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Trinucleotide Repeat ExpansionTrinucleotide RepeatsFriedreich AtaxiaDNA Repeat ExpansionIron-Binding ProteinsSpinocerebellar DegenerationsMyotonic DystrophyFragile X SyndromeHuntington DiseaseFragile X Mental Retardation ProteinAllelesMutationRepetitive Sequences, Nucleic AcidSpinocerebellar AtaxiasMachado-Joseph DiseaseHeredodegenerative Disorders, Nervous SystemBase SequenceMolecular Sequence DataNerve Tissue ProteinsGenomic InstabilityFrontotemporal DementiaFlap EndonucleasesAnticipation, GeneticMicrosatellite RepeatsDNANucleic Acid ConformationInverted Repeat SequencesMinisatellite RepeatsTandem Repeat SequencesPedigreeCerebellar AtaxiaAge of OnsetIntranuclear Inclusion BodiesChromosome FragilityMuscular Dystrophy, OculopharyngealPolymerase Chain ReactionRNA-Binding ProteinsGenetic Diseases, InbornAmyotrophic Lateral SclerosisPolymorphism, GeneticNuclear ProteinsRNA, MessengerPhenotypeNeurodegenerative DiseasesProteinsPeptidesDNA RepairMice, TransgenicSaccharomyces cerevisiaeSequence Analysis, DNAReceptors, AndrogenDNA PrimersModels, GeneticTranscription, GeneticAmino Acid SequenceGenotypeHeterozygoteDisease Models, AnimalIron-Sulfur ProteinsSaccharomyces cerevisiae ProteinsGenes, DominantCell LineDNA-Binding ProteinsDNA ReplicationGenome, HumanMyoclonic Epilepsies, ProgressiveIronAconitate HydrataseMutS Homolog 2 ProteinExonsGenetic MarkersRepetitive Sequences, Amino AcidNucleic Acid HeteroduplexesGene Expression
IntronMitochondrialGeneTriplet repeatHeterochromatinFRDAAmino acidMutationMitochondriaSevereGeneticSigns and symptomsFriedreich'sApproximatelyResultsIncreaseIndividualsLossHealthyPresentShowDiseaseLower frataxin levelsShortage of frataxinMitochondrial proteinLess frataxinFriedreichIntronicPathwaysInsufficientUnexpectedlyBiosynthesisAbnormallySpinal cordCellsOnsetNormalSymptomsFunctionImportantIron
Intron10
  • In 96% of cases, the mutant FXN gene has 90-1,300 GAA trinucleotide repeat expansions in intron 1 of both alleles. (wikipedia.org)
  • The 2100 amino acid protein frataxin is encoded within the first intron of the FXN gene on chromosome 9q13. (wjgnet.com)
  • FA is an autosomal recessive disorder caused by a mutation and abnormal expansion of a GAA repeat in intron 1 of the FXN gene, which is located on chromosome 9. (medscape.com)
  • Approximately 98% of mutant alleles have an expansion of a gossypol acetic acid (GAA) trinucleotide repeat in intron 1 of the gene, leading to reduced levels of frataxin. (medscape.com)
  • TTC triplet in the first intron of the FXN gene, encoding the essential mitochondrial protein frataxin. (frontiersin.org)
  • TTC triplet repeat expansion in an intron of the nuclear FXN gene, which encodes the essential mitochondrial protein frataxin ( 1 ). (frontiersin.org)
  • TTC repeats ( 6 , 7 , 15 ), as well as with reduced histone acetylation and increased histone trimethylation at the FXN promoter ( 6 , 8 ), and in intron 1 adjacent to the repeats ( 5 - 7 ). (frontiersin.org)
  • The causative mutation is a trinucleotide (GAA) repeat expansion in the first intron of the frataxin gene, leading to impaired transcription of frataxin. (researcherprofiles.org)
  • Friedreich's ataxia (FRDA) is caused by large GAA expansions in intron 1 of the frataxin gene (FXN), which lead to reduced FXN expression through a mechanism not fully understood. (ox.ac.uk)
  • Friedreich ataxia (FRDA) is a progressive neurodegenerative disease caused by a GAA repeat in the intron 1 of the frataxin gene (FXN) leading to a lower expression of the frataxin protein. (bvsalud.org)
Mitochondrial6
  • At the cellular level, dysregulation of this small mitochondrial protein results in the overproduction of iron-sulfur clusters, free radical oxidative stress, and mitochondrial iron overload[ 75 ]. (wjgnet.com)
  • It has been hypothesized that frataxin is a mitochondrial protein important for normal production of cellular energy and that a defect in its action may result in abnormal accumulation of iron in mitochondria, leading to excess production of free radicals, which then results in cellular damage and death. (medscape.com)
  • Frataxin insufficiency leads to decreased activity of iron-sulfur cluster enzymes, mitochondrial iron accumulation, and resultant cell death, with the primary sites of pathology being the large sensory neurons of the dorsal root ganglia and the dentate nucleus of the cerebellum ( 9 ). (frontiersin.org)
  • The pathological consequences of frataxin deficiency include a severe disruption of iron-sulfur cluster biosynthesis, mitochondrial iron overload coupled to cellular iron dysregulation, and an increased sensitivity to oxidative stress. (researcherprofiles.org)
  • PMPCB encodes the catalytic subunit of the essential mitochondrial processing protease (MPP), which is required for maturation of the majority of mitochondrial precursor proteins. (regenerativemedicine.net)
  • Introduction of the identified PMPCB variants into the homologous S. cerevisiae Mas1 protein resulted in a severe growth and MPP processing defect leading to the accumulation of mitochondrial precursor proteins and early impairment of the biogenesis of iron-sulfur clusters, which are indispensable for a broad range of crucial cellular functions. (regenerativemedicine.net)
Gene19
  • The condition is caused by mutations in the FXN gene on chromosome 9, which makes a protein called frataxin. (wikipedia.org)
  • FRDA is an autosomal-recessive disorder that affects a gene (FXN) on chromosome 9, which produces an important protein called frataxin. (wikipedia.org)
  • The formation of heterochromatin results in reduced transcription of the gene and low levels of frataxin. (wikipedia.org)
  • Heterozygous carriers of the mutant FXN gene have 50% lower frataxin levels, but this decrease is not enough to cause symptoms. (wikipedia.org)
  • Risdiplam and Branaplam are oral medications which can cross the blood-brain barrier and increase the number of spinal muscular atrophy (SMA) full length proteins by targeting the SMN2 gene. (wjgnet.com)
  • If the neurofibromatosis - 1 gene on chromosome 17 is either mutated or deleted, either no protein product is formed, or a mutated protein is made. (wjgnet.com)
  • This gene encodes a 210-amino-acid protein called frataxin. (medscape.com)
  • Friedreich's ataxia (FA) is an autosomal recessive condition caused by a GAA trinucleotide repeat expansion in the X25 gene on chromosome 9. (bmj.com)
  • DNA analysis of the FRATAXIN gene in the patient showed that the GAA expansion was present in one allele but not the other, while her mother was negative for the GAA expansion in both alleles. (bmj.com)
  • The underlying defect is a GAA trinucleotide repeat expansion in the X25 gene on chromosome 9 with 90% of those studied being homozygous for expanded alleles and over half of the remaining patients being compound heterozygotes, carrying one allele with a repeat expansion and the other with a point mutation. (bmj.com)
  • Histone post-translational modifications near the expanded repeats are consistent with heterochromatin formation and consequent FXN gene silencing. (frontiersin.org)
  • TTC expansion mutation is to reduce expression of frataxin at the level of transcription ( 3 ), through the formation of heterochromatin and subsequent gene silencing ( 4 - 8 ). (frontiersin.org)
  • The study will evaluate up to three doses of single administration of LX2006 (AAVrh.10hFXN), an adeno-associated virus (AAV) gene therapy designed to intravenously deliver the human frataxin (hFXN) gene to cardiac cells over a 52-week period. (researcherprofiles.org)
  • We modified BAC vectors carrying the whole FXN genomic DNA locus by inserting the luciferase gene in exon 5a of the FXN gene (pBAC-FXN-Luc) and replacing the six GAA repeats present in the vector with an ∼310 GAA repeat expansion (pBAC-FXN-GAA-Luc). (ox.ac.uk)
  • We demonstrate that the presence of expanded GAA repeats recapitulates the epigenetic modifications and repression of gene expression seen in FRDA. (ox.ac.uk)
  • Friedreich ataxia (FRDA) is a rare genetic multisystem disorder caused by a pathological GAA trinucleotide repeat expansion in the FXN gene. (bvsalud.org)
  • The YG8sR mice are Knock-Out (KO) for their murine frataxin gene but contain a human frataxin transgene derived from an FRDA patient with 300 GAA repeats. (bvsalud.org)
  • PHP.B coding for a shRNA targeting the human frataxin gene and the YG8-800, a new mouse model with a human transgene containing 800 GAA repeats. (bvsalud.org)
  • Because of the genetic defect in a non-coding region of FXN gene, FRDA cells exhibit severe deficit of frataxin protein levels. (bvsalud.org)
Triplet repeat1
Heterochromatin1
  • This expansion causes epigenetic changes and formation of heterochromatin near the repeat. (wikipedia.org)
FRDA6
  • In FRDA, cells produce less frataxin. (wikipedia.org)
  • Using a newly developed human neuronal cell model, derived from patient-induced pluripotent stem cells, we find that 2-aminobenzamide histone deacetylase (HDAC) inhibitors increase FXN mRNA levels and frataxin protein in FRDA neuronal cells. (frontiersin.org)
  • Our results shed light on the mechanism whereby HDAC inhibitors increase FXN mRNA levels in FRDA neuronal cells. (frontiersin.org)
  • Understanding such mechanism is essential for the identification of novel therapies for FRDA and this can be accelerated by the development of cell models which recapitulate the genomic context of the FXN locus and allow direct comparison of normal and expanded FXN loci with rapid detection of frataxin levels. (ox.ac.uk)
  • We applied the GAA-expanded reporter model to the screening of a library of novel small molecules and identified one molecule which up-regulates FXN expression in FRDA patient primary cells and restores normal histone acetylation around the GAA repeats. (ox.ac.uk)
  • These mice are used as a FRDA model but even with a low frataxin concentration, their phenotype is mild. (bvsalud.org)
Amino acid1
  • 3 Expanded alleles are thought to result in low or absent frataxin levels while point mutations cause single amino acid changes in the C terminal region of the frataxin protein, possibly resulting in a loss of function. (bmj.com)
Mutation2
  • In about 4% of cases, the disease is caused by a (missense, nonsense, or intronic) point mutation, with an expansion in one allele and a point mutation in the other. (wikipedia.org)
  • Depending on the point mutation, cells can produce no frataxin, nonfunctional frataxin, or frataxin that is not properly localized to the mitochondria. (wikipedia.org)
Mitochondria1
  • Mitochondria isolated from two fibroblast cell lines and induced pluripotent stem cells derived from one affected individual and differentiated neuroepithelial stem cells showed reduced PMPCB levels and accumulation of the processing intermediate of frataxin, a sensitive substrate for MPP dysfunction. (regenerativemedicine.net)
Severe1
  • However, these changes were surprisingly mild even at advanced age (18â months), despite a severe decrease in FXN levels to 1% of those of wild type. (bvsalud.org)
Genetic2
  • This study will support genetic modifier studies, biomarker studies, and frataxin protein level assessments by building a sample repository. (researcherprofiles.org)
  • In an important model of premature aging, Werner's Syndrome, the genetic problem seems to be lack of a helicase protein that can unwind G-quadruplexes. (anti-agingfirewalls.com)
Signs and symptoms2
  • Due to trinucleotide repeat expansions ranging from approximately 44-1700 "GAA" triplet sequences, affected individuals experience numerous characteristic signs and symptoms of Friedreich Ataxia. (wjgnet.com)
  • Certain nerve and muscle cells cannot function properly with a shortage of frataxin, leading to the signs and symptoms of FA. (medscape.com)
Friedreich's1
  • A GAA repeat expansion reporter model of Friedreich's ataxia recapitulates the genomic context and allows rapid screening of therapeutic compounds. (ox.ac.uk)
Approximately1
  • TTC repeats, whereas affected individuals have from approximately 70 to more than 1,000 triplets. (frontiersin.org)
Results1
  • The pathology in FA results from lack of frataxin or its function. (medscape.com)
Increase2
  • In conclusion, YG8sR mice have a slight phenotype, and injecting them with an AAV-PHP.B expressing an shRNA targeting frataxin does increase their phenotype. (bvsalud.org)
  • This project aims to find ways to increase frataxin by improving its stability and reducing its turnover in the cell. (curefa.org)
Individuals1
  • People with FDRA might have 5-35% of the frataxin protein compared to healthy individuals. (wikipedia.org)
Loss1
  • However, FA hearts maintain adequate function until advanced disease stages, suggesting initial adaptation to the loss of frataxin (FXN). (bvsalud.org)
Healthy1
  • Both mouse models were compared to Y47R mice containing nine GAA repeats that were considered healthy mice. (bvsalud.org)
Present1
  • Iron-sulfur (Fe-S) clusters are essential cofactors present in all known forms of life and required by hundreds of proteins to perform their function. (curefa.org)
Show1
  • Structural analogs of the active HDAC inhibitors that selectively target either HDAC1 or HDAC3 do not show similar increases in FXN mRNA levels. (frontiersin.org)
Disease1
Lower frataxin levels1
  • Heterozygous carriers of the mutant FXN gene have 50% lower frataxin levels, but this decrease is not enough to cause symptoms. (wikipedia.org)
Shortage of frataxin2
  • Certain nerve and muscle cells cannot function properly with a shortage of frataxin, leading to the signs and symptoms of FA. (medscape.com)
  • A shortage of frataxin appears to decrease the activity of proteins that contain iron-sulfur clusters, which could impair the production of energy in mitochondria. (medlineplus.gov)
Mitochondrial protein5
  • It has been hypothesized that frataxin is a mitochondrial protein important for normal production of cellular energy and that a defect in its action may result in abnormal accumulation of iron in mitochondria, leading to excess production of free radicals, which then results in cellular damage and death. (medscape.com)
  • This nuclear gene encodes a mitochondrial protein which belongs to the FRATAXIN family. (nih.gov)
  • About 99% of mammalian mitochondrial proteins are encoded by the nuclear genome, synthesized as precursors in the cytosol, and imported into mitochondria by mitochondrial protein import machinery. (biomed.news)
  • Mitochondrial protein import systems function not only as independent units for protein translocation, but also are deeply integrated into a functional network of mitochondrial bioenergetics, protein quality control, mitochondrial dynamics and morphology, and interaction with other organelles. (biomed.news)
  • Mitochondrial protein import deficiency is linked to various diseases, including cardiovascular disease. (biomed.news)
Less frataxin1
  • The greater the repeat in patients, the less frataxin is produced and the more severe the disease. (medscape.com)
Friedreich5
Intronic1
  • In about 4% of cases, the disease is caused by a (missense, nonsense, or intronic) point mutation, with an expansion in one allele and a point mutation in the other. (wikipedia.org)
Pathways2
  • Promotes the biosynthesis of heme and assembly and repair of iron-sulfur clusters by delivering Fe(2+) to proteins involved in these pathways. (nih.gov)
  • The major protein import pathways, including the presequence pathway (TIM23 pathway), the carrier pathway (TIM22 pathway), and the mitochondrial intermembrane space import and assembly machinery, related translocases, proteinases, and chaperones, are discussed here. (biomed.news)
Insufficient2
  • As such, disease severity inversely correlates with patient copy number of SMN2 and thus SMA is a disease of insufficient levels of SMN, rather than a complete lack of the functional protein. (medscape.com)
  • Cells with insufficient amounts of frataxin are also particularly sensitive to reactive molecules (free radicals) that can damage and destroy cells. (medlineplus.gov)
Unexpectedly2
  • Rather unexpectedly, we found a high variation of frataxin protein levels among the individuals. (nih.gov)
  • Unexpectedly, depending on mutation heteroplasmy level, the truncation showed multiple threshold effects in cellular reprogramming, neurogenesis and in metabolism of mature motor neurons (MN). (biomed.news)
Biosynthesis1
  • This expansion leads to reduced expression of frataxin, a ubiquitously expressed protein that acts in iron-sulfur cluster and heme biosynthesis. (medscape.com)
Abnormally1
  • In people with this condition, the GAA segment is abnormally repeated 66 to more than 1,000 times. (medlineplus.gov)
Spinal cord1
  • This protein is found in cells throughout the body, with the highest levels in the heart, spinal cord, liver, pancreas, and muscles used for voluntary movement (skeletal muscles). (medlineplus.gov)
Cells1
  • Within cells, frataxin is found in energy-producing structures called mitochondria. (medlineplus.gov)
Onset2
  • The length of the shorter GAA repeat is correlated with the age of onset and disease severity. (wikipedia.org)
  • 40) with the length of the expanded repeat being inversely correlated with age at onset. (neuroweb.us)
Normal2
  • Sometimes, however, the GAA segment is repeated 12 to 33 times (referred to as long normal). (medlineplus.gov)
  • CSF protein and pleocytosis may be elevated in early disease, but later in the course, return to normal. (neuroweb.us)
Symptoms2
  • These models can be very useful for testing the therapeutic ability to upregulate frataxin expression, but translating therapeutic efficacy into amelioration of disease symptoms using these models is challenging due to their mild phenotype. (medscape.com)
  • People with GAA segments repeated fewer than 300 times tend to have a later appearance of symptoms (after age 25) than those with larger GAA trinucleotide repeats. (medlineplus.gov)
Function2
  • The pathology in FA results from lack of frataxin or its function. (medscape.com)
  • Although its function is not fully understood, frataxin appears to help assemble clusters of iron and sulfur molecules that are critical for the function of many proteins, including those needed for energy production. (medlineplus.gov)
Important2
  • Selective inhibitors of the CREB binding protein (CREBBP)/EP300 bromodomains are required to facilitate the elucidation of biology associated with these important epigenetic targets. (bvsalud.org)
  • An important feature of the optimization process was the successful application of rational structure-based drug design to address bromodomain selectivity issues (particularly against the structurally related BRD4 protein). (bvsalud.org)
Iron1
  • The protein functions in regulating mitochondrial iron transport and respiration. (nih.gov)