Mutations in PPCS, Encoding Phosphopantothenoylcysteine Synthetase, Cause Autosomal-Recessive Dilated Cardiomyopathy
| Autor: | Arcangela Iuso, Nicola A. Grzeschik, Holger Prokisch, Iris Barshack, Muhamad Kumbar, Bart Kanon, Thomas Schwarzmayr, Gal Dubnov-Raz, Dorothea Haas, Riccardo Berutti, Bader Alhaddad, Marit Wiersma, Zeev Perles, Ben Pode-Shakked, Georg F. Hoffmann, Mathias Grigat, Tal Tirosh, Caterina Terrile, Elisa Mastantuono, Tim M. Strom, Jürgen G. Okun, Marina Rubinshtein, Matthias C. Braunisch, Yair Anikster, Shachar Abudi, Camilla Avivi, Ana C. Messias, Amir Vardi, Brundel Bianca Johanna Josephina Maria, Ody C. M. Sibon, Eran Eyal, Dina Marek-Yagel, Tobias B. Haack, Yishay Salem, Thomas Meitinger, A Volkov, Ortal Barel, Hans Joachim Schüller |
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| Přispěvatelé: | Molecular Neuroscience and Ageing Research (MOLAR), Movement Disorder (MD), Physiology, ACS - Heart failure & arrhythmias |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine Neurodegeneration with brain iron accumulation COENZYME-A SYNTHESIS chemistry.chemical_compound 0302 clinical medicine Enzyme Stability PANTETHINE RESCUES Phosphopantothenoylcysteine synthetase Peptide Synthases Genetics (clinical) Exome sequencing 2. Zero hunger chemistry.chemical_classification biology Coenzyme A Dilated Cardiomyopathy Pantethine Treatment Pentothenate Phospohopantothenoylcysteine Synthetase Ppcs Pantethine Homozygote Neurodegeneration NEURODEGENERATION High-Throughput Nucleotide Sequencing Heart Magnetic Resonance Imaging Pedigree Biochemistry ESCHERICHIA-COLI Child Preschool Pantetheine Drosophila Female PROTEIN-STRUCTURE Cardiomyopathy Dilated COA Genes Recessive Saccharomyces cerevisiae Article Cofactor 03 medical and health sciences BRAIN IRON ACCUMULATION Carnitine Genetics medicine Animals Humans Amino Acid Sequence MACROMOLECULES Demography Infant Newborn Infant Reproducibility of Results Fibroblasts medicine.disease Biosynthetic Pathways SWISS-MODEL 030104 developmental biology Enzyme chemistry Mutation biology.protein SYSTEM 030217 neurology & neurosurgery |
| Zdroj: | American Journal of Human Genetics, 102(6), 1018-1030. CELL PRESS Am. J. Hum. Genet. 102, 1018-1030 (2018) The American Journal of Human Genetics 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 2018, ' Mutations in PPCS, Encoding Phosphopantothenoylcysteine Synthetase, Cause Autosomal-Recessive Dilated Cardiomyopathy ', American journal of human genetics, vol. 102, no. 6, pp. 1018-1030 . https://doi.org/10.1016/j.ajhg.2018.03.022 American journal of human genetics, 102(6), 1018-1030. Cell Press |
| ISSN: | 0002-9297 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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