Functional cellular analyses reveal energy metabolism defect and mitochondrial DNA depletion in a case of mitochondrial aconitase deficiency
| Autor: | Emanuele Barca, Darryl C. De Vivo, Ali Naini, Salvatore DiMauro, Brett H. Graham, Ruchi Masand, Neil A. Hanchard, Taraka R. Donti, Roa Sadat |
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| Rok vydání: | 2016 |
| Předmět: |
Male
0301 basic medicine Mitochondrial DNA Cellular respiration Endocrinology Diabetes and Metabolism Citric Acid Cycle Mutation Missense Biology Compound heterozygosity DNA Mitochondrial Biochemistry Aconitase Article 03 medical and health sciences Mitochondrial aconitase deficiency MtDNA depletion Neurodegenerative disease TCA cycle Whole exome sequencing Molecular Biology Genetics Endocrinology Humans Exome Gene Exome sequencing Aconitate Hydratase Regulation of gene expression High-Throughput Nucleotide Sequencing ACO2 Neuromuscular Diseases 030104 developmental biology Gene Expression Regulation Child Preschool Metabolism Inborn Errors |
| Zdroj: | Molecular Genetics and Metabolism. 118:28-34 |
| ISSN: | 1096-7192 |
| DOI: | 10.1016/j.ymgme.2016.03.004 |
| Popis: | Defects in the tricaboxylic acid cycle (TCA) are associated with a spectrum of neurological phenotypes that are often difficult to diagnose and manage. Whole-exome sequencing (WES) led to a rapid expansion of diagnostic capabilities in such disorders and facilitated a better understanding of disease pathogenesis, although functional characterization remains a bottleneck to the interpretation of potential pathological variants. We report a 2-year-old boy of Afro-Caribbean ancestry, who presented with neuromuscular symptoms without significant abnormalities on routine diagnostic evaluation. WES revealed compound heterozygous missense variants of uncertain significance in mitochondrial aconitase (ACO2), which encodes the TCA enzyme ACO2. Pathogenic variants in ACO2 have been described in a handful of families as the cause of infantile cerebellar-retinal degeneration syndrome. Using biochemical and cellular assays in patient fibroblasts, we found that ACO2 expression was quantitatively normal, but ACO2 enzyme activity was less than 20% of that observed in control cells. We also observed a deficiency in cellular respiration and, for the first time, demonstrate evidence of mitochondrial DNA depletion and altered expression of some TCA components and electron transport chain subunits. The observed cellular defects were completely restored with ACO2 gene rescue. Our findings demonstrate the pathogenicity of two VUS in ACO2, provide novel mechanistic insights to TCA disturbances in ACO2 deficiency, and implicate mitochondrial DNA depletion in the pathogenesis of this recently described disorder. |
| Databáze: | OpenAIRE |
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