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

Abstract

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.

A Homozygous Splice Site Mutation in SLC25A42, Encoding the Mitochondrial Transporter of Coenzyme A, Causes Metabolic Crises and Epileptic Encephalopathy

“…However, the decrease in cellular CoA suggests pantethine as possible treatment for SLC25S42-affected individuals. In fact, pantethine supplementation replenished CoA levels and improved the phenotype in a Drosophila model of PKAN (PANK2-associated neurodegeneration) presenting with reduced levels of CoA and neurodegeneration (Rana et al 2010) and rescued the viability in a Drosophila model of PPCS deficiency (Iuso et al 2018).…”

“…These include the biosynthesis of fatty acids, ketone bodies, and cholesterol, amino acid metabolism, fatty acid oxidation, biosynthesis neurotransmitter acetylcholine, and acetylation of histones and regulation of gene expression. Defects within three of the five enzymatic steps involved in CoA biosynthesis have been linked both to childhood-onset forms of neurodegeneration with brain iron accumulation (PANK2, COASY) (Dusi et al 2014;Bosveld et al 2008) and to dilated cardiomyopathy with no neurodegeneration (PPCS) (Iuso et al 2018).…”

Homozygous damaging SOD2 variant causes lethal neonatal dilated cardiomyopathy

“…In contrast, exome sequencing (ES) (or genome sequencing) provides a powerful platform for novel disease gene discovery, particularly in congenital or neonatal cardiomyopathy. Successful application of ES to identify novel pathogenic variants in paediatric DCM has been recently demonstrated 13–17…”

Molecular genetic basis of sudden cardiac death in the young with cardiomyopathy of various origins

“…A. Iuso и соавт. [34] обратили внимание, что мутация в гене PPCS (кодирует фосфопантотеноил-цистеинсинтазу) вызывает аутосомно-рецессивно наследуемую ДКМП. По мнению этих авторов, необходимо больше генетических данных для выявления наиболее важных генетических мутаций, связанных с ДКМП.…”

“…Установлено, что мутации в кодировании других генов основных компонентов десмосомы вызывает АКМППЖ, включая десмоплакин (DSP), плакофилин-2 (PKP2), десмоглин-2 (DSG2) и десмоколлин-2 (DSC2) [31][32][33][34][35][36][37][38][39][40][41][42]. Десмосомы представляют собой сложные структуры, состоящие из белков, ответственных за клеточную адгезию и распространение сигналов в клетках.…”