PXD038300-1

PXD038300 is an original dataset announced via ProteomeXchange.

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

Revision	Datetime	Status	ChangeLog Entry
0	2022-11-23 01:38:37	ID requested
⏵ 1	2024-08-09 05:08:04	announced

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]

submitter keyword: titin, cardiac potassium channel, atrial fibrillation, zebrafish

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

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PRIDE project URI

• PRIDE
  1. PXD038300
     1. Label: PRIDE project
     2. Name: Titin-dependent transient ventricular defects result in adult atrial arrhythmia and impaired contractility