Mutations in the tricarboxylic acid cycle enzyme, aconitase 2, cause either isolated or syndromic optic neuropathy with encephalopathy and cerebellar atrophy
| Autor: | Marlène Rio, Jean-Michel Rozet, Agnès Delahodde, Metodi D. Metodiev, Patrizia Amati-Bonneau, Laurence Hubert, Marie-Christine Giacomotto, Nathalie Boddaert, Sylvie Gerber, Xavier Gérard, Josseline Kaplan, Anna Kaminska, Agnès Rötig, Isabelle Desguerre, Claude Besmond, Arnold Munnich, Jeanne Amiel, Dominique Chretien |
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| Rok vydání: | 2014 |
| Předmět: |
Adult
Male Nuclear gene Citric Acid Cycle Gene Expression Genes Recessive Biology Compound heterozygosity Frameshift mutation Optic neuropathy Fatal Outcome Optic Nerve Diseases Genetics medicine Humans Exome Genetics (clinical) Exome sequencing Aconitate Hydratase Ophthalmoscopes Siblings Brain High-Throughput Nucleotide Sequencing ACO2 medicine.disease Magnetic Resonance Imaging Respiratory enzyme Enzyme Activation Patient Outcome Assessment Optic Atrophy mitochondrial fusion Child Preschool Mutation Female |
| Zdroj: | Journal of Medical Genetics. 51:834-838 |
| ISSN: | 1468-6244 0022-2593 |
| DOI: | 10.1136/jmedgenet-2014-102532 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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