Mutations in Phosphopantothenoylcystein Synthetase (PPCS) Cause Dilated Cardiomyopathy

בן פודה-שקד ^1,2,3 Arcangela Iuso ^4,5,6 Marit Wiersma ⁷ Hans-Joachim Schüller ⁸ Dina Marek-Yagel ^1,3 Zeev Perles ⁹ Yishay Salem ^3,10 Ortal Barel ^3,11 Amir Vardi ^3,12 Marina Rubinshtein ¹³ Tal Tirosh ^3,10 Gal Dubnov-Raz ^3,14 Eran Eyal ¹¹ Muhamad Kumbar ¹⁵ Shachar Abudi ^1,3 Georg F Hoffmann ¹⁶ Holger Prokisch ^4,5 Tobias B Haack ^4,5,17 Bianca JJM Brundel ⁷ Dorothea Haas ¹⁶ Ody CM Sibon ¹⁸ Yair Anikster ^1,3

¹Metabolic Disease Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, 52621 Tel-Hashomer, Ramat Gan, Israel
²The Talpiot Medical Leadership Program, Sheba Medical Center, 52621 Tel-Hashomer, Ramat Gan, Israel
³Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
⁴Institute of Human Genetics, Technische Universität München, Munich, Germany
⁵Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany
⁶DZHK (German Centre for Cardiovascular Research), Partner site Munich Heart Alliance, Munich, Germany
⁷Department of Physiology, Amsterdam Cardiovascular Sciences, VUmc, 1081 HZ, Amsterdam, The Netherlands
⁸Institute für Genetik und Funktionelle Genomforschung, Ernst-Moritz-Arndt Universität, Greifswald, Germany
⁹Department of Pediatric Cardiology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
¹⁰Pediatric Cardiology Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, Ramat Gan, Israel
¹¹Sheba Cancer Research Center, Sheba Medical Center, Tel-Hashomer, Ramat Gan, Israel
¹²Department of Pediatric Cardiac Intensive Care, Edmond Safra International Congenital Heart Center, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, Ramat Gan, Israel
¹³Department of Pediatric Critical Care Medicine, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, Ramat Gan, Israel
¹⁴Exercise, Nutrition and Lifestyle clinic, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, Ramat Gan, Israel
¹⁵Clalit, Health Services, Jerusalem, Israel
¹⁶Division of Neuropediatrics and Metabolic Disease, University Children's Hospital, Heidelberg, Germany
¹⁷Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany
¹⁸Department of Cell Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

Coenzyme A (CoA) is an essential metabolic cofactor used by about 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. Phosphopantothenoylcystein synthetase (PPCS) catalyzes the second step of the pathway during which phosphopantothenate reacts with ATP and cysteine to form phosphopantothenoylcystein. 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 for the first time 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 individuals still alive.