.4 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. SLC41A2 is expressed in human iPS-derived sinoatrial node cells (SANC) and localizes to the sarcoplasmic reticulum. Although mouse SLC41A2 knockouts do not show a cardiac pacemaker phenotype, CRISPR-mediated SLC41A2 knockout altered human SANC magnesium dynamics and slowed their calcium transient firing rate. The results suggest 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. Thus, mouse lemur is a valuable model for discovering new genes, molecules, and mechanisms of the primate pacemaker, and for identifying novel candidate genes and therapeutic targets for human arrhythmias.