Gain-of-function cardiomyopathic mutations in RBM20 rewire splicing regulation and re-distribute ribonucleoprotein granules within processing bodies

Aidan M. Fenix, Yuichiro Miyaoka, Alessandro Bertero, Steven M. Blue, Matthew J. Spindler, Kenneth K. B. Tan, Juan A. Perez-Bermejo, Amanda H. Chan, Steven J. Mayerl, Trieu D. Nguyen, Caitlin R. Russell, Paweena P. Lizarraga, Annie Truong, Po-Lin So, Aishwarya Kulkarni, Kashish Chetal, Shashank Sathe, Nathan J. Sniadecki, Gene W. Yeo, Charles E. Murry (), Bruce R. Conklin () and Nathan Salomonis ()
Additional contact information
Aidan M. Fenix: University of Washington
Yuichiro Miyaoka: Tokyo Metropolitan Institute of Medical Science
Alessandro Bertero: University of Washington
Steven M. Blue: University of California San Diego
Matthew J. Spindler: Gladstone Institutes
Kenneth K. B. Tan: Gladstone Institutes
Juan A. Perez-Bermejo: Gladstone Institutes
Amanda H. Chan: Gladstone Institutes
Steven J. Mayerl: Gladstone Institutes
Trieu D. Nguyen: Gladstone Institutes
Caitlin R. Russell: Gladstone Institutes
Paweena P. Lizarraga: Gladstone Institutes
Annie Truong: Gladstone Institutes
Po-Lin So: Gladstone Institutes
Aishwarya Kulkarni: University of Cincinnati
Kashish Chetal: Cincinnati Children’s Hospital Medical Center
Shashank Sathe: University of California San Diego
Nathan J. Sniadecki: University of Washington
Gene W. Yeo: University of California San Diego
Charles E. Murry: University of Washington
Bruce R. Conklin: Gladstone Institutes
Nathan Salomonis: Cincinnati Children’s Hospital Medical Center

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: Abstract Mutations in the cardiac splicing factor RBM20 lead to malignant dilated cardiomyopathy (DCM). To understand the mechanism of RBM20-associated DCM, we engineered isogenic iPSCs with DCM-associated missense mutations in RBM20 as well as RBM20 knockout (KO) iPSCs. iPSC-derived engineered heart tissues made from these cell lines recapitulate contractile dysfunction of RBM20-associated DCM and reveal greater dysfunction with missense mutations than KO. Analysis of RBM20 RNA binding by eCLIP reveals a gain-of-function preference of mutant RBM20 for 3′ UTR sequences that are shared with amyotrophic lateral sclerosis (ALS) and processing-body associated RNA binding proteins (FUS, DDX6). Deep RNA sequencing reveals that the RBM20 R636S mutant has unique gene, splicing, polyadenylation and circular RNA defects that differ from RBM20 KO. Super-resolution microscopy verifies that mutant RBM20 maintains very limited nuclear localization potential; rather, the mutant protein associates with cytoplasmic processing bodies (DDX6) under basal conditions, and with stress granules (G3BP1) following acute stress. Taken together, our results highlight a pathogenic mechanism in cardiac disease through splicing-dependent and -independent pathways.

Date: 2021
References: View references in EconPapers View complete reference list from CitEc
Citations: View citations in EconPapers (1)

Downloads: (external link)
https://www.nature.com/articles/s41467-021-26623-y Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-26623-y

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-021-26623-y

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().