Abstract 12672: A New Genetic Model Organism for Primate-Specific Cardiac Function and Disease

Abstract

Introduction: Due to differences in cardiac structure and function, it has become increasingly clear that many aspects of cardiovascular disease are not well modeled in mice. This has spurred a search for new model organisms with the practical advantages of mice but that more closely mimic human biology. This study examines mouse lemur (Microcebus species) - the world’s smallest, most prolific, and among the most abundant non-human primates - and the cheapest and easiest to maintain, as such a model. Methods: This study characterizes the normal cardiac anatomy and histology, and baseline values for heart rate, cholesterol, and cardiac waveform by ECG (a point-of-care blood assay and a portable 3-lead monitoring device were used to screen ~400 animals). It also describes the development of a whole genome and single cell RNA-sequencing and analysis pipeline for Microcebus murinus. Results: Transcriptomic analysis identified 6000 cardiac cells, including all major and many minor cardiac cell types, including several exceedingly rare cell types. The lipid profiles of these animals more closely resembled that of humans, with an average LDL level of 81 mg/dL, with several obese animals having values >200. 20 naturally-occurring ECG variants were identified, all resembling known human ECG variants including 8 major cardiac arrhythmias. The screen uncovered the first cases of heart disease in lemurs. One is atrial fibrillation; Another is sick sinus syndrome (SSS), whose human familial form arises from mutations in ion channel genes, HCN4 or SCN5A. Both arrythmias show familial clustering, with the SSS pedigree exhibiting an autosomal dominant inheritance pattern. SNP/variant analysis revealed 30 million variants in the SSS animals, and ongoing work has narrowed these to just a handful of high impact, functional variants in SCN5A, suggesting that the underlying mouse lemur SSS disease gene and causative mutation are the same as in humans. Conclusions: The results establish the mouse lemur as the first systematic, high-throughput primate genetic model for cardiovascular physiology and disease, and reveal human-like cardiac cell types and diseases. The approach uncovered naturally-occurring cardiac diseases that have not been found in mice.