ArticleThe Journal of biological chemistry2013
Missense mutations linked to friedreich ataxia have different but synergistic effects on mitochondrial frataxin isoforms.
Article in The Journal of biological chemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 28 citations in OpenAlex.
- Clinical and genetic analysis of multiple mitochondrial dysfunctions syndrome type 6 caused by biallelicFrontiers in pediatrics · 2026Article
- Friedreich ataxia: what can we learn from non-GAA repeat mutations?Neurodegenerative disease management · 2025Review
- An In Silico Analysis of Genetic Variants and Structural Modeling of the Human Frataxin Protein in Friedreich's Ataxia.International journal of molecular sciences · 2024Article
- Phenotypic variation of FXN compound heterozygotes in a Friedreich ataxia cohort.Annals of clinical and translational neurology · 2024Article
- Evolution of an Iron-Detoxifying Protein: Eukaryotic andInternational journal of molecular sciences · 2022Article
- Posttranslational regulation of mitochondrial frataxin and identification of compounds that increase frataxin levels in Friedreich's ataxia.The Journal of biological chemistry · 2022Article
- Mice harboring the FXN I151F pathological point mutation present decreased frataxin levels, a Friedreich ataxia-like phenotype, and mitochondrial alterations.Cellular and molecular life sciences : CMLS · 2022Article
- Advantages and Limitations of Gene Therapy and Gene Editing for Friedreich's Ataxia.Frontiers in genome editing · 2022Review
- Molecular Defects in Friedreich's Ataxia: Convergence of Oxidative Stress and Cytoskeletal Abnormalities.Frontiers in molecular biosciences · 2020Review
- Mechanism of activation of the human cysteine desulfurase complex by frataxin.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- Structure of the human frataxin-bound iron-sulfur cluster assembly complex provides insight into its activation mechanism.Nature communications · 2019Article
- Interactions of iron-bound frataxin with ISCU and ferredoxin on the cysteine desulfurase complex leading to Fe-S cluster assembly.Journal of inorganic biochemistry · 2018Article
- Selected missense mutations impair frataxin processing in Friedreich ataxia.Annals of clinical and translational neurology · 2017Article
- Zinc and the iron donor frataxin regulate oligomerization of the scaffold protein to form new Fe-S cluster assembly centers.Metallomics : integrated biometal science · 2017Article
- Architecture of the Human Mitochondrial Iron-Sulfur Cluster Assembly Machinery.The Journal of biological chemistry · 2016Article
- Stable isotopes and LC-MS for monitoring metabolic disturbances in Friedreich's ataxia platelets.Bioanalysis · 2015Article
- Overlapping binding sites of the frataxin homologue assembly factor and the heat shock protein 70 transfer factor on the Isu iron-sulfur cluster scaffold protein.The Journal of biological chemistry · 2014Article
- Probing the kinetic stabilities of Friedreich's ataxia clinical variants using a solid phase GroEL chaperonin capture platform.Biomolecules · 2014Article
- Fixing frataxin: 'ironing out' the metabolic defect in Friedreich's ataxia.British journal of pharmacology · 2014Review
- Novel Point Mutations in Frataxin Gene in Iranian Patients with Friedreich's Ataxia.Iranian journal of child neurology · 2014Article
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
Friedreich ataxia is an early-onset multisystemic disease linked to a variety of molecular defects in the nuclear gene FRDA. This gene normally encodes the iron-binding protein frataxin (FXN), which is critical for mitochondrial iron metabolism, global cellular iron homeostasis, and antioxidant protection. In most Friedreich ataxia patients, a large GAA-repeat expansion is present within the first intron of both FRDA alleles, that results in transcriptional silencing ultimately leading to insufficient levels of FXN protein in the mitochondrial matrix and probably other cellular compartments. The lack of FXN in turn impairs incorporation of iron into iron-sulfur cluster and heme cofactors, causing widespread enzymatic deficits and oxidative damage catalyzed by excess labile iron. In a minority of patients, a typical GAA expansion is present in only one FRDA allele, whereas a missense mutation is found in the other allele. Although it is known that the disease course for these patients can be as severe as for patients with two expanded FRDA alleles, the underlying pathophysiological mechanisms are not understood. Human cells normally contain two major mitochondrial isoforms of FXN (FXN(42-210) and FXN(81-210)) that have different biochemical properties and functional roles. Using cell-free systems and different cellular models, we show that two of the most clinically severe FXN point mutations, I154F and W155R, have unique direct and indirect effects on the stability, biogenesis, or catalytic activity of FXN(42-210) and FXN(81-210) under physiological conditions. Our data indicate that frataxin point mutations have complex biochemical effects that synergistically contribute to the pathophysiology of Friedreich ataxia.
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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.