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1. Dysregulated ribonucleoprotein granules promote cardiomyopathy in RBM20gene-edited pigs

Author

Schneider, Jay W., Oommen, Saji, Qureshi, Muhammad Y., Goetsch, Sean C., Pease, David R., Sundsbak, Rhianna S., Guo, Wei, Sun, Mingming, Sun, Han, Kuroyanagi, Hidehito, Webster, Dennis A., Coutts, Alexander W., Holst, Kimberly A., Edwards, Brooks S., Newville, Nikolas, Hathcock, Matthew A., Melkamu, Tamene, Briganti, Francesca, Wei, Wu, Romanelli, Maria G., Fahrenkrug, Scott C., Frantz, Doug E., Olson, Timothy M., Steinmetz, Lars M., Carlson, Daniel F., and Nelson, Timothy J.

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 RBM20allele 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 R636Sallele. 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 RBM20mutation.

Published
2020
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2. Author Correction: Dysregulated ribonucleoprotein granules promote cardiomyopathy in RBM20gene-edited pigs

Author

Schneider, Jay W., Oommen, Saji, Qureshi, Muhammad Y., Goetsch, Sean C., Pease, David R., Sundsbak, Rhianna S., Guo, Wei, Sun, Mingming, Sun, Han, Kuroyanagi, Hidehito, Webster, Dennis A., Coutts, Alexander W., Holst, Kimberly A., Edwards, Brooks S., Newville, Nikolas, Hathcock, Matthew A., Melkamu, Tamene, Briganti, Francesca, Wei, Wu, Romanelli, Maria G., Fahrenkrug, Scott C., Frantz, Doug E., Olson, Timothy M., Steinmetz, Lars M., Carlson, Daniel F., and Nelson, Timothy J.

Published
2021
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4. Dysregulated ribonucleoprotein granules promote cardiomyopathy in RBM20 gene-edited pigs.

Author

Schneider JW, Oommen S, Qureshi MY, Goetsch SC, Pease DR, Sundsbak RS, Guo W, Sun M, Sun H, Kuroyanagi H, Webster DA, Coutts AW, Holst KA, Edwards BS, Newville N, Hathcock MA, Melkamu T, Briganti F, Wei W, Romanelli MG, Fahrenkrug SC, Frantz DE, Olson TM, Steinmetz LM, Carlson DF, and Nelson TJ

Subjects
Alleles, Animals, Cardiomyopathy, Dilated physiopathology, Cellular Reprogramming, Disease Models, Animal, Female, Gene Editing, Humans, Male, Mutation genetics, Myocardium pathology, Myocytes, Cardiac metabolism, Myocytes, Cardiac pathology, RNA, Messenger genetics, Sarcoplasmic Reticulum genetics, Sarcoplasmic Reticulum metabolism, Secretory Vesicles genetics, Secretory Vesicles metabolism, Swine, Cardiomyopathy, Dilated genetics, Myocardium metabolism, RNA-Binding Proteins genetics, Ribonucleoproteins genetics
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.

Published
2020
Full Text
View/download PDF

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