Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0016719 (Friedreich's ataxia)
 2,098 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The newly recognized ataxia-ocular apraxia 1 (AOA1; MIM 208920) is the most frequent cause of autosomal recessive ataxia in Japan and is second only to Friedreich ataxia in Portugal. It shares several neurological features with ataxia-telangiectasia, including early onset ataxia, oculomotor apraxia and cerebellar atrophy, but does not share its extraneurological features (immune deficiency, chromosomal instability and hypersensitivity to X-rays). AOA1 is also characterized by axonal motor neuropathy and the later decrease of serum albumin levels and elevation of total cholesterol. We have identified the gene causing AOA1 and the major Portuguese and Japanese mutations. This gene encodes a new, ubiquitously expressed protein that we named aprataxin. This protein is composed of three domains that share distant homology with the amino-terminal domain of polynucleotide kinase 3'- phosphatase (PNKP), with histidine-triad (HIT) proteins and with DNA-binding C2H2 zinc-finger proteins, respectively. PNKP is involved in DNA single-strand break repair (SSBR) following exposure to ionizing radiation and reactive oxygen species. Fragile-HIT proteins (FHIT) cleave diadenosine tetraphosphate, which is potentially produced during activation of the SSBR complex. The results suggest that aprataxin is a nuclear protein with a role in DNA repair reminiscent of the function of the protein defective in ataxia-telangiectasia, but that would cause a phenotype restricted to neurological signs when mutant.
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PMID:The gene mutated in ataxia-ocular apraxia 1 encodes the new HIT/Zn-finger protein aprataxin. 1158

DNA repeat expansion is the genetic basis for a growing number of neurological disorders. While the largest subset of these diseases results in an increase in the length of a polyglutamine tract in the protein encoded by the affected gene, the most common form of inherited mental retardation, fragile X syndrome, and the most common inherited ataxia, Friedreich's ataxia, are both caused by expansions that are transcribed but not translated. These expansions both decrease expression of the gene in which the expanded repeat is located, but they do so by quite different mechanisms. In fragile X syndrome, CGG. CCG expansion in the 5' untranslated region of the FMR1 gene leads to hypermethylation of the repeats and the adjacent CpG-rich promoter. Methylation prevents the binding of the transcription factor alpha-Pal/NRF-1, and may indirectly affect the binding of other factors via the formation of transcriptionally silent chromatin. In Friedreich's ataxia, GAA. TTC expansion in an intron of the FRDA gene reduces expression by interfering with transcription elongation. The model that best describes the available data is transcription-driven formation of a transient purine. purine. pyrimidine DNA triplex behind an advancing RNA polymerase. This structure lassoes the RNA polymerase that caused it, trapping the enzyme on the template.
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PMID:Fragile X syndrome and Friedreich's ataxia: two different paradigms for repeat induced transcript insufficiency. 1171 74

Mitochondrial dysfunction causes or exacerbates a number of diseases. These include genetic disorders such as Friedreich's ataxia where the primary lesion is a defect in a nuclear gene and those diseases caused by mutations to mitochondrial DNA. Mitochondrial damage also contributes to neurodegenerative diseases, diabetes and ischaemia-reperfusion injury. Drug therapies to prevent or alleviate mitochondrial dysfunction use redox active compounds, anti-oxidants or mitochondrial co-factors, however, their effectiveness is limited. A promising approach to increase the selectivity and potency of these compounds is to modify them so that they concentrate within mitochondria. This can be done by incorporating a lipophilic cation which causes the molecules to concentrate several hundred-fold in mitochondria, driven by the membrane potential across the inner membrane. As lipophilic cations cross biological membranes easily, they can be delivered to mitochondria of the heart, brain and skeletal muscle, the organs most affected by mitochondrial damage. Mitochondria-targeted lipophilic cations may lead to improved therapies for diseases involving mitochondrial dysfunction.
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PMID:Development of lipophilic cations as therapies for disorders due to mitochondrial dysfunction. 1172 11

Autosomal recessive ataxias are a heterogeneous group of rare neurodegenerative diseases characterized by early onset cerebellar ataxia associated with various neurologic, ophthalmologic and systemic signs. In comparison with autosomal dominant ataxias, the group of recessive ataxias is less extensively characterized. In fact, only a few conditions have been genetically characterized. The pathogenesis of these forms is associated with a "loss of function" of specific cellular proteins involved in metabolic homeostasis, cell cycle, and DNA repair/protection processing. The two most common autosomal recessive ataxias, in European countries, are Friedreich's ataxia and ataxia telangiectasia. Other forms are much less frequent, and include ataxia with vitamin E deficiency, abetalipoproteinemia. Refsum's disease, spastic ataxia, infantile onset spinocerebellar ataxia, and ataxia with oculomotor apraxia. These pathological conditions, although extremely rare, have nevertheless to be carefully considered in differential diagnosis, not only for correct nosographical classification, but particularly, for specific prognostic and therapeutic implications. Some of these diseases exhibit a peculiar regional distribution. An updated review of the clinical, genetic, and pathogenic aspects of recessive ataxias is presented. Specific management problems with respect to diagnosis and genetic counseling are discussed.
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PMID:The complex clinical and genetic classification of inherited ataxias. II. Autosomal recessive ataxias. 1173 74

Friedreich's ataxia, the most common autosomal recessive inherited ataxia, is characterized by progressive gait and limb ataxia. Friedreich's ataxia is known for its occurrence within the first or second decade of life and is associated with hypertrophic cardiomyopathy, and in some cases with diabetes. Genetically, it is identified by the expression of an unstable trinucleotide GAA repeat expansion located in the first intron of the X25 gene on chromosome 9. Two brothers with very late adult-onset ataxia, and their unaffected sister, were examined for the clinical presentation of FA and for the presence of the mutated FA gene. The relationship of the expanded gene sequence to the severity of disease and age of onset were evaluated. Clinical examination revealed that the two brothers had mild ataxia and proprioceptive loss, with age of onset between 60 and 70 years of age. DNA from peripheral blood nucleated cells demonstrated a small homozygous expansion, with approximately 120-130 GAA repeats in the X25 gene in both patients. The expanded repeats were interrupted either with GAAGAG, GAAGGA, or GAAGAAAA sequences. The unaffected sister carried a normal FA genotype with 8-uninterrupted GAA repeat, observed by sequence analysis. In addition, the levels of FA gene transcript in both brothers were relatively lower than that in the unaffected sister. No detectable cardiomyopathy or diabetes was observed. Phenotypic diversity of FA is increasingly expanding. The age of onset and the structure of GAA repeat expansion plays an important role in determining the clinical features and the differential diagnosis of FA. The confirmation of the FA gene mutation in the atypical case, broadens the clinical spectrum of FA, and supports the idea that patients with even a mild form of ataxia of late adult onset should be considered for molecular testing.
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PMID:Sequence variation in GAA repeat expansions may cause differential phenotype display in Friedreich's ataxia. 1174 52

It is well established that GAA/TTC base triplet expansion is the cause of degenerative disorder in Freidreich's Ataxia. It is also known that these repeat sequences fold back to form the unusual intramolecular triple helix structures in DNA of the type Pyrimidine *Purine *Pyrimidine or Purine *Purine*Pyrimidine. In this paper we report on the stability of Purine *Purine*Pyrimidine intermolecular triple helix DNA containing GAA/TTC repeats under physiological conditions. Using the oligonucleotides 5' TCGC GAA GAA GAA GAA GAA CGCT 3', 5'-AGCG TTC TTC TTC TTC TTC GCGA-3' for duplex and 5'-AAG AAG AAG AAG AAG -3' as triplex forming strand (TFO), we have established the formation of triplex by UV-melting temperature (Tm), stoichiometry of mixing and circular dichroic spectra. This was further confirmed by gel-retardation assay. The thermodynamic parameters Delta G, Delta H and Delta S for both duplex and triplex formation were determined at different salt concentrations. The results suggest the formation of a stable intermolecular, anti - parallel triplex in GAA/TTC repeat sequences where each repeat unit contains two A*A*T and one G*G*C triplet. The therapeutic agents and TFOs, which competitively inhibit the in-vivo intra-molecular triplex by formation of a more stable inter-molecular triplex, could be used to reverse the transcription deficit in GAA/TTC expansions in Frataxin gene.
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PMID:Formation and thermodynamic stability of intermolecular (R*R*Y) DNA triplex in GAA/TTC repeats associated with Freidreich's ataxia. 1184 30

The mitochondrial protein frataxin helps maintain appropriate iron levels in the mitochondria of yeast and humans. A deficiency of this protein in humans causes Friedreich's ataxia, while its complete absence in yeast (Delta yfh1 mutant) results in loss of mitochondrial DNA, apparently due to radicals generated by excess iron. We found that the absence of frataxin in yeast also leads to nuclear damage, as evidenced by inducibility of a nuclear DNA damage reporter, increased chromosomal instability including recombination and mutation, and greater sensitivity to DNA-damaging agents, as well as slow growth. Addition of a human frataxin mutant did not prevent nuclear damage, although it partially complemented the Delta yfh1 mutant in preventing mitochondrial DNA loss. The effects in Delta yfh1 mutants result from reactive oxygen species (ROS), since (i) Delta yfh1 cells produce more hydrogen peroxide, (ii) the effects are alleviated by a radical scavenger and (iii) the glutathione peroxidase gene prevents an increase in mutation rates. Thus, the frataxin protein is concluded to have a protective role for the nucleus as well as the mitochondria.
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PMID:The mitochondrial protein frataxin prevents nuclear damage. 1201 17

Over 100 mutations of mitochondrial DNA (mtDNA) have been associated with human disease. The phenotypic manifestation of mtDNA mutations is extremely broad, from oligosymptomatic patients with isolated deafness, diabetes, ophthalmoplegia, etc., to complex encephalomyopathic disorders that may include dementia, seizures, ataxia, stroke-like episodes, etc. The genotype variants are also wide, with rearrangements (deletions, duplications) and point mutations affecting protein coding genes, tRNAs and rRNAs. There are some broad genotype/phenotype correlations but also substantial overlap. The pathogenetic mechanisms involved in the expression of mtDNA mutations are still not yet fully understood. More recently, mutations of nuclear genes encoding subunits of the respiratory chain, particularly those of complex I, have been identified. These predominantly, but not exclusively, involve infant onset disease with early death. Recently it has become clear that the function of the respiratory chain may be impaired by mutations affecting other mitochondrial proteins or as a secondary phenomenon to other intracellular biochemical derangements. Examples include Friedreich ataxia where a mutation of a nuclear encoded protein (frataxin), probably involved in iron homeostasis in mitochondria, results in severe deficiency of the respiratory chain in a pattern indicative of free radical mediated damage. Mutations of nuclear encoded proteins involved in cytochrome oxidase assembly and maintenance have been characterised and, as predicted, are associated with severe deficiency of cytochrome oxidase and, most frequently, Leigh syndrome. Defects of intracellular metabolism, with particularly excess-free radical generation including nitric oxide or peroxynitrite, may cause secondary damage to the respiratory chain. This is probably of relevance in Huntington disease, motor neuron disease (amyotrophic lateral sclerosis) and Wilson disease. These disorders seem to have defective oxidative phosphorylation as a common pathway in their pathogenesis and it may be that treatments designed to improve respiratory chain function may ameliorate the progression of these disorders.
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PMID:Primary and secondary defects of the mitochondrial respiratory chain. 1213 29

Friedreich's ataxia is caused by the massive expansion of GAA.TTC repeats in intron 1 of the frataxin (X25) gene. Our prior investigations showed that long GAA.TTC repeats formed very stable triplex structures which caused two repeat tracts to adhere to each other (sticky DNA). This process was dependent on negative supercoiling and the presence of divalent metal ions. Herein, we have investigated the formation of sticky DNA from plasmid monomers and dimers; sticky DNA is formed only when two tracts of sufficiently long (GAA.TTC)(n) (n = 59-270) are present in a single plasmid DNA and are in the direct repeat orientation. If the inserts are in the indirect (inverted) repeat orientation, no sticky DNA was observed. Furthermore, kinetic studies support the intramolecular nature of sticky DNA formation. Electron microscopy investigations also provide strong data for sticky DNA as a single long triplex. Hence, these results give new insights into our understanding of the capacity of sticky DNA to inhibit transcription and thereby reduce the level of frataxin protein as related to the etiology of Friedreich's ataxia.
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PMID:Sticky DNA, a long GAA.GAA.TTC triplex that is formed intramolecularly, in the sequence of intron 1 of the frataxin gene. 1216 37

The polypurine.polypyrimidine sequence requirements for the formation of sticky DNA were evaluated in Escherichia coli plasmid systems to determine the potential occurrence of this conformation throughout biological systems. A mirror repeat, dinucleotide tract of (GA.TC)(37), which is ubiquitous in eukaryotes, formed sticky DNA, but shorter sequences of 10 or 20 repeats were inert. (GGA.TCC)(n) inserts (where n = 126, 159, and 222 bp) also formed sticky DNA. As shown previously, the control sequence (GAA.TTC)(150) (450 bp) readily adopted the X-shaped sticky structure; however, this structure has never been found for the nonpathogenic (GAAGGA.TCCTTC)(65) of the same approximate length (390 bp). A sequence that is replete with polypurine.polypyrimidine tracts that can form triplexes and slipped structures but lacks long repeating motifs (the 2.5-kbp intron 21 sequence from the polycystic kidney disease gene 1) was also inert. Interestingly, tracts of (GAA.TTC)(n) (where n = 176 or 80) readily formed sticky DNA with (GAAGGA.TCCTTC)(65) cloned into the same plasmid when the pair of inserts was in the direct, but not in the indirect (inverted), orientation. The stabilities of the triple base (Watson-Crick and Hoogsteen) interactions in the DNA/DNA associated triplex region of the sticky conformations account for these observations. Our results have significant chemical and biological implications for the structure and function of this unusual DNA conformation in Friedreich's ataxia.
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PMID:Sticky DNA: effect of the polypurine.polypyrimidine sequence. 1216 38


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