Pathogenic variants of the coenzyme A biosynthesis‐associated enzyme phosphopantothenoylcysteine decarboxylase cause autosomal‐recessive dilated cardiomyopathy

Abstract

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]), 4 0 -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 4 0 -phosphopantothenoylcysteine to 4 0 -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

Emerging variants, unique phenotypes, and transcriptomic signatures: an integrated study of COASY‐associated diseases

“…35 On the contrary, total CoA levels were found significantly decreased in fibroblasts derived from subjects harboring variants in both phosphopantothenoylcysteine synthetase (PPCS) and phosphopantothenoylcysteine decarboxylase (PPCDC), which catalyze the second and third steps of CoA de novo biosynthesis, respectively. 29,36 At present, we are not entirely clear why CoA levels are normal in fibroblasts derived from COASY patients. The first hypothesis could be related to the residual activity of the COASY protein.…”

Inherited Disorders of Coenzyme A Biosynthesis: Models, Mechanisms, and Treatments

“…Patient-derived fibroblasts showed a complete absence of the PPCDC protein, intracellular CoA levels of about 50% of healthy controls, and defects in mitochondrial respiration. Moreover, the evaluations conducted in yeast confirmed the pathogenicity of the variants [ 8 ].…”

“…They presented fatal dilated cardiomyopathy, as well as lactic acidosis, elevated creatine kinase, hyperammoniemia, liver disease, and a neurological involvement with lethargy and limbs’ hypertonia. The echocardiographic evaluation showed a systolic dysfunction and a decrease in ejection fraction that result quickly in fatal outcomes [ 8 ]. Biochemical analysis in body fluids revealed hypoglycemia, ketonuria, alanine elevation, urinary excretion of dicarboxylic acids, and increased levels of long-chain acylcarnitine in plasma samples, all suggestive of a defect in fatty acid oxidation (FAO) or mitochondrial disease [ 8 ].…”

“…Subsequently, three of the six PPCS patients reported having received oral pantetheine supplementation, but with contrasting and unclear results due to the severity of the phenotype and the treatment’s late introduction [ 6 , 7 ]. The use of pantethine in one PPCDC patient has provided encouraging indications [ 8 ]. The effectiveness of pantethine was observed also in a model of Escherichia coli in which the gene coaBC , which encodes a bifunctional protein that has PPCS and PPCDC function, was deleted [ 122 ].…”

“…A few years ago, a rapidly fatal dilated cardiomyopathy was linked to pathogenic variants in the second enzyme of the pathway (phosphopantothenoylcysteine synthetase, PPCS) with the discovery of three affected families [ 6 , 7 ]. Very recently, variants in the third enzyme of the pathway (phosphopantothenoylcysteine decarboxylase, PPCDC) were associated with a similar cardiac condition in two sisters [ 8 ].…”