Key result
RBM20 gain-of-function variants disrupt mitochondrial function vs loss-of-function variants via oxidative phosphorylation failure.
Why the study?
The mechanism by which RBM20 mislocalization drives cardiac dysfunction in RBM20-related dilated cardiomyopathy remains unknown.
Does cytoplasmic mislocalization of RBM20 in gain-of-function variants impair mitochondrial function compared to loss-of-function variants in models of dilated cardiomyopathy?
Does cytoplasmic mislocalization of RBM20 in gain-of-function variants impair mitochondrial function compared to loss-of-function variants in models of dilated cardiomyopathy?
Cytoplasmic mislocalization of RBM20 in gain-of-function variants disrupts mitochondrial function, providing a mechanistic explanation for the more severe heart failure phenotype observed in these patients compared to those with loss-of-function variants.
RBM20 GoF variants may drive severe DCM via mitochondrial failure; extends splicing mechanisms but leaves open human therapeutic relevance.
BACKGROUND: Pathogenic variants in RBM20 cause severe dilated cardiomyopathy. Loss-of-function variants disrupt splicing; neomorphic gain-of-function (GoF) variants also mislocalize RBM20 to cytoplasmic ribonucleoprotein granules and are associated with more aggressive disease. The mechanism by which RBM20 mislocalization drives cardiac dysfunction remains unknown. METHODS: We investigated the effects of Rbm20 GoF and loss-of-function (LoF) variants using proteomic profiling, protein solubility assays, mitochondrial respiration and calcium flux analyses, and ultrastructural imaging in mouse models. Human induced pluripotent stem cell–derived cardioids were used to validate variant-specific phenotypes. RESULTS: Rbm20 GoF, but not LoF, variants caused posttranscriptional downregulation of soluble mitochondrial proteins, including the calcium efflux regulator TMEM65 (transmembrane protein 65), and reduced solubility of mitochondrial membrane proteins. Electron microscopy revealed enlarged mitochondria with cristae disorganization. Functional assays confirmed impaired oxidative phosphorylation, reduced mitochondrial membrane potential, and abnormal calcium handling in Rbm20 GoF models. Human cardioids reproduced these findings, demonstrating that cytoplasmic mislocalization, rather than splicing deficiency, drives mitochondrial dysfunction. CONCLUSIONS: Cytoplasmic mislocalization of RBM20 disrupts mitochondrial function by reducing mitochondrial protein abundance, leading to oxidative phosphorylation failure and abnormal mitochondrial calcium handling. This mechanism distinguishes RBM20 GoF from LoF variants and may explain the more severe heart failure phenotype observed in patients with RBM20 GoF variants. These insights advance the mechanistic understanding of RBM20 -related cardiomyopathy and identify mitochondrial mRNA/protein regulation as a key node in cardiac energetics.
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Kornienko et al. (2026) studied RBM20-Related Dilated Cardiomyopathy. RBM20 Gain-of-Function (GoF) variants vs. RBM20 Loss-of-Function (LoF) variants was evaluated on Mitochondrial function, protein solubility, and calcium handling. RBM20 gain-of-function variants disrupted mitochondrial function by reducing mitochondrial protein abundance and causing oxidative phosphorylation failure compared to loss-of-function variants.
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