Exonic Deletions of FXN and Early-Onset Friedreich Ataxia

Anheim, Mathieu; Mariani, Louise‐Laure; Calvas, Patrick; Cheuret, Emmanuel; Zagnoli, Fabien; Odent, Sylvie; Seguela, Claire; Marelli, Cécilia; Fritsch, M.; Delaunoy, Jean‐Pierre; Brice, Alexis; Dürr, Alexandra; Kœnig, M.

doi:10.1001/archneurol.2011.834

Cited by 38 publications

(31 citation statements)

References 14 publications

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“…On the other hand, the phenotype is not to be separated from classical FA if the missense mutation affects the carboxy-terminal half of frataxin. Deletions are usually associated with early onset, fast progression and severe phenotype with a higher incidence of non-neurological symptoms [52]. …”

Section: Geneticsmentioning

confidence: 99%

Friedreich Ataxia: current status and future prospects

2017

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Friedreich ataxia (FA) represents the most frequent type of inherited ataxia. Most patients carry homozygous GAA expansions in the first intron of the frataxin gene on chromosome 9. Due to epigenetic alterations, frataxin expression is significantly reduced. Frataxin is a mitochondrial protein. Its deficiency leads to mitochondrial iron overload, defective energy supply and generation of reactive oxygen species. This review gives an overview over clinical and genetic aspects of FA and discusses current concepts of frataxin biogenesis and function as well as new therapeutic strategies.

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Section: Geneticsmentioning

confidence: 99%

Friedreich Ataxia: current status and future prospects

2017

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“…Approximately 4% of FRDA patients are compound heterozygotes, having a GAA repeat expansion on one allele and an inactivating or loss- of- function mutation, such as a point mutation [165, 166] or a deletion/ duplication [167–169] on the other allele. The incidence of FRDA is 1– 2 in 50,000 in Caucasian populations with an equal occurrence in both genders [170, 171] and an estimated carrier frequency of 1: 60 to 1: 100 [172].…”

Section: Friedreich’s Ataxia (Mim# 229300)mentioning

confidence: 99%

Iron –sulfur cluster biogenesis in mammalian cells: New insights into the molecular mechanisms of cluster delivery

Maio

Rouault

2015

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

177

178

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Iron-sulfur (Fe-S) clusters are ancient, ubiquitous cofactors composed of iron and inorganic sulfur. The combination of the chemical reactivity of iron and sulfur, together with many variations of cluster composition, oxidation states and protein environments, enables Fe-S clusters to participate in numerous biological processes. Fe-S clusters are essential to redox catalysis in nitrogen fixation, mitochondrial respiration and photosynthesis, to regulatory sensing in key metabolic pathways (i. e. cellular iron homeostasis and oxidative stress response), and to the replication and maintenance of the nuclear genome. Fe-S cluster biogenesis is a multistep process that involves a complex sequence of catalyzed protein- protein interactions and coupled conformational changes between the components of several dedicated multimeric complexes. Intensive studies of the assembly process have clarified key points in the biogenesis of Fe-S proteins. However several critical questions still remain, such as: what is the role of frataxin? Why do some defects of Fe-S cluster biogenesis cause mitochondrial iron overload? How are specific Fe-S recipient proteins recognized in the process of Fe-S transfer? This review focuses on the basic steps of Fe-S cluster biogenesis, drawing attention to recent advances achieved on the identification of molecular features that guide selection of specific subsets of nascent Fe-S recipients by the cochaperone HSC20. Additionally, it outlines the distinctive phenotypes of human diseases due to mutations in the components of the basic pathway.

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“…Compound heterozygous of GAA expansion and exonic deletions were recently described ( Fig. 2A) [20].…”

Section: Pathogenesis and Molecular Basismentioning

confidence: 94%

“…2C). In this situation, further molecular tests are needed, such as analysis of FXN exons (1-5a and 5b) for point mutations [19,41] [42] and for exonic deletions [20].…”

Section: Pathogenesis and Molecular Basismentioning

confidence: 99%

Milestones in Friedreich ataxia: more than a century and still learning

et al. 2015

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Friedreich ataxia (FRDA) is the most common autosomal recessive ataxia worldwide. This review highlights the main clinical features, pathophysiological mechanisms, and therapeutic approaches for FRDA patients. The disease is characterized by a combination of neurological involvement (ataxia and neuropathy), cardiomyopathy, skeletal abnormalities, and glucose metabolism disturbances. FRDA is caused by expanded guanine-adenine-adenine (GAA) triplet repeats in the first intron of the frataxin gene (FXN), resulting in reduction of messenger RNA and protein levels of frataxin in different tissues. The molecular and metabolic disturbances, including iron accumulation, lead to pathological changes characterized by spinal cord and dorsal root ganglia atrophy, dentate nucleus atrophy without global cerebellar volume reduction, and hypertrophic cardiomyopathy. DNA analysis is the hallmark for the diagnosis of FRDA. There is no specific treatment to stop the disease progression in FRDA patients. However, a number of drugs are under investigation. Therapeutic approaches intend to improve mitochondrial functioning and to increase FXN expression.

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Exonic Deletions of FXN and Early-Onset Friedreich Ataxia

Cited by 38 publications

References 14 publications

Friedreich Ataxia: current status and future prospects

Friedreich Ataxia: current status and future prospects

Iron –sulfur cluster biogenesis in mammalian cells: New insights into the molecular mechanisms of cluster delivery

Milestones in Friedreich ataxia: more than a century and still learning

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