Mutations in the tricarboxylic acid cycle enzyme, aconitase 2, cause either isolated or syndromic optic neuropathy with encephalopathy and cerebellar atrophy

  • J Med Genet. 2014 Dec;51(12):834-8. doi: 10.1136/jmedgenet-2014-102532.
Metodi Dimitrov Metodiev  1 ,  Sylvie Gerber  1 ,  Laurence Hubert  1 ,  Agnès Delahodde  2 ,  Dominique Chretien  1 ,  Xavier Gérard  1 ,  Patrizia Amati-Bonneau  3 ,  Marie-Christine Giacomotto  4 ,  Nathalie Boddaert  5 ,  Anna Kaminska  5 ,  Isabelle Desguerre  5 ,  Jeanne Amiel  5 ,  Marlène Rio  5 ,  Josseline Kaplan  1 ,  Arnold Munnich  6 ,  Agnès Rötig  1 ,  Jean Michel Rozet  1 ,  Claude Besmond  1
Affiliations
  • 1. UMR1163, Université Paris Descartes, Sorbonne Paris Cité, Institut IMAGINE, Paris, France.
  • 2. Institut de Génétique et Microbiologie UMR 8621, Université Paris-Sud, Orsay, France.
  • 3. Département de Biochimie et Génétique, CHU d'Angers, Angers, France.
  • 4. Service d'Ophtalmologie, Polyclinique du Maine, Laval, France.
  • 5. Departments of Pediatrics, Radiology and Genetics, Hôpital Necker-Enfants Malades, Paris, France.
  • 6. UMR1163, Université Paris Descartes, Sorbonne Paris Cité, Institut IMAGINE, Paris, France Departments of Pediatrics, Radiology and Genetics, Hôpital Necker-Enfants Malades, Paris, France.
PMID: 25351951 DOI: 10.1136/jmedgenet-2014-102532
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.

Keywords
Genetics; Genome-wide; Metabolic disorders; Neurology; Ophthalmology.