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Query: UMLS:C0016719 (Friedreich's ataxia)
 2,098 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Several neuromuscular and neurodegenerative diseases are caused by genetically unstable triplet repeat sequences (CTG.CAG, CGG.CCG, or AAG.CTT) in or near the responsible genes. We implemented novel cloning strategies with chemically synthesized oligonucleotides to clone seven of the triplet repeat sequences (GTA.TAC, GAT.ATC, GTT.AAC, CAC.GTG, AGG.CCT, TCG.CGA, and AAG.CTT), and the adjoining paper (Ohshima, K., Kang, S., Larson, J. E., and Wells, R. D.(1996) J. Biol. Chem. 271, 16784-16791) describes studies on TTA.TAA. This approach in conjunction with in vivo expansion studies in Escherichia coli enabled the preparation of at least 81 plasmids containing the repeat sequences with lengths of approximately 16 up to 158 triplets in both orientations with varying extents of polymorphisms. The inserts were characterized by DNA sequencing as well as DNA polymerase pausings, two-dimensional agarose gel electrophoresis, and chemical probe analyses to evaluate the capacity to adopt negative supercoil induced non-B DNA conformations. AAG.CTT and AGG.CCT form intramolecular triplexes, and the other five repeat sequences do not form any previously characterized non-B structures. However, long tracts of TCG.CGA showed strong inhibition of DNA synthesis at specific loci in the repeats as seen in the cases of CTG.CAG and CGG.CCG (Kang, S., Ohshima, K., Shimizu, M., Amirhaeri, S., and Wells, R. D.(1995) J. Biol. Chem. 270, 27014-27021). This work along with other studies (Wells, R. D.(1996) J. Biol. Chem. 271, 2875-2878) on CTG.CAG, CGG.CCG, and TTA.TAA makes available long inserts of all 10 triplet repeat sequences for a variety of physical, molecular biological, genetic, and medical investigations. A model to explain the reduction in mRNA abundance in Friedreich's ataxia based on intermolecular triplex formation is proposed.
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PMID:Cloning, characterization, and properties of seven triplet repeat DNA sequences. 866 77

Friedreich's ataxia (FA) was studied in a large inbred Arab family living near Jeddah, Saudi Arabia, in which DNA linkage studies localised the disease gene to 9q13-q21.1. Five siblings (aged 19-35 years), and their 27 year old cousin, had the typical features of FA, however in two patients, tendon reflexes were retained and were indeed brisk in the lower limbs, 13 and 19 years respectively after onset of symptoms: retention of lower limb tendon reflexes is exceptional in FA. Another 6 deceased individuals from two related families are presumed to have had FA.
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PMID:Friedreich's ataxia, with retained lower limb tendon reflexes, in a Saudi Arabian family. 868 84

Molecular genetics is currently the most powerful tool for studying hereditary diseases of the central nervous system: Huntington's disease, dopa-nonresponsive dystonia, Friedreich's disease, etc. The review presents the most important results obtained in this field by the Department of Neurogenetics, Institute of Neurology, in collaboration with several Russian and foreign research institutes. The authors were the first to perform a molecular analysis of mutations and haplotypes in Huntington's disease, dopa-nonresponsive dystonia, Wilson's disease and studied the frequencies of various mutations and main genotype-phenotype correlations in the Russian population. The first direct diagnosis of Huntington's disease in Russia, as well as indirect diagnosis of Friedreich's disease, dopa-nonresponsive dystonia and Wilson's disease have been made. The authors began to investigate trinucleotide repeat expansion in dominant spinocerebellar ataxias and related disorders. The Department of Neurogenetics collected a valuable bank of DNA samples, which is sufficient to perform linkage analysis in essential tremor, novel forms of congenital cerebellar atrophy and progressive muscular atrophy.
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PMID:[Molecular genetic analysis--a new stage in the study of hereditary diseases of the central nervous system]. 875 71

Friedreich's ataxia is the most common inherited spinocerebellar ataxia. A decade of linkage and physical mapping studies have culminated in the identification of the Friedreich's ataxia gene. The presence of homologues in purple bacterial genomes, but not in other bacteria, allows us to infer a mitochondrial location for frataxin (Friedreich's ataxia protein) on the basis of bacterial phylogeny. Frataxin possesses a non-globular N-terminus domain providing a candidate mitochondrial targeting peptide. Clues to the function of frataxin are provided by the mitochondrial location, a clinically similar ataxia with vitamin E deficiency, and certain neuropathies with mitochondrial DNA instability caused by mutations in nuclear genes.
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PMID:Friedreich's ataxia protein: phylogenetic evidence for mitochondrial dysfunction. 893 Dec 68

In the past few years, a new type of genetic mutation, expansion of trinucleotide repeats, has been shown to cause neurologic disease. This new class of mutations was first identified in 1991 as the underlying genetic defect in spinal and bulbar muscular atrophy and the fragile X syndrome, and in recent years, trinucleotide repeat expansions have been found to be the causative mechanism in 10 other neurologic diseases. These mutations are produced by heritable unstable DNA and are termed "dynamic mutations" because of changes in the number of repeat units inherited from generation to generation. In the normal population, these repeat units, although polymorphic, are stably inherited. To date four types of trinucleotide repeat expansions have been identified: (1) long cytosine-guanine-guanine (CGG) repeats in the two fragile X syndromes (FRAXA and FRAXE), (2) long cytosine-thymine-guanine (CTG) repeat expansions in myotonic dystrophy, (3) long guanine-adenine-adenine repeat expansions in Friedreich's ataxia and (4) short cytosine-adenine-guanine repeat expansions (CAG) which are implicated in eight neurodegenerative disorders and are the focus of this review. Diseases that are caused by trinucleotide repeat expansions exhibit a phenomenon called anticipation that can not be explained by conventional Mendelian genetics. Anticipation is defined as increase in the severity of disease with an earlier age of onset of symptoms in successive generations. Anticipation is often influenced by the sex of the transmitting parent, and for most CAG repeat disorders, the disease is more severe when paternally transmitted. The severity and the age of onset of the disease have been correlated with the size of the repeats on mutant alleles, with the age of onset being inversely correlated with the size of the expansion. In all eight disorders caused by CAG repeat expansion, the repeat is located within the coding region of the gene involved and in all cases it is translated into a stretch of polyglutamines in the respective proteins. All the proteins are unrelated outside of the polyglutamine stretch and most are novel with exception of the androgen receptor and the voltage gated alpha 1A calcium channel, which are mutated in spinal and bulbar muscular atrophy and spinocerebellar ataxia type 6. It is intriguing that the proteins are ubiquitously expressed in both peripheral and nervous tissue but in each disorder only a select population of nerve cells are targeted for degeneration as a consequence of the expanded CAG repeat. Current thinking among scientists working on the molecular mechanisms of neurodegeneration in these diseases is that the presence of an expanded polyglutamine confers a gain of function onto the involved protein. To understand the mechanisms underlying the pathogenesis of these diseases, investigators have turned to generating transgenic mice which recapitulate some of the features of the human disease and hence are excellent model systems to study the progression of the disease in vivo.
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PMID:The CAG/polyglutamine tract diseases: gene products and molecular pathogenesis. 921 76

Friedreich's ataxia (FRDA) is an autosomal recessive degenerative disorder that primarily affects the nervous system and heart. Patients with FRDA have point mutations or trinucleotide repeat expansions in both alleles of FRDA, which encodes a protein termed frataxin. We show that the yeast frataxin homologue, which we have named YFH1, localizes to mitochondria and is required to maintain mitochondrial DNA. The YFH1-homologous domain of frataxin functions in yeast and a disease-associated missense mutation of this domain, or the corresponding domain in YFH1, reduces function. Our data suggest that mitochondrial dysfunction contributes to FRDA pathophysiology.
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PMID:Respiratory deficiency due to loss of mitochondrial DNA in yeast lacking the frataxin homologue. 924 Dec 71

Deletion of YDL120, the yeast homologue of the human gene responsible for Friedreich's ataxia, elicits decreased cellular respiration associated with decreased cytochrome c oxidase activity and, in certain nuclear backgrounds, mitochondrial DNA is lost. In the null mutants, the cellular growth is highly sensitive to oxidants, such as H2O2, iron and copper. However, only ferrous sulfate elicits loss of mitochondrial DNA. Mitochondria of the null mutants contain 10 times more iron than wild-type. The neurodegeneration observed in Friedreich's ataxia can be well explained on the basis of a mitochondrial iron overload responsible for an increased production of highly toxic free radicals.
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PMID:Deletion of the yeast homologue of the human gene associated with Friedreich's ataxia elicits iron accumulation in mitochondria. 927 Dec 39

Friedreich ataxia (FRDA), an autosomal recessive, neurodegenerative disease is the most common inherited ataxia. The vast majority of patients are homozygous for an abnormal expansion of a polymorphic GAA triplet repeat in the first intron of the X25 gene, which encodes a mitochondrial protein, frataxin. Cellular degeneration in FRDA may be caused by mitochondrial dysfunction, possibly due to abnormal iron accumulation, as observed in yeast cells deficient for a frataxin homologue. Using RNase protection assays, we have shown that patients homozygous for the expansion have a marked deficiency of mature X25 mRNA. The mechanism(s) by which the intronic GAA triplet expansion results in this reduction of X25 mRNA is presently unknown. No evidence was found for abnormal splicing of the expanded intron 1. Using cloned repeat sequences from FRDA patients, we show that the GAA repeat per se interferes with in vitro transcription in a length-dependent manner, with both prokaryotic and eukaryotic enzymes. This interference was most pronounced in the physiological orientation of transcription, when synthesis of the GAA-rich transcript was attempted. These results are consistent with the observed negative correlation between triplet-repeat length and the age at onset of disease. Using in vitro chemical probing strategies, we also show that the GAA triplet repeat adopts an unusual DNA structure, demonstrated by hyperreactivity to osmium tetroxide, hydroxylamine, and diethyl pyrocarbonate. These results raise the possibility that the GAA triplet-repeat expansion may result in an unusual yet stable DNA structure that interferes with transcription, ultimately leading to a cellular deficiency of frataxin.
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PMID:The GAA triplet-repeat expansion in Friedreich ataxia interferes with transcription and may be associated with an unusual DNA structure. 944 73

The lengthening of tracts of CTG, CGG and GAA triplet repeats during progression of a pedigree has been associated with more than 12 human genetic diseases, including fragile X syndrome, myotonic dystrophy and Friedreich's ataxia. These repetitive sequence elements have the potential to form alternative DNA secondary structures that may contribute to their instability. The alternative DNA secondary structures may mediate errors during DNA replication, repair or recombination of the triplet repeat, leading to expansion. Here we show that DNA composed of pure CTG or CGG repeats exhibits anomalously fast mobility on polyacrylamide gels, confirming a previous observation for DNA containing CTG and CGG triplet repeats flanked by mixed sequence DNA. Moreover, we show that even short tracts of duplex CTG repeats have an unusual helix structure. CTG repeats reduce overall curvature associated with phased A-tract or GGCC curves, but alone they do not introduce curvature into DNA. The reduction in curvature of phased A-tracts by CTG repeats is similar to that afforded by an interspersed flexible region associated with a (TT).(TT) mispair. CTG-containing DNAs exhibit a rapid rate of cyclization, consistent with a flexible helix. These results suggest that tracts of (CTG).(CAG) repeats are inherently flexible. In addition, our results suggest that the unusual rapid electrophoretic mobility of CTG or CGG-containing DNA may be a consequence of an extended flexible DNA chain.
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PMID:CTG repeats associated with human genetic disease are inherently flexible. 946 18

Friedreich ataxia (FRDA) is associated with the expansion of a GAA. TTC triplet repeat in the first intron of the frataxin gene, resulting in reduced levels of frataxin mRNA and protein. To investigate the mechanisms by which the intronic expansion produces its effect, GAA.TTC repeats of various lengths (9 to 270 triplets) were cloned in both orientations in the intron of a reporter gene. Plasmids containing these repeats were transiently transfected into COS-7 cells. A length- and orientation-dependent inhibition of reporter gene expression was observed. RNase protection and Northern blot analyses showed very low levels of mature mRNA when longer GAA repeats were transcribed, with no accumulation of primary transcript. Replication of plasmids carrying long GAA.TTC tracts (approximately 250 triplets) was greatly inhibited in COS-7 cells compared with plasmids carrying (GAA.TTC)9 and (GAA.TTC)90. Replication inhibition was five times greater for the plasmid whose transcript contains (GAA)230 than for the plasmid whose transcript contains (UUC)270. Our in vivo investigation revealed that expanded GAA.TTC repeats from intron I of the FRDA gene inhibit transcription rather than post-transcriptional RNA processing and also interfere with replication. The molecular basis for these effects may be the formation of non-B DNA structures.
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PMID:Inhibitory effects of expanded GAA.TTC triplet repeats from intron I of the Friedreich ataxia gene on transcription and replication in vivo. 960 75


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