Functional cellular analyses reveal energy metabolism defect and mitochondrial DNA depletion in a case of mitochondrial aconitase deficiency
Open accessAbstract
Defects in the tricarboxylic 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 <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.
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Certain variants of aconitase cause infantile cerebellar-retinal degeneration syndrome, characterised by neurological and muscular symptoms.
“Certain variants of aconitase have been found to cause infantile cerebellar-retinal degeneration syndrome, which is characterised by various neurological and muscular symptoms [110].”
From Superoxide Anion Chemistry—Its Role at the Core of the Innate Immunity (2023) · cites this paper as [110]
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Superoxide Anion Chemistry—Its Role at the Core of the Innate Immunity
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- Authors
- Sadat, R., Barca, E., Masand, R., Donti, T. R., Naini, A., De Vivo, D. C., DiMauro, S., Hanchard, N. A., & Graham, B. H.
- Affiliations
- Baylor College of Medicine (US)
- University of Messina (IT)
- Columbia University Irving Medical Center (US)
- Corresponding author
- Graham, Brett H.
- ORCID
- Venue
- Molecular Genetics and Metabolism
- Publisher
- Elsevier BV
- Published
- 2016-05
- Volume
- 118
- Issue
- 1
- Pages
- 28-34
- ISSN
- 1096-7192 (ISSN-L)
- PMC
- PMC4833660
- OpenAlex
- W2294888177
- Cited by
- 38
- References
- 26
- Citations by year
- 2026: 1 · 2024: 6 · 2023: 5 · 2022: 1 · 2021: 6 · 2020: 5 · 2019: 5 · 2018: 4 · 2017: 3 · 2016: 2
- FWCI
- 2.43
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular Genetics and Metabolism (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Doris Duke Charitable Foundation (2013096)
- National Institutes of Health
- Intellectual and Developmental Disabilities Research Center
- National Cancer Institute (P30CA125123)
- National Institute of General Medical Sciences (R21GM110190, R01GM098387)
- National Institute of Allergy and Infectious Diseases (P30AI036211)
- National Center for Research Resources (S10RR024574)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54HD083092, P01HD080642)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Keywords
- ACO2, mitochondrial DNA depletion, TCA cycle, variants of uncertain significance, compound heterozygosity, gene rescue, electron transport chain, neuromuscular symptoms
- MeSH terms
- Aconitate Hydratase, Child, Preschool, Citric Acid Cycle, DNA, Mitochondrial, Gene Expression Regulation, Humans, Male, Metabolism, Inborn Errors, Neuromuscular Diseases, Mutation, Missense, High-Throughput Nucleotide Sequencing, Exome
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