PXD051917

PXD051917 is an original dataset announced via ProteomeXchange.

Title	Excessive intermediate filament degradation and mitochondrial changes in heart failure patients carrying KLHL24 gain-of-function mutation
Description	A striking aspect of epidermolysis bullosa patients with a mutation in KLHL24 (KLHL24mut) is their life-threatening heart deterioration. The encoded protein, KLHL24, belongs to the ubiquitin-proteasome system that regulates protein turnover, acting as a substrate-specific adaptor protein to E3 ubiquitin ligase. It is thought that KLHL24mut is a gain-of-function mutation and associated cardiac and skin pathologies stem from excessive degradation of KLHL24mut target proteins. Thus far, all reported targets of KLHL24mut belong to the intermediate filament protein family and a reduction of desmin in cardiomyocytes is the only reported mechanism of KLHL24mut-driven heart pathology. In this study we investigate the cardiac phenotype driven by KLHL24mut and its underlying mechanism by combining clinical patient data with proteomic analysis. Using human induced pluripotent stem cell-derived cardiac models and patient cardiac tissue we demonstrate that KLHL24mut leads to defects in mitochondria, muscle fibers and intermediate filament proteins. Our study shows that KHL24mut affects multiple cardiac cell types and has numerous downstream targets, notably synemin and desmin in cardiomyocytes and vimentin in cardiac fibroblasts. Thus, KLHL24mut can affect several proteins in multiple types of cells, underscoring the need for a holistic approach when designing diagnosis, treatment, and research models tackling this disease.
HostingRepository	PRIDE
AnnounceDate	2025-12-03
AnnouncementXML	Submission_2025-12-03_07:43:55.506.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Rayman Tjokrodirijo
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Exploris 480

Revision	Datetime	Status	ChangeLog Entry
0	2024-05-01 02:52:44	ID requested
⏵ 1	2025-12-03 07:43:56	announced

Dataset with its publication pending

submitter keyword: desmin, epidermolysis bullosa,KLHL24

Peter A. van Veelen
contact affiliation	Head Proteomics Group, Leiden University Medical Center, Center for Proteomics and Metabolomics, PO Box 9600, Postal zone P1-Q, 2300 RC Leiden, The Netherlands
contact email	P.A.van_Veelen@lumc.nl
lab head
Rayman Tjokrodirijo
contact affiliation	Leiden University Medical Center, Proteomics group
contact email	r.t.n.tjokrodirijo@lumc.nl
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD051917
     1. Label: PRIDE project
     2. Name: Excessive intermediate filament degradation and mitochondrial changes in heart failure patients carrying KLHL24 gain-of-function mutation