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PXD038790-1

PXD038790 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleMislocalization of pathogenic RBM20 variants in dilated cardiomyopathy is caused by loss-of-interaction with Transportin-3
DescriptionSevere 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.
HostingRepositoryPRIDE
AnnounceDate2023-06-19
AnnouncementXMLSubmission_2023-06-19_04:58:20.097.xml
DigitalObjectIdentifier
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportUnsupported dataset by repository
PrimarySubmitterFrankStein
SpeciesList scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationListNo PTMs are included in the dataset
InstrumentOrbitrap Fusion Lumos
Dataset History
RevisionDatetimeStatusChangeLog Entry
02022-12-12 23:20:11ID requested
12023-06-19 04:58:20announced
Publication List
Dataset with its publication pending
Keyword List
submitter keyword: Human, heart, splicing, dilated cardiomyopathy
Contact List
Lars M.Steinmetz
contact affiliationGenome Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany; Genome Center, Department of Genetics, Stanford University School of Medicine, CA, USA.
contact emaillarsms@embl.de
lab head
FrankStein
contact affiliationEMBL
contact emailfrank.stein@embl.de
dataset submitter
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Dataset FTP location
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