title: 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.
authors.affiliation: 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.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Dusi
authors.affiliation: 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.
authors.forename: Lorella
authors.initials: L
authors.lastname: Valletta
authors.affiliation: Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany; Institute of Human Genetics, Helmholtz Zentrum München, 85764 Munich, Germany.
authors.forename: Tobias B
authors.initials: TB
authors.lastname: Haack
authors.affiliation: Institute of Structural and Molecular Biology, University College London, London WC1E 6BT, UK.
authors.forename: Yugo
authors.initials: Y
authors.lastname: Tsuchiya
authors.affiliation: 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.
authors.forename: Paola
authors.initials: P
authors.lastname: Venco
authors.affiliation: Crystallography Unit, Department of Experimental Oncology, European Institute of Oncology, IFOM-IEO Campus, 20139 Milan, Italy.
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Pasqualato
authors.affiliation: Department of Life Sciences, University of Parma, 43124 Parma, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Goffrini
authors.affiliation: Department of Life Sciences, University of Parma, 43124 Parma, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Tigano
authors.affiliation: Institute of Structural and Molecular Biology, University College London, London WC1E 6BT, UK.
authors.forename: Nikita
authors.initials: N
authors.lastname: Demchenko
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München, 85764 Munich, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Wieland
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München, 85764 Munich, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Schwarzmayr
authors.affiliation: Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany; Institute of Human Genetics, Helmholtz Zentrum München, 85764 Munich, Germany.
authors.forename: Tim M
authors.initials: TM
authors.lastname: Strom
authors.affiliation: 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.
authors.forename: Federica
authors.initials: F
authors.lastname: Invernizzi
authors.affiliation: 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.
authors.forename: Barbara
authors.initials: B
authors.lastname: Garavaglia
authors.affiliation: Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR 97329, USA.
authors.forename: Allison
authors.initials: A
authors.lastname: Gregory
authors.affiliation: Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR 97329, USA.
authors.forename: Lynn
authors.initials: L
authors.lastname: Sanford
authors.affiliation: Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR 97329, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Hamada
authors.affiliation: UCL Institute of Neurology and The National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK.
authors.forename: Conceição
authors.initials: C
authors.lastname: Bettencourt
authors.affiliation: UCL Institute of Neurology and The National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK.
authors.forename: Henry
authors.initials: H
authors.lastname: Houlden
authors.affiliation: Unit of Neuroradiology, IRCCS Foundation Neurological Institute "C. Besta," 20133 Milan, Italy.
authors.forename: Luisa
authors.initials: L
authors.lastname: Chiapparini
authors.affiliation: Unit of Child Neurology, IRCCS Foundation Neurological Institute "C. Besta," 20133 Milan, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Zorzi
authors.affiliation: 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.
authors.forename: Manju A
authors.initials: MA
authors.lastname: Kurian
authors.affiliation: Unit of Child Neurology, IRCCS Foundation Neurological Institute "C. Besta," 20133 Milan, Italy.
authors.forename: Nardo
authors.initials: N
authors.lastname: Nardocci
authors.affiliation: Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany; Institute of Human Genetics, Helmholtz Zentrum München, 85764 Munich, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Prokisch
authors.affiliation: Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR 97329, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Hayflick
authors.affiliation: Institute of Structural and Molecular Biology, University College London, London WC1E 6BT, UK.
authors.forename: Ivan
authors.initials: I
authors.lastname: Gout
authors.affiliation: 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.
authors.forename: Valeria
authors.initials: V
authors.lastname: Tiranti
mesh_terms: D001921:Brain / Q000187:drug effects* / Q000473:pathology; D003001:Cloning, Molecular; D003065:Coenzyme A / Q000378:metabolism; D004926:Escherichia coli / Q000235:genetics; D059472:Exome; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D007501:Iron / Q000378:metabolism*; D008297:Male; D008928:Mitochondria / Q000201:enzymology / Q000235:genetics; D020125:Mutation, Missense; D009410:Nerve Degeneration / Q000473:pathology*; D010204:Pantetheine / Q000031:analogs & derivatives / Q000378:metabolism; D010375:Pedigree; D010766:Phosphorylation; D012441:Saccharomyces cerevisiae / Q000235:genetics; D014166:Transferases / Q000235:genetics / Q000378:metabolism
chemical_list: C015787:dephosphocoenzyme A; D010204:Pantetheine; D007501:Iron; D014166:Transferases; C509687:COASY protein, human; C003129:4'-phosphopantetheine; D003065:Coenzyme A