ArticleAnnals of neurology2020
ATPase Domain AFG3L2 Mutations Alter OPA1 Processing and Cause Optic Neuropathy.
Article in Annals of neurology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed, 49 citations in OpenAlex.
- Loss of Function of AFG3L2 Leading to Developmental and Epileptic Encephalopathy.CNS neuroscience & therapeutics · 2026Article
- Expanding theNeurology. Genetics · 2026Article
- The Neuro-Ophthalmologic Manifestations ofJournal of personalized medicine · 2025Review
- Quality control at the powerhouse: mitochondrial proteostasis dysfunction and disease.Biochemical Society transactions · 2025Article
- Dual Role of CRABP2 in Colorectal Cancer: Oncogenesis via Nuclear RB1 and Cytoplasmic AFG3L2/SLC25A39 Axis, While Limiting Liver Metastasis through Cytoplasmic AFG3L2/PINK1/Parkin-Mediated Mitophagy.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Contrasting pathophysiological mechanisms of OPA1 mutations in autosomal dominant optic atrophy.Cell death discovery · 2025Article
- 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
- Semiautomated approach focused on new genomic information results in time and effort-efficient reannotation of negative exome data.Human genetics · 2024Article
- Sustained OMA1-mediated integrated stress response is beneficial for spastic ataxia type 5.Brain : a journal of neurology · 2024Article
- Sectorial Ganglion Cell Complex Thickness as Biomarker of Vision Outcome in Patients With Dominant Optic Atrophy.Investigative ophthalmology & visual science · 2024Article
- Optic Neuropathy AFG3L2 Related in a Patient Affected by Congenital Stationary Night Blindness.Case reports in ophthalmological medicine · 2024Article
- AFG3L2 Biallelic Mutation: Clinical Heterogeneity in Two Italian Patients.Cerebellum (London, England) · 2023Article
- The Italian reappraisal of the most frequent genetic defects in hereditary optic neuropathies and the global top 10.Brain : a journal of neurology · 2023Article
- Identification ofAmerican journal of ophthalmology case reports · 2023Article
- Modeling mitochondrial DNA diseases: from base editing to pluripotent stem-cell-derived organoids.EMBO reports · 2023Review
- Mitochondrial biology and dysfunction in secondary mitochondrial disease.Open biology · 2022Review
- Levodopa Responsive Dystonia Parkinsonism, Intellectual Disability, and Optic Atrophy Due to a Heterozygous Missense Variant inMovement disorders clinical practice · 2022Article
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Authors and funding
31 authors at 10 institutions in 3 countries.
Funding
Abstract
objectiveDominant optic atrophy (DOA) is the most common inherited optic neuropathy, with a prevalence of 1:12,000 to 1:25,000. OPA1 mutations are found in 70% of DOA patients, with a significant number remaining undiagnosed.
methodsWe screened 286 index cases presenting optic atrophy, negative for OPA1 mutations, by targeted next generation sequencing or whole exome sequencing. Pathogenicity and molecular mechanisms of the identified variants were studied in yeast and patient-derived fibroblasts.
resultsTwelve cases (4%) were found to carry novel variants in AFG3L2, a gene that has been associated with autosomal dominant spinocerebellar ataxia 28 (SCA28). Half of cases were familial with a dominant inheritance, whereas the others were sporadic, including de novo mutations. Biallelic mutations were found in 3 probands with severe syndromic optic neuropathy, acting as recessive or phenotype-modifier variants. All the DOA-associated AFG3L2 mutations were clustered in the ATPase domain, whereas SCA28-associated mutations mostly affect the proteolytic domain. The pathogenic role of DOA-associated AFG3L2 mutations was confirmed in yeast, unraveling a mechanism distinct from that of SCA28-associated AFG3L2 mutations. Patients' fibroblasts showed abnormal OPA1 processing, with accumulation of the fission-inducing short forms leading to mitochondrial network fragmentation, not observed in SCA28 patients' cells.
interpretationThis study demonstrates that mutations in AFG3L2 are a relevant cause of optic neuropathy, broadening the spectrum of clinical manifestations and genetic mechanisms associated with AFG3L2 mutations, and underscores the pivotal role of OPA1 and its processing in the pathogenesis of DOA. ANN NEUROL 2020 ANN NEUROL 2020;88:18-32.
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