PXD038790-1

PXD038790 is an original dataset announced via ProteomeXchange.

Title	Mislocalization of pathogenic RBM20 variants in dilated cardiomyopathy is caused by loss-of-interaction with Transportin-3
Description	Severe forms of dilated cardiomyopathy (DCM) are associated with point mutations in the alternative splicing regulator RBM20 that are frequently located in the arginine/serine-rich domain (RS-domain). Such mutations can cause defective splicing and cytoplasmic mislocalization, which leads to the formation of detrimental cytoplasmic granules. Successful development of personalized therapies requires identifying the direct mechanisms of pathogenic RBM20 variants. Here, we decipher the molecular mechanism of RBM20 mislocalization and its specific role in DCM pathogenesis. We demonstrate that mislocalized RBM20 variants retain their splice regulatory activity, which reveals that aberrant cellular localization drives the pathological phenotype. A genome-wide CRISPR knock-out screen combined with image-enabled cell sorting identified Transportin-3 (TNPO3) as the main nuclear importer of RBM20. We show that the direct RBM20-TNPO3 interaction involves the RS-domain, disrupted by pathogenic variants. Re-localization of pathogenic RBM20 variants to the nucleus restores alternative splicing and dissolves cytoplasmic granules in cell culture and animal models. These findings provide proof-of-principle for developing therapeutic strategies to restore RBM20’s nuclear localization in RBM20-DCM patients.
HostingRepository	PRIDE
AnnounceDate	2023-06-19
AnnouncementXML	Submission_2023-06-19_04:58:20.097.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	FrankStein
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2022-12-12 23:20:11	ID requested
⏵ 1	2023-06-19 04:58:20	announced

Dataset with its publication pending

submitter keyword: Human, heart, splicing, dilated cardiomyopathy

Lars M.Steinmetz
contact affiliation	Genome Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany; Genome Center, Department of Genetics, Stanford University School of Medicine, CA, USA.
contact email	larsms@embl.de
lab head
FrankStein
contact affiliation	EMBL
contact email	frank.stein@embl.de
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2023/06/PXD038790

PRIDE project URI

• PRIDE
  1. PXD038790
     1. Label: PRIDE project
     2. Name: Mislocalization of pathogenic RBM20 variants in dilated cardiomyopathy is caused by loss-of-interaction with Transportin-3