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

Iuso, A., Wiersma, M., Schüller, H-J., Pode-Shakked, B., Marek-Yagel, D., Grigat, M., Schwarzmayr, T., Berutti, R., Alhaddad, B., Kanon, B., Grzeschik, N. A., Okun, J. G., Perles, Z., Salem, Y., Barel, O., Vardi, A., Rubinshtein, M., Tirosh, T., Dubnov-Raz, G., Messias, A. C., Terrile, C., Barshack, I., Volkov, A., Avivi, C., Eyal, E., Mastantuono, E., Kumbar, M., Abudi, S., Braunisch, M., Strom, T. M., Meitinger, T., Hoffmann, G. F., Prokisch, H., Haack, T. B., Brundel, B. J. J. M., Haas, D., Sibon, O. C. M. & Anikster, Y., 7-Jun-2018, In : American Journal of Human Genetics. 102, 6, p. 1018-1030 13 p.

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

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DOI

  • Arcangela Iuso
  • Marit Wiersma
  • Hans-Joachim Schüller
  • Ben Pode-Shakked
  • Dina Marek-Yagel
  • Mathias Grigat
  • Thomas Schwarzmayr
  • Riccardo Berutti
  • Bader Alhaddad
  • Bart Kanon
  • Nicola A Grzeschik
  • Jürgen G Okun
  • Zeev Perles
  • Yishay Salem
  • Ortal Barel
  • Amir Vardi
  • Marina Rubinshtein
  • Tal Tirosh
  • Gal Dubnov-Raz
  • Ana C Messias
  • Caterina Terrile
  • Iris Barshack
  • Alex Volkov
  • Camilla Avivi
  • Eran Eyal
  • Elisa Mastantuono
  • Muhamad Kumbar
  • Shachar Abudi
  • Matthias Braunisch
  • Tim M Strom
  • Thomas Meitinger
  • Georg F Hoffmann
  • Holger Prokisch
  • Tobias B Haack
  • Bianca J J M Brundel
  • Dorothea Haas
  • Ody C M Sibon
  • Yair Anikster

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.

Original languageEnglish
Pages (from-to)1018-1030
Number of pages13
JournalAmerican Journal of Human Genetics
Volume102
Issue number6
Publication statusPublished - 7-Jun-2018

    Keywords

  • SYSTEM, COA, BRAIN IRON ACCUMULATION, COENZYME-A SYNTHESIS, PROTEIN-STRUCTURE, SWISS-MODEL, PANTETHINE RESCUES, ESCHERICHIA-COLI, NEURODEGENERATION, MACROMOLECULES

ID: 60270999