title: Mutations in the tricarboxylic acid cycle enzyme, aconitase 2, cause either isolated or syndromic optic neuropathy with encephalopathy and cerebellar atrophy.
abstract: BACKGROUND
  Inherited optic neuropathy has been ascribed to mutations in mitochondrial fusion/fission dynamics genes, nuclear and mitochondrial DNA-encoded respiratory enzyme genes or nuclear genes of poorly known mitochondrial function. However, the disease causing gene remains unknown in many families.
  
  
  METHODS
  We used exome sequencing in order to identify the gene responsible for isolated or syndromic optic atrophy in five patients from three independent families.
  
  
  RESULTS
  We found homozygous or compound heterozygous missense and frameshift mutations in the gene encoding mitochondrial aconitase (ACO2), a tricarboxylic acid cycle enzyme, catalysing interconversion of citrate into isocitrate. Unlike wild type ACO2, all mutant ACO2 proteins failed to complement the respiratory growth of a yeast aco1-deletion strain. Retrospective studies using patient-derived cultured skin fibroblasts revealed various degrees of deficiency in ACO2 activity, but also in ACO1 cytosolic activity.
  
  
  CONCLUSIONS
  Our study shows that autosomal recessive ACO2 mutations can cause either isolated or syndromic optic neuropathy. This observation identifies ACO2 as the second gene responsible for non-syndromic autosomal recessive optic neuropathies and provides evidence for a genetic overlap between isolated and syndromic forms, giving further support to the view that optic atrophy is a hallmark of defective mitochondrial energy supply.
authors.affiliation: UMR1163, Université Paris Descartes, Sorbonne Paris Cité, Institut IMAGINE, Paris, France.
authors.forename: Metodi Dimitrov
authors.initials: MD
authors.lastname: Metodiev
authors.affiliation: UMR1163, Université Paris Descartes, Sorbonne Paris Cité, Institut IMAGINE, Paris, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Gerber
authors.affiliation: UMR1163, Université Paris Descartes, Sorbonne Paris Cité, Institut IMAGINE, Paris, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Hubert
authors.affiliation: Institut de Génétique et Microbiologie UMR 8621, Université Paris-Sud, Orsay, France.
authors.forename: Agnès
authors.initials: A
authors.lastname: Delahodde
authors.affiliation: UMR1163, Université Paris Descartes, Sorbonne Paris Cité, Institut IMAGINE, Paris, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Chretien
authors.affiliation: UMR1163, Université Paris Descartes, Sorbonne Paris Cité, Institut IMAGINE, Paris, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Gérard
authors.affiliation: Département de Biochimie et Génétique, CHU d'Angers, Angers, France.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Amati-Bonneau
authors.affiliation: Service d'Ophtalmologie, Polyclinique du Maine, Laval, France.
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Giacomotto
authors.affiliation: Departments of Pediatrics, Radiology and Genetics, Hôpital Necker-Enfants Malades, Paris, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Boddaert
authors.affiliation: Departments of Pediatrics, Radiology and Genetics, Hôpital Necker-Enfants Malades, Paris, France.
authors.forename: Anna
authors.initials: A
authors.lastname: Kaminska
authors.affiliation: Departments of Pediatrics, Radiology and Genetics, Hôpital Necker-Enfants Malades, Paris, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Desguerre
authors.affiliation: Departments of Pediatrics, Radiology and Genetics, Hôpital Necker-Enfants Malades, Paris, France.
authors.forename: Jeanne
authors.initials: J
authors.lastname: Amiel
authors.affiliation: Departments of Pediatrics, Radiology and Genetics, Hôpital Necker-Enfants Malades, Paris, France.
authors.forename: Marlène
authors.initials: M
authors.lastname: Rio
authors.affiliation: UMR1163, Université Paris Descartes, Sorbonne Paris Cité, Institut IMAGINE, Paris, France.
authors.forename: Josseline
authors.initials: J
authors.lastname: Kaplan
authors.affiliation: UMR1163, Université Paris Descartes, Sorbonne Paris Cité, Institut IMAGINE, Paris, France Departments of Pediatrics, Radiology and Genetics, Hôpital Necker-Enfants Malades, Paris, France.
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.affiliation: UMR1163, Université Paris Descartes, Sorbonne Paris Cité, Institut IMAGINE, Paris, France.
authors.forename: Agnès
authors.initials: A
authors.lastname: Rötig
authors.affiliation: UMR1163, Université Paris Descartes, Sorbonne Paris Cité, Institut IMAGINE, Paris, France.
authors.forename: Jean Michel
authors.initials: JM
authors.lastname: Rozet
authors.affiliation: UMR1163, Université Paris Descartes, Sorbonne Paris Cité, Institut IMAGINE, Paris, France.
authors.forename: Claude
authors.initials: C
authors.lastname: Besmond
mesh_terms: D000154:Aconitate Hydratase / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D001921:Brain / Q000473:pathology; D002675:Child, Preschool; D002952:Citric Acid Cycle; D004789:Enzyme Activation; D059472:Exome; D017809:Fatal Outcome; D005260:Female; D015870:Gene Expression; D005808:Genes, Recessive; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D009154:Mutation; D019721:Ophthalmoscopes; D009896:Optic Atrophy / Q000175:diagnosis / Q000235:genetics; D009901:Optic Nerve Diseases / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D063868:Patient Outcome Assessment; D035781:Siblings
chemical_list: C476079:ACO2 protein, human; D000154:Aconitate Hydratase
keywords: Genetics; Genome-wide; Metabolic disorders; Neurology; Ophthalmology