Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models
Abstract 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 worldw...
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2025-07-01
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| author | Fangfang Zhang Tatjana Dorn Barbara Gnutti Yair Anikster Sarah Kuebler Rebecca Ahrens-Nicklas Rachel Gosselin Shamima Rahman Ronen Durst Enrica Zanuttigh Miriam A. Güra Christine M. Poch Anna B. Meier Karl-Ludwig Laugwitz Hans-Joachim Schüller Ana C. Messias Ody C. Sibon Dario Finazzi Alyssa Rippert Dong Li Kristen Truxal Deipanjan Nandi Brent C. Lampert Mildrid Yeo Alice Gardham Batel Nissan Smadar Horowitz Cederboim Alessandra Moretti Arcangela Iuso |
| author_facet | Fangfang Zhang Tatjana Dorn Barbara Gnutti Yair Anikster Sarah Kuebler Rebecca Ahrens-Nicklas Rachel Gosselin Shamima Rahman Ronen Durst Enrica Zanuttigh Miriam A. Güra Christine M. Poch Anna B. Meier Karl-Ludwig Laugwitz Hans-Joachim Schüller Ana C. Messias Ody C. Sibon Dario Finazzi Alyssa Rippert Dong Li Kristen Truxal Deipanjan Nandi Brent C. Lampert Mildrid Yeo Alice Gardham Batel Nissan Smadar Horowitz Cederboim Alessandra Moretti Arcangela Iuso |
| author_sort | Fangfang Zhang |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-39affc8f14094f11a90216c2c642f1cd |
| institution | Kabale University |
| issn | 2730-664X |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
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| spelling | doaj-art-39affc8f14094f11a90216c2c642f1cd2025-08-20T03:43:15ZengNature PortfolioCommunications Medicine2730-664X2025-07-015111710.1038/s43856-025-01017-zPantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line modelsFangfang Zhang0Tatjana Dorn1Barbara Gnutti2Yair Anikster3Sarah Kuebler4Rebecca Ahrens-Nicklas5Rachel Gosselin6Shamima Rahman7Ronen Durst8Enrica Zanuttigh9Miriam A. Güra10Christine M. Poch11Anna B. Meier12Karl-Ludwig Laugwitz13Hans-Joachim Schüller14Ana C. Messias15Ody C. Sibon16Dario Finazzi17Alyssa Rippert18Dong Li19Kristen Truxal20Deipanjan Nandi21Brent C. Lampert22Mildrid Yeo23Alice Gardham24Batel Nissan25Smadar Horowitz Cederboim26Alessandra Moretti27Arcangela Iuso28Regenerative Medicine in Cardiovascular Diseases, First Department of Medicine, TUM University Hospital, Klinikum Rechts der Isar, Technical University of Munich, School of Medicine and HealthRegenerative Medicine in Cardiovascular Diseases, First Department of Medicine, TUM University Hospital, Klinikum Rechts der Isar, Technical University of Munich, School of Medicine and HealthInstitute of Neurogenomics, Helmholtz Zentrum MünchenMetabolic Disease Unit, Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Tel-HashomerRegenerative Medicine in Cardiovascular Diseases, First Department of Medicine, TUM University Hospital, Klinikum Rechts der Isar, Technical University of Munich, School of Medicine and HealthThe Children’s Hospital of Philadelphia, Division of Human GeneticsNationwide Children’s Hospital, Division of Genetic and Genomic MedicineUCL Great Ormond Street Institute of Child Health and Great Ormond Street Hospital for Children NHS Foundation TrustFaculty of Medicine, The Hebrew UniversityInstitute of Neurogenomics, Helmholtz Zentrum MünchenInstitute of Neurogenomics, Helmholtz Zentrum MünchenRegenerative Medicine in Cardiovascular Diseases, First Department of Medicine, TUM University Hospital, Klinikum Rechts der Isar, Technical University of Munich, School of Medicine and HealthRegenerative Medicine in Cardiovascular Diseases, First Department of Medicine, TUM University Hospital, Klinikum Rechts der Isar, Technical University of Munich, School of Medicine and HealthRegenerative Medicine in Cardiovascular Diseases, First Department of Medicine, TUM University Hospital, Klinikum Rechts der Isar, Technical University of Munich, School of Medicine and HealthCenter for Functional Genomics of Microbes, Abteilung Molekulare GenetikInstitute of Structural Biology, Molecular Targets and Therapeutics Center, Helmholtz Zentrum MünchenDepartment of Biomedical Sciences of Cells and Systems, University Medical Center Groningen, University of GroningenDepartment of Molecular and Translational Medicine, University of BresciaThe Children’s Hospital of Philadelphia, Division of Human GeneticsThe Children’s Hospital of Philadelphia, Division of Human GeneticsNationwide Children’s Hospital, Division of Genetic and Genomic MedicineNationwide Children’s Hospital, Division of CardiologyDivision of Cardiology, Department of Medicine, The Ohio State University Wexner Medical CenterUCL Great Ormond Street Institute of Child Health and Great Ormond Street Hospital for Children NHS Foundation TrustUCL Great Ormond Street Institute of Child Health and Great Ormond Street Hospital for Children NHS Foundation TrustFaculty of Medicine, The Hebrew UniversityFaculty of Medicine, The Hebrew UniversityRegenerative Medicine in Cardiovascular Diseases, First Department of Medicine, TUM University Hospital, Klinikum Rechts der Isar, Technical University of Munich, School of Medicine and HealthRegenerative Medicine in Cardiovascular Diseases, First Department of Medicine, TUM University Hospital, Klinikum Rechts der Isar, Technical University of Munich, School of Medicine and HealthAbstract 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.https://doi.org/10.1038/s43856-025-01017-z |
| spellingShingle | Fangfang Zhang Tatjana Dorn Barbara Gnutti Yair Anikster Sarah Kuebler Rebecca Ahrens-Nicklas Rachel Gosselin Shamima Rahman Ronen Durst Enrica Zanuttigh Miriam A. Güra Christine M. Poch Anna B. Meier Karl-Ludwig Laugwitz Hans-Joachim Schüller Ana C. Messias Ody C. Sibon Dario Finazzi Alyssa Rippert Dong Li Kristen Truxal Deipanjan Nandi Brent C. Lampert Mildrid Yeo Alice Gardham Batel Nissan Smadar Horowitz Cederboim Alessandra Moretti Arcangela Iuso Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models Communications Medicine |
| title | Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models |
| title_full | Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models |
| title_fullStr | Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models |
| title_full_unstemmed | Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models |
| title_short | Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models |
| title_sort | pantethine ameliorates dilated cardiomyopathy features in ppcs deficiency disorder in patients and cell line models |
| url | https://doi.org/10.1038/s43856-025-01017-z |
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