La revue scientifique BRAIN consacrée à la neurologie publie un article rédigé par l'équipe de recherche sur les mitochondries du CHU d'Angers (MITOLAB), suite au projet de recherche lancé en 2020 avec le soutien de l'association ACO2 GENE.
La première publication d'ampleur sur ACO2, qui recense 61 patients
En criblant des cohortes européennes d'individus présentant des neuropathies optiques héréditaires non résolues génétiquement, Charif et al. rapportent 61 nouveaux cas hébergeant des variants de l'ACO2, dont 50 avec des mutations dominantes, soulignant pour la première fois la contribution importante des variants pathogènes monoalléliques de l'ACO2 à l'atrophie optique dominante.
By screening European cohorts of individuals with genetically unsolved inherited optic neuropathies, Charif et al. report 61 new cases harboring variants in ACO2, among whom 50 with dominant mutations, emphasizing for the first time the important contribution of ACO2 monoallelic pathogenic variants to dominant optic atrophy.
Funding: We are indebted to the financial support of the Université d’Angers, Centre Hospitalier Universitaire d’Angers, the Region Pays de la Loire, Angers Loire Metropole, the Fondation Maladies Rares, Fondation pour la Recherche Me´dicale, Retina France, Union Nationale des Aveugles et Déficients Visuels, Association Française contre les Myopathies, Ouvrir Les Yeux, KjerFrance, Association ACO2 Gène, Fondation de France and the Fondation VISIO.
Summary:
Biallelic mutations in ACO2, encoding the mitochondrial aconitase 2, have been identified in individuals with neurodegenerative syndromes, including infantile cerebellar retinal degeneration and recessive optic neuropathies (locus OPA9). By screening European cohorts of individuals with genetically unsolved inherited optic neuropathies, we identified 61 cases harbouring variants in ACO2, among whom 50 carried dominant mutations, emphasizing for the first time the important contribution of ACO2 monoallelic pathogenic variants to dominant optic atrophy. Analysis of the ophthalmological and clinical data revealed that recessive cases are affected more severely than dominant cases, while not significantly earlier. In addition, 27% of the recessive cases and 11% of the dominant cases manifested with extraocular features in addition to optic atrophy. In silico analyses of ACO2 variants predicted their deleterious impacts on ACO2 biophysical properties. Skin derived fibroblasts from patients harbouring dominant and recessive ACO2 mutations revealed a reduction of ACO2 abundance and enzymatic activity, and the impairment of the mitochondrial respiration using citrate and pyruvate as substrates, while the addition of other Krebs cycle intermediates restored a normal respiration, suggesting a possible short-cut adaptation of the tricarboxylic citric acid cycle. Analysis of the mitochondrial genome abundance disclosed a significant reduction of the mitochondrial DNA amount in all ACO2 fibroblasts. Overall, our data position ACO2 as the third most frequently mutated gene in autosomal inherited optic neuropathies, after OPA1 and WFS1, and emphasize the crucial involvement of the first steps of the Krebs cycle in the maintenance and survival of retinal ganglion cells.
Lien vers l'abstract de la publication sur le site web de Brain: https://doi.org/10.1093/braincomms/fcab063
« Avec cette publication, nos efforts et nos travaux de recherche sur le gène ACO2 sont récompensés ». Guy Lenaers I CHU Angers - MITOLAB
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Keywords: ACO2, aconitase 2, mitochondria, krebs cycle, optic neuropathy