Dysregulated ribonucleoprotein granules promote cardiomyopathy in RBM20 gene-edited pigs

Wanek Program Preclinical Pipeline

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Ribonucleoprotein (RNP) granules are biomolecular condensates—liquid–liquid phase-separated droplets that organize and manage messenger RNA metabolism, cell signaling, biopolymer assembly, biochemical reactions and stress granule responses to cellular adversity. Dysregulated RNP granules drive neuromuscular degenerative disease but have not previously been linked to heart failure. By exploring the molecular basis of congenital dilated cardiomyopathy (DCM) in genome-edited pigs homozygous for an RBM20 allele encoding the pathogenic R636S variant of human RNA-binding motif protein-20 (RBM20), we discovered that RNP granules accumulated abnormally in the sarcoplasm, and we confirmed this finding in myocardium and reprogrammed cardiomyocytes from patients with DCM carrying the R636S allele. Dysregulated sarcoplasmic RBM20 RNP granules displayed liquid-like material properties, docked at precisely spaced intervals along cytoskeletal elements, promoted phase partitioning of cardiac biomolecules and fused with stress granules. Our results link dysregulated RNP granules to myocardial cellular pathobiology and heart failure in gene-edited pigs and patients with DCM caused by RBM20 mutation.

Original languageEnglish (US)
Pages (from-to)1788-1800
Number of pages13
JournalNature Medicine
Volume26
Issue number11
DOIs
StatePublished - Nov 2020

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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