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Exome sequence reveals mutations in CoA synthase as a cause of neurodegeneration with brain iron accumulation.

ABSTRACT: Neurodegeneration with brain iron accumulation (NBIA) comprises a clinically and genetically heterogeneous group of disorders with progressive extrapyramidal signs and neurological deterioration, characterized by iron accumulation in the basal ganglia. Exome sequencing revealed the presence of recessive missense mutations in COASY, encoding coenzyme A (CoA) synthase in one NBIA-affected subject. A second unrelated individual carrying mutations in COASY was identified by Sanger sequence analysis. CoA synthase is a bifunctional enzyme catalyzing the final steps of CoA biosynthesis by coupling phosphopantetheine with ATP to form dephospho-CoA and its subsequent phosphorylation to generate CoA. We demonstrate alterations in RNA and protein expression levels of CoA synthase, as well as CoA amount, in fibroblasts derived from the two clinical cases and in yeast. This is the second inborn error of coenzyme A biosynthesis to be implicated in NBIA.

SUBMITTER: Dusi S

PROVIDER: S-EPMC3882905 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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Exome sequence reveals mutations in CoA synthase as a cause of neurodegeneration with brain iron accumulation.

Dusi Sabrina S Valletta Lorella L Haack Tobias B TB Tsuchiya Yugo Y Venco Paola P Pasqualato Sebastiano S Goffrini Paola P Tigano Marco M Demchenko Nikita N Wieland Thomas T Schwarzmayr Thomas T Strom Tim M TM Invernizzi Federica F Garavaglia Barbara B Gregory Allison A Sanford Lynn L Hamada Jeffrey J Bettencourt Conceição C Houlden Henry H Chiapparini Luisa L Zorzi Giovanna G Kurian Manju A MA Nardocci Nardo N Prokisch Holger H Hayflick Susan S Gout Ivan I Tiranti Valeria V

American journal of human genetics 20131219 1

Neurodegeneration with brain iron accumulation (NBIA) comprises a clinically and genetically heterogeneous group of disorders with progressive extrapyramidal signs and neurological deterioration, characterized by iron accumulation in the basal ganglia. Exome sequencing revealed the presence of recessive missense mutations in COASY, encoding coenzyme A (CoA) synthase in one NBIA-affected subject. A second unrelated individual carrying mutations in COASY was identified by Sanger sequence analysis. ...[more]

PMID: 24360804

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Project description:Coenzyme A (CoA), which is widely distributed and vital for cellular metabolism, is a critical molecule essential in both synthesizing and breaking down key energy sources in the body. Inborn errors of metabolism in the cellular de novo biosynthetic pathway of CoA have been linked to human genetic disorders, emphasizing the importance of this pathway. The COASY gene encodes the bifunctional enzyme CoA synthase, which catalyzes the last two reactions of the CoA biosynthetic pathway and serves as one of the rate-limiting components of the pathway. Recessive variants of this gene cause an exceptionally rare and devastating disease called COASY protein-associated neurodegeneration (CoPAN) while complete loss-of-function variants in COASY have been identified in fetuses/neonates with Pontocerebellar Hypoplasia type 12 (PCH 12). Understanding why the different symptoms emerge in these disorders and what determines the development of one syndrome over the other is still not achieved. To shed light on the pathogenesis, we generated a new conditional animal model in which Coasy was deleted under the control of the human GFAP promoter. We used this mouse model to investigate how defects in the CoA biosynthetic pathway affect brain development. This model showed a broad spectrum of severity of the in vivo phenotype, ranging from very short survival (less than 2 weeks) to normal life expectancy in some animals. Surviving mice displayed a behavioral phenotype with sensorimotor defects. Ex vivo histological analysis revealed variable but consistent cerebral and cerebellar cortical hypoplasia, in parallel with a broad astrocytic hyper-proliferation in the cerebral cortex. In addition, primary astrocytes derived from this model exhibited lipid peroxidation, iron dyshomeostasis, and impaired mitochondrial respiration. Notably, Coasy ablation in radial glia and astrocytic lineage triggers abnormal neuronal development and chronic neuroinflammation, offering new insights into disease mechanisms.

Dataset Information

Exome sequence reveals mutations in CoA synthase as a cause of neurodegeneration with brain iron accumulation.

Publications

Exome sequence reveals mutations in CoA synthase as a cause of neurodegeneration with brain iron accumulation.

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