PXD058221

PXD058221 is an original dataset announced via ProteomeXchange.

Title	Impaired exocytosis Weibel-Palade bodies due to biallelic MADD mutations
Description	The regulated secretion of von Willebrand factor (VWF) from Weibel-Palade bodies (WPB) in endothelial cells is fundamental to hemostasis. This process relies on the recruitment of Rab GTPases and their effectors to the WPB membrane, with the guanine nucleotide exchange factor (GEF) MAP-kinase activating death domain (MADD) playing a central role. Biallelic mutations in MADD lead to a pleiotropic disorder that can include bleeding abnormalities. This study investigates the impact of pathogenic MADD mutations on VWF secretion using patient-derived endothelial cells. We isolated endothelial colony forming cells (ECFCs) from the peripheral blood of three pediatric patients with biallelic MADD mutations, unaffected heterozygous family members, and healthy controls All patients exhibited low VWF plasma levels. Proteomic analysis of patient-derived ECFCs revealed an absence of MADD peptides, reduced VWF, and downregulation of proteins involved in the exocytotic machinery, including Rab3D and the Rab3/27 effector Slp4-a. Functional assays demonstrated diminished Rab27A and Rab3D activity and their failure to localize to WPBs in patient cells. Biochemical and live-imaging studies showed that histamine-induced VWF and VWF propeptide secretion were significantly reduced in patient cells as a result of delayed and reduced degranulation of WPBs. Our findings demonstrate the critical role of MADD in maintaining the secretion competence of WPBs and the magnitude of VWF secretion by regulating the recruitment of the endothelial exocytotic machinery. This study highlights the in vivo significance of WPB exocytosis in maintaining plasma VWF levels and establishes MADD as the first causal gene for quantitative von Willebrand Disease (VWD) in patients without pathogenic VWF variants.
HostingRepository	PRIDE
AnnounceDate	2025-07-17
AnnouncementXML	Submission_2025-07-17_06:07:45.266.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Stijn Groten
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2024-11-25 02:49:47	ID requested
⏵ 1	2025-07-17 06:07:45	announced

10.1182/BLOOD.2024027935;

ProteomeXchange project tag: Human Proteome Project

submitter keyword: MADD, VWF,ECFC, VWD

Maartje van den Biggelaar
contact affiliation	Department of Molecular Hematology, Sanquin Research, Amsterdam, the Netherlands
contact email	m.vandenbiggelaar@sanquin.nl
lab head
Stijn Groten
contact affiliation	Sanquin Research
contact email	s.groten@sanquin.nl
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2025/07/PXD058221

PRIDE project URI

• PRIDE
  1. PXD058221
     1. Label: PRIDE project
     2. Name: Impaired exocytosis Weibel-Palade bodies due to biallelic MADD mutations