PXD057114

PXD057114 is an original dataset announced via ProteomeXchange.

Title	PCBP1 regulates aberrant alternative splicing of AARS2 in congenital cardiomyopathy
Description	Alanyl-transfer RNA synthetase 2 (AARS2) is a nuclear encoded mitochondrial tRNA synthetase that is responsible for charging of tRNA-Ala with alanine during mitochondrial translation. Homozygous or compound heterozygous mutations in the Aars2 gene, including those affecting its splicing, are linked to infantile cardiomyopathy in humans. However, how Aars2 regulates heart development, and the underlying molecular mechanism of heart disease remains unknown. Here, we found that poly(rC) binding protein 1 (PCBP1) interacts with the Aars2 transcript to mediate its alternative splicing and is critical for the expression and function of Aars2. Cardiomyocyte-specific deletion of Pcbp1 in mice resulted in defects in heart development that are reminiscent of human congenital cardiac defects, including noncompaction cardiomyopathy and a disruption of the cardiomyocyte maturation trajectory. Loss of Pcbp1 led to an aberrant alternative splicing and a premature termination of Aars2 in cardiomyocytes. Additionally, Aars2 mutant mice with exon-16 skipping recapitulated heart developmental defects observed in Pcbp1 mutant mice. Mechanistically, we found dysregulated gene and protein expression of the oxidative phosphorylation pathway in both Pcbp1 and Aars2 mutant hearts; these date provide further evidence that the infantile hypertrophic cardiomyopathy associated with the disorder oxidative phosphorylation defect type 8 (COXPD8) is mediated by Aars2. Our study therefore identifies Pcbp1 and Aars2 as critical regulators of heart development and provides important molecular insights into the role of disruptions in metabolism on congenital heart defects.
HostingRepository	PRIDE
AnnounceDate	2026-02-16
AnnouncementXML	Submission_2026-02-16_13:49:48.486.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Kerry Dorr
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: NEWT:10090;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Exploris 480

Revision	Datetime	Status	ChangeLog Entry
0	2024-10-23 12:26:20	ID requested
⏵ 1	2026-02-16 13:49:48	announced

Dataset with its publication pending

submitter keyword: None

Frank Conlon
contact affiliation	University of North Carolina, Department of Biology and Genetics, Lineberger Comprehensive Cancer Center, USA
contact email	frank_conlon@med.unc.edu
lab head
Kerry Dorr
contact affiliation	University of North Carolina
contact email	kerry_dorr@med.unc.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD057114
     1. Label: PRIDE project
     2. Name: PCBP1 regulates aberrant alternative splicing of AARS2 in congenital cardiomyopathy