Pathogenic variants of the coenzyme A biosynthesis-associated enzyme phosphopantothenoylcysteine decarboxylase cause autosomal-recessive dilated cardiomyopathy
Entity
UAM. Departamento de Biología MolecularPublisher
WileyDate
2022-12-23Citation
10.1002/jimd.12584
Journal of Inherited Metabolic Disease (2023): 1-12
ISSN
0141-8955DOI
10.1002/jimd.12584Funded by
Consejería de Educaci on, Juventud y Deporte, Comunidad de Madrid, Grant/Award Number: B2017/BMD3721; Instituto de Salud Carlos III, Grant/Award Number: PI19/01155; Ministerio de Economía, Industria y Competitividad, Grant/Award Number: BFU2017-82574-PProject
Gobierno de España. PI19/01155; Gobierno de España. BFU2017-82574-PEditor's Version
https://doi.org/10.1002/jimd.12584Subjects
Biosynthesis of coenzyme A; Dilated cardiomyopathy; Inborn errors of metabolism; PPCDC; Biología y Biomedicina / BiologíaAbstract
Coenzyme A (CoA) is an essential cofactor involved in a range of metabolic
pathways including the activation of long-chain fatty acids for catabolism.
Cells synthesize CoA de novo from vitamin B5 (pantothenate) via a pathway
strongly conserved across prokaryotes and eukaryotes. In humans, it involves
five enzymatic steps catalyzed by four enzymes: pantothenate kinase (PANK
[isoforms 1–4]), 40
-phosphopantothenoylcysteine synthetase (PPCS), phosphopantothenoylcysteine decarboxylase (PPCDC), and CoA synthase (COASY). To
date, inborn errors of metabolism associated with all of these genes, except
PPCDC, have been described, two related to neurodegeneration with brain iron
accumulation (NBIA), and one associated with a cardiac phenotype. This
paper reports another defect in this pathway (detected in two sisters), associated with a fatal cardiac phenotype, caused by biallelic variants (p.Thr53Pro
and p.Ala95Val) of PPCDC. PPCDC enzyme (EC 4.1.1.36) catalyzes the decarboxylation of 40
-phosphopantothenoylcysteine to 40
-phosphopantetheine in
CoA biosynthesis. The variants p.Thr53Pro and p.Ala95Val affect residues
highly conserved across different species; p.Thr53Pro is involved in the binding
of flavin mononucleotide, and p.Ala95Val is likely a destabilizing mutation.
Patient-derived fibroblasts showed an absence of PPCDC protein, and nearly
50% reductions in CoA levels. The cells showed clear energy deficiency problems, with defects in mitochondrial respiration, and mostly glycolytic ATP
synthesis. Functional studies performed in yeast suggest these mutations to be functionally relevant. In summary, this work describes a new, ultra-rare,
severe inborn error of metabolism due to pathogenic variants of PPCDC
Files in this item
Google Scholar:Bravo Alonso, Irene
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Morin, Matías
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Arribas Carreira, Laura
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Álvarez, Mar
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Pedrón Giner, Consuelo
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Soletto, Lucia
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Santolaria, Carlos
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Ramón Maiques, Santiago
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Ugarte, Magdalena
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Rodríguez Pombo, Pilar
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Ariño, Joaquín
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Moreno Pelayo, Miguel Ángel
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Pérez González, María Belén
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