ArticleActa neuropathologica communications2020
A novel AFG3L2 mutation close to AAA domain leads to aberrant OMA1 and OPA1 processing in a family with optic atrophy.
Article in Acta neuropathologica communications, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 21 citations in OpenAlex.
- Mitochondrial Control of Myelination, Bioenergetics, Oxidative Stress, and the Pathogenesis of Optic Neuropathies.International journal of molecular sciences · 2026Review
- Loss of Function of AFG3L2 Leading to Developmental and Epileptic Encephalopathy.CNS neuroscience & therapeutics · 2026Article
- Expanding theNeurology. Genetics · 2026Article
- Molecular mechanisms of mitochondrial AAA+ proteases.The Journal of biological chemistry · 2026Review
- 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
- Mitochondria in Retinal Ganglion Cells: Unraveling the Metabolic Nexus and Oxidative Stress.International journal of molecular sciences · 2024Review
- Multifaceted Roles of AFG3L2, a Mitochondrial ATPase in Relation to Neurological Disorders.Molecular neurobiology · 2024Review
- Sustained OMA1-mediated integrated stress response is beneficial for spastic ataxia type 5.Brain : a journal of neurology · 2024Article
- AFG3L2 Biallelic Mutation: Clinical Heterogeneity in Two Italian Patients.Cerebellum (London, England) · 2023Article
- Novel compound heterozygous mutations in theHeliyon · 2023Article
- Levodopa Responsive Dystonia Parkinsonism, Intellectual Disability, and Optic Atrophy Due to a Heterozygous Missense Variant inMovement disorders clinical practice · 2022Article
- A novel mutation located in the intermembrane space domain of AFG3L2 causes dominant optic atrophy through decreasing the stability of the encoded protein.Cell death discovery · 2022Article
- Therapy Prospects for Mitochondrial DNA Maintenance Disorders.International journal of molecular sciences · 2021Review
- Molecular Mechanisms behind Inherited Neurodegeneration of the Optic Nerve.Biomolecules · 2021Review
- The Role of Mitochondria in Optic Atrophy With Autosomal Inheritance.Frontiers in neuroscience · 2021Review
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Authors and funding
8 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Autosomal dominant optic atrophy (ADOA) is a neuro-ophthalmic condition characterized by bilateral degeneration of the optic nerves. Although heterozygous mutations in OPA1 represent the most common genetic cause of ADOA, a significant number of cases remain undiagnosed.Here, we describe a family with a strong ADOA history with most family members spanning three generation having childhood onset of visual symptoms. The proband, in addition to optic atrophy, had neurological symptoms consistent with relapsing remitting multiple sclerosis. Clinical exome analysis detected a novel mutation in the AFG3L2 gene (NM_006796.2:c.1010G > A; p.G337E), which segregated with optic atrophy in family members. AFG3L2 is a metalloprotease of the AAA subfamily which exerts quality control in the inner mitochondrial membrane. Interestingly, the identified mutation localizes close to the AAA domain of AFG3L2, while those localized in the proteolytic domain cause dominant spinocerebellar ataxia type 28 (SCA28) or recessive spastic ataxia with epilepsy (SPAX5). Functional studies in patient fibroblasts demonstrate that the p.G337E AFG3L2 mutation strongly destabilizes the long isoforms of OPA1 via OMA hyper-activation and leads to mitochondrial fragmentation, thus explaining the family phenotype. This study widens the clinical spectrum of neurodegenerative diseases caused by AFG3L2 mutations, which shall be considered as genetic cause of ADOA.
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