Congenital heart disease (CHD) remains the most common birth defect and the leading cause of morbidity and mortality in children worldwide, however, the molecular basis for most CHDs remains unknown. AARS2-related cardiomyopathy, a rare inherited disorder driven by mutations in the alanyl–transfer RNA synthetase 2 (AARS2) gene, is associated with onset at birth and high mortality within the first year of life, with no approved disease-modifying therapies. The recessively inherited AARS2 mutation was first described in patients with infantile cardiomyopathy associated with defects in oxidative phosphorylation (OXPHOS). Because one pathogenic variant disrupts the canonical splice donor or acceptor sites, the authors were predicting that this mutation causes AARS2 exon-16 skipping.
New findings published in Nature Cardiovascular Research identify poly(rC)-binding protein 1 (PCBP1) as a key regulator of AARS2 exon splicing. This elegant research study combines molecular, cellular, bioinformatics, and imaging techniques to study the role of PCBP1 in the regulation of splicing, mitochondrial function, and embryonic cardiac development, with implications for genetic heart diseases. Lu et al. first show that PCBP1 interacts with AARS2 RNA near exon 16, particularly through pyrimidine-rich motifs. They used eCLIP-seq, RIP and minigenes experiments to support the model that loss of PCBP1 causes Aars2 exon-16 skipping and reduced expression of AARS2. Thus, regulation of Aars2 splicing by PCBP1 is crucial for the stability and function of Aars2.
Cardiomyocyte-specific deletion of PCPB1 or AARS2-exon16 resulted in non-compaction cardiomyopathy and defects in ventricular apex formation, underscoring the essential role of both genes in cardiac development. Transcriptomic analyses of both mutants highlighted a ventricular maturation defect associated with a reduced Notch signaling and a downregulation of the expression of mitochondrial respiratory chain proteins, disrupting oxidative phosphorylation. These results show that loss of PCBP1 or Aars2 activates stress pathways, including UPR/ISR, and activates MYC to compensate for mitochondrial dysfunction.
The researchers identified a chain of events linking PCBP1, AARS2 and heart muscle disease. When PCBP1 is missing, the genetic message from AARS2 is processed incorrectly in a way that looks very similar to the AARS2-related cardiomyopathy seen in human patients. The result is that mitochondrial activity is disrupted, reducing the cell's energy supply. In an attempt to compensate, heart cells switch on stress signals that cause further damage.