PXD038300 is an
original dataset announced via ProteomeXchange.
Dataset Summary
Title | Titin-dependent transient ventricular defects result in adult atrial arrhythmia and impaired contractility |
Description | Atrial fibrillation (AF), the most common arrhythmia, is occasionally associated with cardiac developmental defects, but causal relationships are poorly defined. Importantly, functional compensation for developmental defects may mask increased risk of arrhythmia in adults. Here, we deleted 9 amino acids (Δ9) within a highly conserved A-band region of titin, a giant protein that serves as a molecular spring in cardiomyocytes, in both zebrafish and human induced pluripotent stem cell-derived atrial cardiomyocytes (hiPSC-aCMs). We find that the cardiac morphology of ttnaΔ9/Δ9 homozygous zebrafish embryos is perturbed and accompanied by reduced functional output, but ventricular function recovers within a few days of embryonic development, with most embryos reaching adulthood. Despite normal ventricular function, ttnaΔ9/Δ9 adults exhibit AF and atrial cardiomyopathy, with a striking absence of fibrosis, and these findings are recapitulated in TTNΔ9/Δ9-hiPSC-aCMs. Electrophysiological and proteomics analyses reveal atrial action potential shortening and increased expression and function of the cardiac potassium channel Kv7.1 and the slow delayed rectifier potassium current (IKs). Pharmacological suppression of IKs in both models prevents AF and improves atrial contractility. Collectively, these findings reveal how a small internal deletion in a large structural protein causes developmental abnormalities that functionally recover but increase the risk of adult cardiac disease via ion channel remodeling. The observed rescue with targeted antiarrhythmic therapy may have broader implications for the treatment of patients who harbor disease-causing rare variants in sarcomeric proteins. |
HostingRepository | PRIDE |
AnnounceDate | 2024-08-09 |
AnnouncementXML | Submission_2024-08-09_05:08:03.596.xml |
DigitalObjectIdentifier | |
ReviewLevel | Peer-reviewed dataset |
DatasetOrigin | Original dataset |
RepositorySupport | Unsupported dataset by repository |
PrimarySubmitter | Ziwei Zhang |
SpeciesList | scientific name: Danio rerio (Zebrafish) (Brachydanio rerio); NCBI TaxID: 7955; |
ModificationList | TMT6plex-126 reporter+balance reagent acylated residue; acetylated residue; iodoacetamide derivatized residue |
Instrument | Q Exactive HF |
Dataset History
Revision | Datetime | Status | ChangeLog Entry |
0 | 2022-11-23 01:38:37 | ID requested | |
⏵ 1 | 2024-08-09 05:08:04 | announced | |
Publication List
10.1016/j.isci.2024.110395; |
Jiang X, Ly OT, Chen H, Zhang Z, Ibarra BA, Pavel MA, Brown GE, Sridhar A, Tofovic D, Swick A, Marszalek R, Vanoye CG, Navales F, George AL, Khetani SR, Rehman J, Gao Y, Darbar D, Saxena A, Transient titin-dependent ventricular defects during development lead to adult atrial arrhythmia and impaired contractility. iScience, 27(7):110395(2024) [pubmed] |
Keyword List
submitter keyword: titin, cardiac potassium channel, atrial fibrillation, zebrafish |
Contact List
Yu Gao |
contact affiliation | University of Illinois at Chicago |
contact email | yugao@uic.edu |
lab head | |
Ziwei Zhang |
contact affiliation | University of Illinois at Chicago |
contact email | zzhan60@uic.edu |
dataset submitter | |
Full Dataset Link List
Dataset FTP location
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PRIDE project URI |
Repository Record List
[ + ]
[ - ]
- PRIDE
- PXD038300
- Label: PRIDE project
- Name: Titin-dependent transient ventricular defects result in adult atrial arrhythmia and impaired contractility