{"database":"GEO","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Other":["ftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE305nnn/GSE305648/"]},"type":"primary"},"statusCode":"OK","statusCodeValue":200}],"scores":null,"additional":{"omics_type":["Transcriptomics"],"species":["Homo sapiens"],"gds_type":["Expression profiling by high throughput sequencing"],"full_dataset_link":["https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE305648"],"repository":["GEO"],"entry_type":["GSE"],"additional_accession":[]},"is_claimable":false,"name":"Dysregulated ribonucleoprotein granules impair mitochondrial activity in RBM20-dilated cardiomyopathy","description":"Pathogenic variants in the RNA-binding motif protein 20 (RBM20) cause severe dilated cardiomyopathy (DCM). While loss-of-function (LoF) variants lead to splicing dysfunction, gain-of-function (GoF) variants also mislocalize the protein to cytoplasmic ribonucleoprotein (RNP) granules resulting in a more aggressive disease phenotype with a yet unknown pathogenic mechanism. Here, we show that the induction of severe mitochondrial dysfunction is a key consequence of RBM20 mislocalization. Proteomic profiling of RBM20-GoF mouse hearts reveals a predominant reduction in mitochondrial membrane protein solubility and widespread post-transcriptional downregulation of mitochondrial proteins, including Transmembrane Protein 65 (TMEM65), a regulator of mitochondrial calcium efflux. Ultrastructural analysis shows enlarged mitochondria with aberrant morphology. Functional assays confirm impaired mitochondrial respiration, transmembrane potential, and calcium handling in RBM20-GoF, but not LoF models. Using human iPSC-derived cardioids, we validate that RBM20 mislocalization, not splicing deficiency, drives mitochondrial dysfunction in DCM. These findings establish a mechanistic link between dysregulated RNP granules and mitochondrial defects in RBM20-DCM, resembling pathogenic features observed in Fused in Sarcoma protein (FUS)-associated neurodegeneration causing amyotrophic lateral sclerosis (ALS), where cytoplasmic mislocalization of an RNA-binding protein disrupts granule dynamics and organelle function.","dates":{"publication":"2026/07/17"},"accession":"GSE305648","cross_references":{"GSM":["GSM9181359","GSM9181358","GSM9181355","GSM9181354","GSM9181357","GSM9181356","GSM9181362","GSM9181361","GSM9181364","GSM9181353","GSM9181363","GSM9181360"],"GPL":["30173"],"GSE":["305648"],"taxon":["Homo sapiens"]}}