PXD014812-2

PXD014812 is an original dataset announced via ProteomeXchange.

Title	Sequential defects in cardiac lineage commitment and maturation cause hypoplastic left heart syndrome
Description	Complex molecular programs in specific cell lineages govern human heart development. Hypoplastic left heart syndrome (HLHS) is the most severe congenital heart defect encompassing a spectrum of left-ventricular hypoplasia occurring in association with outflow-tract obstruction. The current clinical paradigm assumes HLHS is largely of hemodynamic origin. Here, by combining whole-exome sequencing of 87 HLHS parent-offspring trios and transcriptome of cardiomycytes (CMs) from healthy and patient native ventricles at different stages of development we identified perturbations in coherent gene programs controlling ventricular muscle lineage development. Single-cell and 3D molecular/functional modeling with iPSCs demonstrated intrinsic defects in the cell-cycle/ciliogenesis/autophagy hub resulting in disrupted differentiation of early cardiac progenitor (CP) lineages and ultimate defective CM-subtype differentiation/maturation in HLHS. Moreover, premature cellcycle exit of ventricular CM prevents tissue response to cues of developmental growth leading to multinucleation/polyploidy, accumulation of DNA damage, exacerbated apoptosis, and eventually ventricle hypoplasia. Our results highlight how genetic heterogeneity in HLHS converges in perturbations of sequential cellular processes driving cardiogenesis and facilitate potential novel nodes for therapy beside surgical intervention.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_05:31:31.129.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Mario Oroshi
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2019-07-29 08:27:56	ID requested
1	2022-02-15 09:31:14	announced
⏵ 2	2024-10-22 05:31:33	announced	2024-10-22: Updated project metadata.

Krane M, Dre, ß, en M, Santamaria G, My I, Schneider CM, Dorn T, Laue S, Mastantuono E, Berutti R, Rawat H, Gilsbach R, Schneider P, Lahm H, Schwarz S, Doppler SA, Paige S, Puluca N, Doll S, Neb I, Brade T, Zhang Z, Abou-Ajram C, Northoff B, Holdt LM, Sudhop S, Sahara M, Goedel A, Dendorfer A, Tjong FVY, Rijlaarsdam ME, Cleuziou J, Lang N, Kupatt C, Bezzina C, Lange R, Bowles NE, Mann M, Gelb BD, Crotti L, Hein L, Meitinger T, Wu S, Sinnecker D, Gruber PJ, Laugwitz KL, Moretti A, Sequential Defects in Cardiac Lineage Commitment and Maturation Cause Hypoplastic Left Heart Syndrome. Circulation, 144(17):1409-1428(2021) [pubmed]

10.1161/circulationaha.121.056198;

submitter keyword: hypoplastic left heart syndrome

Alessandra Moretti
contact affiliation	First Department of Medicine, Cardiology, Klinikum rechts der Isar - Technical University of Munich, Ismaninger Strasse 22, 81675 Munich, Germany
contact email	amoretti@mytum.de
lab head
Mario Oroshi
contact affiliation	Proteomics
contact email	oroshi@biochem.mpg.de
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD014812
     1. Label: PRIDE project
     2. Name: Sequential defects in cardiac lineage commitment and maturation cause hypoplastic left heart syndrome