ArticlePLoS genetics2011
Whole-exome sequencing identifies homozygous AFG3L2 mutations in a spastic ataxia-neuropathy syndrome linked to mitochondrial m-AAA proteases.
Article in PLoS genetics, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 124 papers.
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Who cites it
124 citing papers in PubMed, 227 citations in OpenAlex.
- Insights from cerebellar transcriptomic analysis into the pathogenesis of ataxia.JAMA neurology · 2014Trial
- Loss of Function of AFG3L2 Leading to Developmental and Epileptic Encephalopathy.CNS neuroscience & therapeutics · 2026Article
- Expanding the Spectrum of AFG3L2 Mutations: A Case with Late-Onset Autosomal Recessive Spinocerebellar Ataxia from Iran.Cerebellum (London, England) · 2026Article
- Expanding theNeurology. Genetics · 2026Article
- Molecular mechanisms of mitochondrial AAA+ proteases.The Journal of biological chemistry · 2026Review
- Editorial: Proteostasis disruption in neurodegenerative disorders: mechanisms and treatment strategies.Frontiers in molecular neuroscience · 2026Article
- Biallelic Variants in AFG3L2 Causing Spastic Ataxia Type 5 (SPAX5): Report of Two Pediatric Cases from Bogotá, Colombia.Movement disorders clinical practice · 2025Article
- Quality control at the powerhouse: mitochondrial proteostasis dysfunction and disease.Biochemical Society transactions · 2025Article
- Approach to Oculomotor Apraxia: A Syndromic Approach to Genetic Causes.Cerebellum (London, England) · 2025Review
- Maintaining the Integral Membrane Proteome: Revisiting the Functional Repertoire of Integral Membrane Proteases.Chembiochem : a European journal of chemical biology · 2025Review
- HRI protein kinase in cytoplasmic heme sensing and mitochondrial stress response: Relevance to hematological and mitochondrial diseases.The Journal of biological chemistry · 2025Review
- Compound heterozygous mutation of AFG3L2 causes autosomal recessive spinocerebellar ataxia through mitochondrial impairment and MICU1 mediated CaScience China. Life sciences · 2025Article
- Multi-omics-based phenotyping of AFG3L2-mutant lymphoblasts determines key factors of a pathophysiological interplay between mitochondrial vulnerability and neurodegeneration in spastic ataxia type 5.Frontiers in molecular neuroscience · 2025Article
- Mitochondrial Parkinsonism: A Practical Guide to Genes and Clinical Diagnosis.Movement disorders clinical practice · 2024Review
- Multifaceted Roles of AFG3L2, a Mitochondrial ATPase in Relation to Neurological Disorders.Molecular neurobiology · 2024Review
- Mitochondrial protein synthesis quality control.Human molecular genetics · 2024Review
- Sustained OMA1-mediated integrated stress response is beneficial for spastic ataxia type 5.Brain : a journal of neurology · 2024Article
- Dual regulation of SLC25A39 by AFG3L2 and iron controls mitochondrial glutathione homeostasis.Molecular cell · 2024Article
- Review
- Hereditary Optic Neuropathies: A Systematic Review on the Interplay between Biomaterials and Induced Pluripotent Stem Cells.Bioengineering (Basel, Switzerland) · 2024Review
64 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
21 authors at 4 institutions in 2 countries.
Funding
Abstract
We report an early onset spastic ataxia-neuropathy syndrome in two brothers of a consanguineous family characterized clinically by lower extremity spasticity, peripheral neuropathy, ptosis, oculomotor apraxia, dystonia, cerebellar atrophy, and progressive myoclonic epilepsy. Whole-exome sequencing identified a homozygous missense mutation (c.1847G>A; p.Y616C) in AFG3L2, encoding a subunit of an m-AAA protease. m-AAA proteases reside in the mitochondrial inner membrane and are responsible for removal of damaged or misfolded proteins and proteolytic activation of essential mitochondrial proteins. AFG3L2 forms either a homo-oligomeric isoenzyme or a hetero-oligomeric complex with paraplegin, a homologous protein mutated in hereditary spastic paraplegia type 7 (SPG7). Heterozygous loss-of-function mutations in AFG3L2 cause autosomal-dominant spinocerebellar ataxia type 28 (SCA28), a disorder whose phenotype is strikingly different from that of our patients. As defined in yeast complementation assays, the AFG3L2(Y616C) gene product is a hypomorphic variant that exhibited oligomerization defects in yeast as well as in patient fibroblasts. Specifically, the formation of AFG3L2(Y616C) complexes was impaired, both with itself and to a greater extent with paraplegin. This produced an early-onset clinical syndrome that combines the severe phenotypes of SPG7 and SCA28, in additional to other "mitochondrial" features such as oculomotor apraxia, extrapyramidal dysfunction, and myoclonic epilepsy. These findings expand the phenotype associated with AFG3L2 mutations and suggest that AFG3L2-related disease should be considered in the differential diagnosis of spastic ataxias.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.