PXD031612 is an
original dataset announced via ProteomeXchange.
Dataset Summary
Title | Gene editing reverses arrhythmia susceptibility in humanized PLN-R14del mice: modeling a European cardiomyopathy with global impact |
Description | Aims: A mutation in the phospholamban (PLN) gene, leading to deletion of Arg14 (R14del), has been associated with malignant arrhythmias and ventricular dilation. Identifying pre-symptomatic carriers with vulnerable myocardium is crucial because arrhythmia can result in sudden cardiac death, especially in young adults with PLN-R14del mutation. This study aimed at assessing the efficiency and efficacy of in vivo genome editing, using CRISPR/Cas9 and a cardiotropic adeno-associated virus (AAV9), in improving cardiac function in young adult mice expressing the human PLN-R14del. Methods and Results: Humanized mice were generated expressing human wild-type (hPLN-WT) or mutant (hPLN-R14del) PLN in the heterozygous state, mimicking human carriers. Cardiac magnetic resonance imaging at 12 weeks of age showed bi-ventricular dilation and increased stroke volume in mutant vs. WT mice, with no deficit in ejection fraction or cardiac output. Challenge of ex vivo hearts with isoproterenol and rapid pacing unmasked higher propensity for sustained ventricular tachycardia (VT) in hPLN-R14del relative to hPLN-WT. Specifically, the VT threshold was significantly reduced (20.3±1.2 Hz in hPLN-R14del vs. 25.7±1.3 Hz in WT, p<0.01) reflecting higher arrhythmia burden. To inactivate the R14del allele, mice were tail-vein-injected with AAV9.CRISPR/Cas9/gRNA or AAV9 empty capsid (controls). CRISPR-Cas9 efficiency was evaluated by droplet digital PCR and NGS-based amplicon sequencing. In vivo gene editing significantly reduced end diastolic and stroke volumes in hPLN-R14del CRISPR-treated mice compared to controls. Susceptibility to VT was also reduced, as the VT threshold was significantly increased relative to controls (30.9±2.3 Hz vs. 21.3±1.5 Hz; p<0.01). Conclusions: This study is the first to show that disruption of hPLN-R14del allele by AAV9- CRISPR/Cas9 improves cardiac function and reduces VT susceptibility in humanized PLN-R14del mice, offering preclinical evidence for translatable approaches to therapeutically suppress the arrhythmogenic phenotype in human patients with PLN-R14del disease. |
HostingRepository | PRIDE |
AnnounceDate | 2023-11-14 |
AnnouncementXML | Submission_2023-11-14_08:40:42.439.xml |
DigitalObjectIdentifier | https://dx.doi.org/10.6019/PXD031612 |
ReviewLevel | Peer-reviewed dataset |
DatasetOrigin | Original dataset |
RepositorySupport | Supported dataset by repository |
PrimarySubmitter | Xiaoke Yin |
SpeciesList | scientific name: Mus musculus (Mouse); NCBI TaxID: 10090; |
ModificationList | TMT6plex-126 reporter+balance reagent acylated residue; monohydroxylated residue; iodoacetamide derivatized residue |
Instrument | Orbitrap Fusion Lumos |
Dataset History
Revision | Datetime | Status | ChangeLog Entry |
0 | 2022-02-11 06:22:01 | ID requested | |
1 | 2023-03-11 02:26:24 | announced | |
⏵ 2 | 2023-11-14 08:40:43 | announced | 2023-11-14: Updated project metadata. |
Publication List
10.6019/PXD031612; |
Dave J, Raad N, Mittal N, Zhang L, Fargnoli A, Oh JG, Savoia ME, Hansen J, Fava M, Yin X, Theofilatos K, Ceholski D, Kohlbrenner E, Jeong D, Wills L, Nonnenmacher M, Haghighi K, Costa KD, Turnbull IC, Mayr M, Cai CL, Kranias EG, Akar FG, Hajjar RJ, Stillitano F, Gene editing reverses arrhythmia susceptibility in humanized PLN-R14del mice: modelling a European cardiomyopathy with global impact. Cardiovasc Res, 118(15):3140-3150(2022) [pubmed] |
Keyword List
submitter keyword: phospholamban, mouse model, TMT, R14del,cardiomyopathy, LC-MS/MS |
Contact List
Manuel Mayr |
contact affiliation | King's British Heart Foundation Centre, King's College London, UK |
contact email | manuel.mayr@kcl.ac.uk |
lab head | |
Xiaoke Yin |
contact affiliation | Cardiovascular Division, King's College London |
contact email | xiaoke.yin@kcl.ac.uk |
dataset submitter | |
Full Dataset Link List
Dataset FTP location
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PRIDE project URI |
Repository Record List
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[ - ]
- PRIDE
- PXD031612
- Label: PRIDE project
- Name: Gene editing reverses arrhythmia susceptibility in humanized PLN-R14del mice: modeling a European cardiomyopathy with global impact