ArticleHuman molecular genetics2017
ATPase-deficient mitochondrial inner membrane protein ATAD3A disturbs mitochondrial dynamics in dominant hereditary spastic paraplegia.
Article in Human molecular genetics, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 48 papers, 1 of them a synthesis that pooled it.
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Who cites it
48 citing papers in PubMed, 1 synthesis or guideline pooled it, 88 citations in OpenAlex.
- Modelling mitochondrial diseases in neuronsJournal of neuromuscular diseases · 2025Pooled it
- Pathogenic mutations in ATAD3A cause dysregulation of RagC/D-TFEB axis and disrupt lysosomal homeostasis.bioRxiv : the preprint server for biology · 2026Article
- ATAD3 megadalton complex in Plasmodium falciparum is essential for mitochondrial and cellular viability.PLoS pathogens · 2026Article
- PHRINL Syndrome: A Case of Infantile Cataract and Cardiomyopathy.Molecular syndromology · 2026Article
- Clinical characteristics and induced pluripotent stem cells (iPSCs) disease model of Harel-Yoon syndrome caused by compound heterozygous ATAD3A variants.Human cell · 2025Article
- Transcriptome analysis of atad3-null zebrafish embryos elucidates possible disease mechanisms.Orphanet journal of rare diseases · 2025Article
- Optimizing gRNA selection for high-penetrance F0 CRISPR screening for interrogating disease gene function.Nucleic acids research · 2025Article
- Review
- Primary mitochondrial disorders and mimics: Insights from a large French cohort.Annals of clinical and translational neurology · 2024Article
- Elevated cholesterol in ATAD3 mutants is a compensatory mechanism that leads to membrane cholesterol aggregation.Brain : a journal of neurology · 2024Article
- Article
- Mutations in mitochondrialFrontiers in neuroscience · 2024Review
- The SIRT3-ATAD3A axis regulates MAM dynamics and mitochondrial calcium homeostasis in cardiac hypertrophy.International journal of biological sciences · 2024Article
- Article
- Movement disorders in hereditary spastic paraplegias.Arquivos de neuro-psiquiatria · 2023Review
- ATAD3A: A Key Regulator of Mitochondria-Associated Diseases.International journal of molecular sciences · 2023Review
- ATAD3A-related pontocerebellar hypoplasia: new patients and insights into phenotypic variability.Orphanet journal of rare diseases · 2023Article
- Mitochondrial biology and dysfunction in secondary mitochondrial disease.Open biology · 2022Review
- Severe spinal cord hypoplasia due to a novelMolecular genetics and metabolism reports · 2022Article
- TMEM63C mutations cause mitochondrial morphology defects and underlie hereditary spastic paraplegia.Brain : a journal of neurology · 2022Article
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Authors and funding
16 authors at 7 institutions in 5 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
De novo mutations in ATAD3A (ATPase family AAA-domain containing protein 3A) were recently found to cause a neurological syndrome with developmental delay, hypotonia, spasticity, optic atrophy, axonal neuropathy, and hypertrophic cardiomyopathy. Using whole-exome sequencing, we identified a dominantly inherited heterozygous variant c.1064G > A (p.G355D) in ATAD3A in a mother presenting with hereditary spastic paraplegia (HSP) and axonal neuropathy and her son with dyskinetic cerebral palsy, both with disease onset in childhood. HSP is a clinically and genetically heterogeneous disorder of the upper motor neurons. Symptoms beginning in early childhood may resemble spastic cerebral palsy. The function of ATAD3A, a mitochondrial inner membrane AAA ATPase, is yet undefined. AAA ATPases form hexameric rings, which are catalytically dependent on the co-operation of the subunits. The dominant-negative patient mutation affects the Walker A motif, which is responsible for ATP binding in the AAA module of ATAD3A, and we show that the recombinant mutant ATAD3A protein has a markedly reduced ATPase activity. We further show that overexpression of the mutant ATAD3A fragments the mitochondrial network and induces lysosome mass. Similarly, we observed altered dynamics of the mitochondrial network and increased lysosomes in patient fibroblasts and neurons derived through differentiation of patient-specific induced pluripotent stem cells. These alterations were verified in patient fibroblasts to associate with upregulated basal autophagy through mTOR inactivation, resembling starvation. Mutations in ATAD3A can thus be dominantly inherited and underlie variable neurological phenotypes, including HSP, with intrafamiliar variability. This finding extends the group of mitochondrial inner membrane AAA proteins associated with spasticity.
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