Abstract P3038: Novel MicroRNAs Targeting Myosin Binding Protein-C3 Gene In Hypertrophic Cardiomyopathy

Abstract

Background: Mutations in cardiac myosin binding protein-C3 ( MYBPC3 ) constitute a significant cause of hypertrophic cardiomyopathy (HCM) with incomplete penetrance, and later age of onset. MYBPC3 variant with 25 base pair deletion in intron 32 ( MYBPC3 Δ25bp ) leads to exon 33 skipping and 3’-untranslated region truncation. Independent transcriptomics studies in HCM individuals carrying c.927-2A>G, c.2373insG, c.3624delC and c.3369_3370insC MYBPC3 variants reported altered levels of cardiac and circulating microRNAs (miRNAs). However, the miRNA-mediated post-transcriptional regulation of the MYBPC3 and MYBPC3 Δ25bp in the HCM phenotype remains largely unknown. Methods: Using a computational consensus approach, top-scoring cardiac-specific miRNAs predicted to target wild-type MYBPC3 (WT) and MYBPC3 Δ25bp were identified. To further characterize the potential regulators, the miRNAs with earlier reports on cardiac and skeletal diseases were selected and their targets were intersected with a compiled set of HCM and heart failure (HF) candidate genes. The overlapping genes were subjected to enrichment analysis for biological processes. Results: The computational analyses predicted 7 high scoring miRNAs for MYBPC3, among which miR-146b-3p, miR-2355-5p, miR-4508, miR-4800-5p and miR-214-5p were predicted to regulate both the WT and MYBPC3 Δ25bp variant, whereas the binding sites for miR-5588-5p, and miR-6500-3p were lost in MYBPC3 Δ25bp variant. In specific, miR-146-3p, miR-214-5p, and miR-2355-5p have been reported to be associated with skeletal muscle dysfunction, HCM and myocardial ischemia-reperfusion injury, respectively. The putative targets of these 3 miRNAs intersected with HCM and HF candidate genes, in addition the intersected targets displayed enrichment for cardiac disease-associated biological processes. Conclusions: Computational prediction suggests that predicted MYBPC3 miRNAs affect biological processes and pathways associated with HCM and HF. Importantly, MYBPC3 Δ25bp show a loss of miRNA regulation compared to the WT. Further studies and experimental validations are required to determine the influence of loss of miRNA regulation in the MYBPC3 Δ25bp and their impact on HCM interventions.