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Am J Hum Genet. 2014 Jan 2;94(1):11-22. doi: 10.1016/j.ajhg.2013.11.008. Epub 2013 Dec 19.

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

Author information

1
Unit of Molecular Neurogenetics - Pierfranco and Luisa Mariani Center for the study of Mitochondrial Disorders in Children, IRCCS Foundation Neurological Institute "C. Besta," 20126 Milan, Italy.
2
Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany; Institute of Human Genetics, Helmholtz Zentrum München, 85764 Munich, Germany.
3
Institute of Structural and Molecular Biology, University College London, London WC1E 6BT, UK.
4
Crystallography Unit, Department of Experimental Oncology, European Institute of Oncology, IFOM-IEO Campus, 20139 Milan, Italy.
5
Department of Life Sciences, University of Parma, 43124 Parma, Italy.
6
Institute of Human Genetics, Helmholtz Zentrum München, 85764 Munich, Germany.
7
Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR 97329, USA.
8
UCL Institute of Neurology and The National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK.
9
Unit of Neuroradiology, IRCCS Foundation Neurological Institute "C. Besta," 20133 Milan, Italy.
10
Unit of Child Neurology, IRCCS Foundation Neurological Institute "C. Besta," 20133 Milan, Italy.
11
Neurosciences Unit, UCL-Institute of Child Health, Great Ormond Street Hospital, London WC1N 3JH, UK; Department of Neurology, Great Ormond Street Hospital, London WC1N 3JH, UK.
12
Unit of Molecular Neurogenetics - Pierfranco and Luisa Mariani Center for the study of Mitochondrial Disorders in Children, IRCCS Foundation Neurological Institute "C. Besta," 20126 Milan, Italy. Electronic address: tiranti@istituto-besta.it.

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.

PMID:
24360804
PMCID:
PMC3882905
DOI:
10.1016/j.ajhg.2013.11.008
[Indexed for MEDLINE]
Free PMC Article
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