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)
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)
Essential mitochondrial1
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)
Mitochondrial iron overload1
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)
Protein3
This gene encodes a 210-amino-acid protein called frataxin. (medscape.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)
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)
Gene3
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)
Huntington's disease (HD) is a fatal neurodegenerative disorder caused by the expansion of a CAG trinucleotide repeat in the Huntingtin gene. (bvsalud.org)
Triplet4
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)
In animal models, FAN1 prevents somatic expansion of CAG triplet repeats, whereas MMR proteins promote this process. (bvsalud.org)
To understand the molecular basis of these opposing effects, we evaluated FAN1 nuclease function on DNA extrahelical extrusions that represent key intermediates in triplet repeat expansion. (bvsalud.org)
Activation of FAN1 in this manner results in DNA cleavage in the vicinity of triplet repeat extrahelical extrusions thereby leading to their removal in human cell extracts. (bvsalud.org)
Abnormal expansion1
Myotonic dystrophy type 1 is the most frequent form of muscular dystrophy in adults caused by an abnormal expansion of the CTG trinucleotide. (bvsalud.org)
Proteins1
Mitochondria, however, depend on other proteins that are encoded by nuclear genes, constructed in the cytoplasm and then transported into the mitochondria. (wikipedia.org)
Genes1
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)
Levels1
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)
Results2
The pathology in FA results from lack of frataxin or its function. (medscape.com)
These results provide a mechanistic basis for the role of FAN1 in preventing repeat expansion and could explain the antagonistic effects of MMR and FAN1 in disease onset/progression. (bvsalud.org)
Enhance2
Treatment with cisplatin coupled with DHA might enhance cisplatin-induced expansion hang-up throughout SKOV3/DDP tissue. (pkcpathway.com)
Co-transcriptional formation of stable RNA·DNA hybrids can also enhance the instability of repeat tracts. (bvsalud.org)
The resulting expansion either causes a loss of function (e.g. frataxin in Friedreich's ataxia ) or a new gain of function in that gene product (e.g. huntingtin in Huntington's disease ). (pediagenosis.com)
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. (globalgenes.org)
Nuclear2
Mitochondria, however, depend on other proteins that are encoded by nuclear genes, constructed in the cytoplasm and then transported into the mitochondria. (wikipedia.org)
Mitochondria contain their own DNA and synthesize a number of the proteins in the respiratory chain responsible for oxidative phosphorylation (see Chapter 60), although the vast majority of mitochondrial proteins are encoded by nuclear DNA. (pediagenosis.com)
Triplet-repeat2
A number of different disorders have now been identified that have as their major genetic defect an expanded triplet repeat, i.e. there is a large and abnormal expansion of three bases in the genome. (pediagenosis.com)
In normal individuals triplet repeat sequences are not uncommon but once the number of repeats exceeds a certain number the disease will definitely appear. (pediagenosis.com)
Deficiency1
Deficiency of frataxin E is a consequence of FRDA-specific epigenetic silencing, and therapeutic strategies may need to address this deficiency. (nih.gov)
The pathology in FA results from lack of frataxin or its function. (medscape.com)
FRDA1
The remaining individuals with FRDA are compound heterozygotes for an abnormally expanded GAA repeat in the disease-causing range on one allele and another intragenic pathogenic variant on the other allele. (nih.gov)
Mutations1
Mutations in mitochondrial DNA encoded subunit of ATP synthase, MT-ATP6, are frequent causes of neurological mitochondrial diseases with a range of phenotypes from Leigh syndrome and NARP to ataxias and neuropathies. (biomed.news)