Mutations in PPCS, Encoding Phosphopantothenoylcysteine Synthetase, Cause Autosomal-Recessive Dilated Cardiomyopathy

  • Am J Hum Genet. 2018 Jun 7;102(6):1018-1030. doi: 10.1016/j.ajhg.2018.03.022.
Arcangela Iuso  1 ,  Marit Wiersma  2 ,  Hans-Joachim Schüller  3 ,  Ben Pode-Shakked  4 ,  Dina Marek-Yagel  5 ,  Mathias Grigat  3 ,  Thomas Schwarzmayr  6 ,  Riccardo Berutti  7 ,  Bader Alhaddad  8 ,  Bart Kanon  9 ,  Nicola A Grzeschik  9 ,  Jürgen G Okun  10 ,  Zeev Perles  11 ,  Yishay Salem  12 ,  Ortal Barel  13 ,  Amir Vardi  14 ,  Marina Rubinshtein  15 ,  Tal Tirosh  12 ,  Gal Dubnov-Raz  16 ,  Ana C Messias  17 ,  Caterina Terrile  6 ,  Iris Barshack  18 ,  Alex Volkov  18 ,  Camilla Avivi  18 ,  Eran Eyal  19 ,  Elisa Mastantuono  6 ,  Muhamad Kumbar  20 ,  Shachar Abudi  5 ,  Matthias Braunisch  21 ,  Tim M Strom  6 ,  Thomas Meitinger  1 ,  Georg F Hoffmann  10 ,  Holger Prokisch  6 ,  Tobias B Haack  22 ,  Bianca J J M Brundel  2 ,  Dorothea Haas  23 ,  Ody C M Sibon  9 ,  Yair Anikster  24
Affiliations
  • 1. Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany; Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany; DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, 80802 Munich, Germany.
  • 2. Department of Physiology, Amsterdam Cardiovascular Sciences, VUmc, 1081 HZ Amsterdam, the Netherlands.
  • 3. Institut für Genetik und Funktionelle Genomforschung, Ernst-Moritz-Arndt Universität, 17489 Greifswald, Germany.
  • 4. Metabolic Disease Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, 52621 Tel-Hashomer, Israel; The Dr. Pinchas Borenstein Talpiot Medical Leadership Program, Sheba Medical Center, 52621 Tel-Hashomer, Israel; Sackler Faculty of Medicine, Tel-Aviv University, 6997801 Tel-Aviv, Israel.
  • 5. Metabolic Disease Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, 52621 Tel-Hashomer, Israel; Sackler Faculty of Medicine, Tel-Aviv University, 6997801 Tel-Aviv, Israel.
  • 6. Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany; Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
  • 7. Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
  • 8. Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany.
  • 9. Department of Cell Biology, University of Groningen, University Medical Center Groningen, 9713 AV Groningen, the Netherlands.
  • 10. Division of Neuropediatrics and Metabolic Medicine, University Children's Hospital, 69120 Heidelberg, Germany.
  • 11. Department of Pediatric Cardiology, Hadassah-Hebrew University Medical Center, 91120 Jerusalem, Israel.
  • 12. Sackler Faculty of Medicine, Tel-Aviv University, 6997801 Tel-Aviv, Israel; Pediatric Cardiology Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, 52621 Tel-Hashomer, Ramat Gan, Israel.
  • 13. Sackler Faculty of Medicine, Tel-Aviv University, 6997801 Tel-Aviv, Israel; Sheba Cancer Research Center, Sheba Medical Center, 52621 Tel-Hashomer, Israel.
  • 14. Sackler Faculty of Medicine, Tel-Aviv University, 6997801 Tel-Aviv, Israel; Department of Pediatric Cardiac Intensive Care, Edmond Safra International Congenital Heart Center, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, 52621 Tel-Hashomer, Israel.
  • 15. Department of Pediatric Critical Care Medicine, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, 52621 Tel-Hashomer, Israel.
  • 16. Sackler Faculty of Medicine, Tel-Aviv University, 6997801 Tel-Aviv, Israel; Exercise, Nutrition and Lifestyle clinic, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, 52621 Tel-Hashomer, Israel.
  • 17. Institute of Structural Biology, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Center for Integrated Protein Science Munich at Biomolecular NMR Spectroscopy, Department Chemistry, Technische Universität München, 85747 Garching, Germany.
  • 18. Sackler Faculty of Medicine, Tel-Aviv University, 6997801 Tel-Aviv, Israel; Department of Pathology, Sheba Medical Center, 52621 Tel-Hashomer, Israel.
  • 19. Sheba Cancer Research Center, Sheba Medical Center, 52621 Tel-Hashomer, Israel.
  • 20. Clalit Health Services, 93133 Jerusalem, Israel.
  • 21. Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany; Department of Nephrology, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany.
  • 22. Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany; Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Institute of Medical Genetics and Applied Genomics, University of Tübingen, 72076 Tübingen, Germany.
  • 23. Division of Neuropediatrics and Metabolic Medicine, University Children's Hospital, 69120 Heidelberg, Germany. Electronic address: [email protected].
  • 24. Metabolic Disease Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, 52621 Tel-Hashomer, Israel; Sackler Faculty of Medicine, Tel-Aviv University, 6997801 Tel-Aviv, Israel; The Wohl Institute for Translational Medicine, Sheba Medical Center, 52621 Tel-Hashomer, Israel. Electronic address: [email protected].
PMID: 29754768 DOI: 10.1016/j.ajhg.2018.03.022
Abstract

Coenzyme A (CoA) is an essential metabolic cofactor used by around 4% of cellular Enzymes. Its role is to carry and transfer acetyl and acyl groups to Other molecules. Cells can synthesize CoA de novo from vitamin B5 (pantothenate) through five consecutive enzymatic steps. Phosphopantothenoylcysteine synthetase (PPCS) catalyzes the second step of the pathway during which phosphopantothenate reacts with ATP and cysteine to form phosphopantothenoylcysteine. Inborn errors of CoA biosynthesis have been implicated in neurodegeneration with brain iron accumulation (NBIA), a group of rare neurological disorders characterized by accumulation of iron in the basal ganglia and progressive neurodegeneration. Exome Sequencing in five individuals from two unrelated families presenting with dilated cardiomyopathy revealed biallelic mutations in PPCS, linking CoA synthesis with a cardiac phenotype. Studies in yeast and fruit flies confirmed the pathogenicity of identified mutations. Biochemical analysis revealed a decrease in CoA levels in fibroblasts of all affected individuals. CoA biosynthesis can occur with pantethine as a source independent from PPCS, suggesting pantethine as targeted treatment for the affected individuals still alive.

Keywords
PPCS; coenzyme A; dilated cardiomyopathy; pantethine treatment; pentothenate; phospohopantothenoylcysteine synthetase.