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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.

SUBMITTER: Iuso A 

PROVIDER: S-EPMC5992122 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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

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

American journal of human genetics 20180510 6


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 b  ...[more]

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