AnatomyOrganismsDiseasesChemicals and DrugsAnalytical, Diagnostic and Therapeutic Techniques and EquipmentPsychiatry and PsychologyPhenomena and ProcessesInformation ScienceHealth Care
Trinucleotide Repeat ExpansionFriedreich AtaxiaTrinucleotide RepeatsIron-Binding ProteinsDNA Repeat ExpansionSpinocerebellar DegenerationsMyotonic DystrophyFragile X SyndromeHuntington DiseaseFragile X Mental Retardation ProteinPhosphotransferases (Alcohol Group Acceptor)AllelesMutationRepetitive Sequences, Nucleic AcidGenetic Diseases, InbornMachado-Joseph DiseaseSpinocerebellar AtaxiasHeredodegenerative Disorders, Nervous SystemBase SequenceNerve Tissue ProteinsMolecular Sequence DataPedigreeMicrosatellite RepeatsGenomic InstabilityFrontotemporal DementiaDNAFlap EndonucleasesAnticipation, GeneticNucleic Acid ConformationInverted Repeat SequencesMinisatellite RepeatsAge of OnsetTandem Repeat SequencesCerebellar AtaxiaIntranuclear Inclusion BodiesPolymerase Chain ReactionChromosome FragilityMuscular Dystrophy, OculopharyngealPhenotypeRNA-Binding ProteinsPolymorphism, GeneticGenetic MarkersModels, GeneticNuclear ProteinsChromosome MappingAmyotrophic Lateral SclerosisGenome, HumanGenetic LinkageProteinsDiseaseNeurodegenerative DiseasesGenes, DominantSequence Analysis, DNAGenotypePeptidesSaccharomyces cerevisiaeHeterozygoteDNA RepairMice, TransgenicDNA PrimersHaplotypesAmino Acid SequenceReceptors, AndrogenExonsTranscription, GeneticRepetitive Sequences, Amino AcidGene FrequencyDNA Mutational AnalysisRNA, MessengerDisease Models, AnimalIron-Sulfur ProteinsChromosomes, Human, XSaccharomyces cerevisiae ProteinsMyoclonic Epilepsies, ProgressiveDNA ReplicationGenetic TestingGenetic Variation
IntronProtein called frataxinChromosomeMitochondrial iron overloadMutationTriplet-repeatHeterochromatinFRDACardiacAllelesHistoneExpressionDegenerationSpinocerebellarPhenotypeLevelsRepressionRegulationFriedreichFriedreich's AtaxiaAccumulationNeurologicSpinalNerveConsistentRepositoryCardiomyopathySubsequentNeuromuscularResultsDecreaseSeverityDisorderApproximatelySKYCLARYSBiomedical researchLossHumanStagesIncreaseTreatmentsPatientsIndividualsStudiesRegion
Intron12
  • 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)
  • 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)
  • n engl j med 1996 oct 17;335(16):1169-75) the severity of friedreich ataxia associated with expansion of gaa repeats in the first intron of the frataxin gene correlates with the number of trinucleotide repeats. (icd9data.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)
  • Friedreich's ataxia is an ultra-rare, genetic, life-shortening, debilitating, and degenerative neuromuscular disorder typically caused by a trinucleotide repeat expansion in the first intron of the frataxin gene, which encodes the mitochondrial protein frataxin. (biogen.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)
  • 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)
  • 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)
Protein called frataxin3
  • 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)
  • This gene encodes a 210-amino-acid protein called frataxin. (medscape.com)
Chromosome5
  • In patients with Prader-Willi syndrome (PWS) and Angelman syndrome (AS), the imprinted gene abnormality is the 15q11-q13 region of chromosome 15. (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)
  • Most forms of this condition are associated with a mutation in a gene on chromosome 9, at band q13, which codes for the mitochondrial protein frataxin. (icd9data.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)
  • 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)
Mitochondrial iron overload2
  • 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)
  • Pathogenic repeat expansions can lead to impaired transcription and reduced frataxin expression, which can result in mitochondrial iron overload and poor cellular iron regulation, increased sensitivity to oxidative stress, and impaired mitochondrial ATP production. (biogen.com)
Mutation5
  • 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)
  • Parents of a child diagnosed with FA are both obligate carriers of an FXN gene mutation. (medscape.com)
  • However, these children only have a risk of being affected if the unaffected parent is a carrier of a mutation in the FXN gene. (medscape.com)
  • 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)
Triplet-repeat1
Heterochromatin3
  • This expansion causes epigenetic changes and formation of heterochromatin near the repeat. (wikipedia.org)
  • The formation of heterochromatin results in reduced transcription of the gene and low levels of frataxin. (wikipedia.org)
  • Histone post-translational modifications near the expanded repeats are consistent with heterochromatin formation and consequent FXN gene silencing. (frontiersin.org)
FRDA14
  • Friedreich's ataxia (FRDA or FA) is an autosomal-recessive genetic disease that causes difficulty walking, a loss of coordination in the arms and legs, and impaired speech that worsens over time. (wikipedia.org)
  • In FRDA, cells produce less frataxin. (wikipedia.org)
  • FRDA shortens life expectancy due to heart disease, but some people can live into their 60s or older. (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)
  • Friedreich ataxia (FRDA) is a rare genetic multisystem disorder caused by a pathological GAA trinucleotide repeat expansion in the FXN gene. (bvsalud.org)
  • The numerous drawbacks of historical cellular and rodent models of FRDA have caused difficulty in performing effective mechanistic and translational studies to investigate the disease. (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)
  • These mice are used as a FRDA model but even with a low frataxin concentration, their phenotype is mild. (bvsalud.org)
  • Friedreich's ataxia (FRDA) is a rare monogenic disease characterized by multisystem, slowly progressive degeneration. (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)
  • 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 demonstrate that the presence of expanded GAA repeats recapitulates the epigenetic modifications and repression of gene expression seen in FRDA. (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 results suggest the potential use of genomic reporter cell models for the study of FRDA and the identification of novel therapies, combining physiologically relevant expression with the advantages of quantitative reporter gene expression. (ox.ac.uk)
Cardiac2
  • 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)
  • To combat these cardiac diseases, the AHA provides funding for biomedical research, advocates for public health policies and resources, and provides education training and tools to the greater community about heart health. (curefa.org)
Alleles2
  • 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)
  • 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)
Histone1
  • By interrogating microarray data from neuronal cells treated with inhibitors of different specificity, we selected two genes encoding histone macroH2A ( H2AFY2 ) and Polycomb group ring finger 2 ( PCGF2 ) that were specifically down-regulated by the inhibitors targeting HDACs1 and 3 versus the more selective inhibitors for further investigation. (frontiersin.org)
Expression2
  • In PWS, the disease results due to loss of paternal gene expression. (wjgnet.com)
  • We now know those structures are very relevant to many critical biological processes like gene regulation, expression of telomerase and telomere maintenance, understanding of growth/oncogenes like C-myc, understanding of organismic development, comprehension of certain enigmatic diseases like ALS and possible new cancer treatments. (anti-agingfirewalls.com)
Degeneration1
  • An autosomal recessive disease, usually of childhood onset, characterized pathologically by degeneration of the spinocerebellar tracts, posterior columns, and to a lesser extent the corticospinal tracts. (icd9data.com)
Spinocerebellar1
  • DNA analysis was negative for the autosomal dominant spinocerebellar ataxia genes of types 1, 2, 3, and 6. (bmj.com)
Phenotype2
  • Although the abnormality is in the same region, the difference in disease and phenotype depends on the parental contribution. (wjgnet.com)
  • 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)
Levels2
  • Heterozygous carriers of the mutant FXN gene have 50% lower frataxin levels, but this decrease is not enough to cause symptoms. (wikipedia.org)
  • 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)
Repression1
  • Both genes are involved in transcriptional repression and we speculate their involvement in FXN gene silencing. (frontiersin.org)
Regulation1
  • Reata is a clinical-stage biopharmaceutical company that develops novel therapeutics for patients with serious or life-threatening diseases by targeting molecular pathways involved in the regulation of cellular metabolism and inflammation. (starkvilledailynews.com)
Friedreich3
  • 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)
  • This project is a global, multicenter, prospective, observational natural history study that can be used to understand the disease progression and support the development of safe and effective drugs and biological products for Friedreich ataxia. (researcherprofiles.org)
  • Clinical management guidelines for Friedreich ataxia: best practice in rare diseases. (medscape.com)
Friedreich's Ataxia7
  • A hallmark of Friedreich's ataxia is impairment of antioxidative defense mechanisms, which play a major role in disease progression. (researcherprofiles.org)
  • Therefore, the ability of omaveloxolone (RTA 408) to activate Nrf2 and induce antioxidant target genes is hypothesized to be therapeutic in patients with Friedreich's ataxia. (researcherprofiles.org)
  • Friedreich's ataxia is an inherited disease that damages your nervous system. (icd9data.com)
  • Friedreich's ataxia is a debilitating neuromuscular disease that progressively robs patients of their mobility and independence," said Susan Perlman, MD, Clinical Professor, Department of Neurology, David Geffen School of Medicine, UCLA. (pharmashots.com)
  • The approval of SKYCLARYS represents an important step forward in the treatment of Friedreich's ataxia, providing physicians with the first disease-specific treatment option approved for patients living with this ultra-rare and progressive disease. (pharmashots.com)
  • The entire Friedreich's ataxia community including patients, clinicians, scientists, pharmaceutical companies, government agencies, and others have worked collaboratively for decades to enable therapeutic development for this debilitating disease. (pharmashots.com)
  • A GAA repeat expansion reporter model of Friedreich's ataxia recapitulates the genomic context and allows rapid screening of therapeutic compounds. (ox.ac.uk)
Accumulation2
  • 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)
Neurologic1
  • Reata has made significant advancements developing therapeutics that regulate cellular metabolism and inflammation in serious neurologic diseases. (biogen.com)
Spinal2
  • 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)
  • Onset of symptoms occurs prior to the age of 10, with the disease primarly impacting the CNS (brain and spinal cord) peripheral nerves, heart, and pancreas. (uchicago.edu)
Nerve1
  • Certain nerve and muscle cells cannot function properly with a shortage of frataxin, leading to the signs and symptoms of FA. (medscape.com)
Consistent1
  • Transcriptional changes were found in all models, but differentially expressed genes consistent with cardiomyopathy and ISRmt were only identified in FXNG127V hearts. (bvsalud.org)
Repository1
  • This study will support genetic modifier studies, biomarker studies, and frataxin protein level assessments by building a sample repository. (researcherprofiles.org)
Cardiomyopathy1
  • Approximately, 60% of patients succumb to the disease in early adulthood due to cardiomyopathy ( 12 ). (frontiersin.org)
Subsequent1
  • The recent discovery and subsequent development of induced pluripotent stem cell (iPSC) technology provides an exciting platform to enable enhanced disease modelling for studies of rare genetic diseases. (bvsalud.org)
Neuromuscular1
  • This is a unique opportunity for Biogen to bolster our near-term growth trajectory, and SKYCLARYS is an excellent complement to our global portfolio of treatments for neuromuscular and rare disease. (biogen.com)
Results1
  • The pathology in FA results from lack of frataxin or its function. (medscape.com)
Decrease1
  • However, the ISRmt has not been investigated in models with disease-relevant, partial decrease in FXN. (bvsalud.org)
Severity1
Disorder1
  • An autosomal recessive inherited disorder caused by mutations in the fxn gene. (icd9data.com)
Approximately1
  • TTC repeats, whereas affected individuals have from approximately 70 to more than 1,000 triplets. (frontiersin.org)
SKYCLARYS3
  • With extensive expertise in rare disease product development and global commercialization, as demonstrated by SPINRAZA and the recent launch of QALSODY, we believe Biogen has the foundation in place to accelerate the delivery of SKYCLARYS to patients around the world," said Christopher Viehbacher, Biogen's President and Chief Executive Officer. (biogen.com)
  • With its clear understanding of the rare disease patient journey and existing commercial infrastructure, we believe Biogen will establish SKYCLARYS as the standard of care in the treatment of this devastating genetic disease. (biogen.com)
  • Reata Pharmaceuticals has partnered with an independent specialty pharmacy specializing in rare disease services to serve as the exclusive SKYCLARYS pharmacy. (pharmashots.com)
Biomedical research1
Loss1
  • However, FA hearts maintain adequate function until advanced disease stages, suggesting initial adaptation to the loss of frataxin (FXN). (bvsalud.org)
Human1
  • 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)
Stages1
  • Advanced stages of disease are associated with supraventricular tachyarrhythmias, most commonly atrial fibrillation. (wikipedia.org)
Increase1
  • This project aims to find ways to increase frataxin by improving its stability and reducing its turnover in the cell. (curefa.org)
Treatments1
  • American Heart Association (AHA) - Founded in 1924, the AHA is the nation's largest and oldest organization dedicated to developing treatments and cures against heart disease and stroke. (curefa.org)
Patients1
  • For patients that require replacement of the SMA1 gene, Zolgensma is an intravenous medication that uses an adeno-associated viral vector to deliver a functional copy of the gene. (wjgnet.com)
Individuals1
  • People with FDRA might have 5-35% of the frataxin protein compared to healthy individuals. (wikipedia.org)
Studies1
  • These models enable studies of the molecular mechanisms underlying GAA-induced pathology, as well as providing an exciting tool for the screening and testing of novel disease-modifying therapies. (bvsalud.org)
Region1