Mutations in the tricarboxylic acid cycle enzyme, aconitase 2, cause either isolated or syndromic optic neuropathy with encephalopathy and cerebellar atrophy. Issue 12 (28th October 2014)

• Record Type: Journal Article
• Authors: Metodiev, Metodi Dimitrov; Gerber, Sylvie; Hubert, Laurence; Delahodde, Agnès; Chretien, Dominique; Gérard, Xavier; Amati-Bonneau, Patrizia; Giacomotto, Marie-Christine; Boddaert, Nathalie; Kaminska, Anna; Desguerre, Isabelle; Amiel, Jeanne; Rio, Marlène; Kaplan, Josseline; Munnich, Arnold; Rötig, Agnès; Rozet, Jean Michel; Besmond, Claude
• Is Part Of: Journal of medical genetics. Volume 51:Issue 12(2014)
• Page Start: 834
• Page End: 838
• Publication Date: 2014-10-28
• Subjects: Ophthalmology -- Genetics -- Genome-wide -- Metabolic disorders -- Neurology; Medical genetics -- Periodicals; 616.042
• DOI: 10.1136/jmedgenet-2014-102532
• Languages: English
• ISSNs: 1468-6244

Abstract

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.