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.

核糖核蛋白 (RNP) 颗粒是生物分子凝聚物——液-液相分离的液滴，可组织和管理信使 RNA 代谢、细胞信号传导、生物聚合物组装、生化反应和应激颗粒对细胞逆境的反应。失调的 RNP 颗粒会导致神经肌肉退行性疾病，但之前并未与心力衰竭相关联。通过探索基因组编辑猪中先天性扩张型心肌病 (DCM) 的分子基础，这些猪是编码人 RNA 结合基序蛋白 20 (RBM20) 的致病性R636S变体的 RBM20 等位基因纯合子，我们发现 RNP 颗粒在肌浆中异常积累，并且我们在携带 R636S 的 DCM 患者的心肌和重新编程的心肌细胞中证实了这一发现等位基因。失调的肌浆 RBM20 RNP 颗粒显示出类似液体的材料特性，沿细胞骨架元件以精确间隔对接，促进心脏生物分子的相分配并与应激颗粒融合。我们的结果将失调的 RNP 颗粒与基因编辑猪和RBM20突变引起的扩张型心肌病患者的心肌细胞病理学和心力衰竭联系起来。