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Zhang, F.* ; Dorn, T.* ; Gnutti, B. ; Anikster, Y.* ; Kuebler, S.* ; Ahrens-Nicklas, R.* ; Gosselin, R.* ; Rahman, S.* ; Durst, R.* ; Zanuttigh, E. ; Güra, M. ; Poch, C.M.* ; Meier, A.B.* ; Laugwitz, K.L.* ; Schüller, H.J.* ; Messias, A.C. ; Sibon, O.C.* ; Finazzi, D.* ; Rippert, A.L.* ; Li, D.* ; Truxal, K.* ; Nandi, D.* ; Lampert, B.C.* ; Yeo, M.* ; Gardham, A.* ; Nissan, B.* ; Horowitz Cederboim, S.* ; Moretti, A.* ; Iuso, A.*

Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.

Commun. Med. 5:323 (2025)
Publ. Version/Full Text Research data DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
BACKGROUND: PPCS deficiency disorder (PPCS DD) is an ultra-rare, autosomal recessive form of dilated cardiomyopathy (DCM) caused by pathogenic variants in PPCS, which encodes the enzyme catalyzing the second step in the coenzyme A (CoA) biosynthesis pathway. To date, only six patients worldwide have been identified. METHODS: Whole-exome sequencing was performed to identify pathogenic PPCS variants in affected individuals. Protein stability was assessed by Western blotting. CoA levels were quantified using a microplate-based assay in patient-derived fibroblasts, cardiac progenitor cells, and cardiomyocytes. Functional evaluation of cardiac cells and engineered heart patches was conducted to investigate contractile performance and arrhythmogenicity. Pantethine was tested as a potential therapeutic agent both in vitro and through long-term clinical follow-up in patients. RESULTS: Causative PPCS variants are identified in six individuals with DCM and variable associated features, including neuromuscular and neurological symptoms. Identified variants lead to reduced PPCS protein stability and decreased cellular CoA levels. Cardiac cells exhibit impaired contractility and arrhythmias, which are partially rescued by pantethine treatment. Clinically, patients receiving pantethine show sustained improvement over time. CONCLUSIONS: Our study expands the genetic and clinical spectrum of PPCS deficiency disorder, identifying six new cases with diverse phenotypes. Functional investigations reveal reduced CoA levels and dysfunction in patient-derived cardiac cells. Pantethine treatment shows promise in partially rescuing DCM phenotypes, both in vitro and in patients. However, complete reversal may require early intervention. These findings underscore the importance of timely diagnosis and treatment in PPCS DD. Future research should focus on optimizing pantethine supplementation and exploring additional therapies to enhance CoA levels and cardiac function in affected individuals.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Phosphopantothenoylcysteine Synthetase; Escherichia-coli; Neurodegeneration; Biosynthesis; Maturation; Rescues; System
Language english
Publication Year 2025
HGF-reported in Year 2025
ISSN (print) / ISBN 2730-664X
e-ISSN 2730-664X
Journal Communications Medicine
Quellenangaben Volume: 5, Issue: 1, Pages: , Article Number: 323 Supplement: ,
Publisher Springer
Publishing Place Campus, 4 Crinan St, London, N1 9xw, England
Reviewing status Peer reviewed
Institute(s) Institute of Neurogenomics (ING)
Institute of Structural Biology (STB)
POF-Topic(s) 30205 - Bioengineering and Digital Health
30203 - Molecular Targets and Therapies
Research field(s) Genetics and Epidemiology
Enabling and Novel Technologies
PSP Element(s) G-503200-001
G-503292-001
G-503000-001
Grants DZHK fellowship
NIH
NBIA Disorders Association
Hoffnungsbaum e.V., NBIA Suisse, NBIA Poland
Bavarian Research Alliance
European Research Council
German Research Foundation (Transregio Research Units)
German Center for Cardiovascular Research (DZHK)
ZonMw Open-Call grant
Dutch Organisation for Health Research and Development
NWO-ENW-open
Dutch Organisation for Scientific Research
Biotechnology and Experimental Medicine Program at the University of Brescia, Italy
NBIA Disorders Association (Neurodegeneration with Brain Iron Accumulation Disorders Association)
DOI 10.1038/s43856-025-01017-z
WOS ID 001541384800004
Scopus ID 105012272173
PubMed ID 40745475
Erfassungsdatum 2025-10-27
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