Exploring the Regulation and Function of Rpl3l in the Development of Early-Onset Dilated Cardiomyopathy and Congestive Heart Failure Using Systems Genetics Approach.

Abstract

Cardiomyopathies, diseases affecting the myocardium, are common causes of congestive heart failure (CHF) and sudden cardiac death. Recently, biallelic variants in ribosomal protein L3-like (RPL3L) have been reported to be associated with severe neonatal dilated cardiomyopathy (DCM) and CHF. This study employs a systems genetics approach to gain understanding of the regulatory mechanisms underlying the role of RPL3L in DCM. Genetic correlation, expression quantitative trait loci (eQTL) mapping, differential expression analysis and comparative functional analysis were performed using cardiac gene expression data from the patients and murine genetic reference populations (GRPs) of BXD mice (recombinant inbred strains from a cross of C57BL/6J and DBA/2J mice). Additionally, immune infiltration analysis was performed to understand the relationship between DCM, immune cells and RPL3L expression. Systems genetics analysis identified high expression of Rpl3l mRNA, which ranged from 11.31 to 12.16 across murine GRPs of BXD mice, with an ~1.8-fold difference. Pathways such as "diabetic cardiomyopathy", "focal adhesion", "oxidative phosphorylation" and "DCM" were significantly associated with Rpl3l. eQTL mapping suggested Myl4 (Chr 11) and Sdha (Chr 13) as the upstream regulators of Rpl3l. The mRNA expression of Rpl3l, Myl4 and Sdha was significantly correlated with multiple echocardiography traits in BXD mice. Immune infiltration analysis revealed a significant association of RPL3L and SDHA with seven immune cells (CD4, CD8-naive T cell, CD8 T cell, macrophages, cytotoxic T cell, gamma delta T cell and exhausted T cell) that were also differentially infiltrated between heart samples obtained from DCM patients and normal individuals. RPL3L is highly expressed in the heart tissue of humans and mice. Expression of Rpl3l and its upstream regulators, Myl4 and Sdha, correlate with multiple cardiac function traits in murine GRPs of BXD mice, while RPL3L and SDHA correlate with immune cell infiltration in DCM patient hearts, suggesting important roles for RPL3L in DCM and CHF pathogenesis via immune inflammation, necessitating experimental validations of Myl4 and Sdha in Rpl3l regulation.