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

The human genome, made of about 3 billion bases, encodes between 75 and 100,000 genes. However, most of the genome is made of non coding sequences, whose function is still unknown. When a base variation occurs in a DNA fragment, base change, deletion or insertion of one or several bases, a mutation or a polymorphism is generated depending whether this base change modifies or not the function of the encoded gene. In 1991, a new type of mutation has been discovered, namely the expansion beyond a critical length of a three-base repeat, called triplet. These anomalies due to genome instability are not rare and are now responsible for at least twelve diseases. It is expected that other diseases due to the same mechanism will be discovered in the near future. This article illustrates the concept of mutation by triplet expansion and presents 3 diseases frequently observed in Pediatrics: the fragile X syndrome, myotonic dystrophy and Friedreich's ataxia.
 ...
PMID:[Triple expansion diseases: a new mutational concept]. 1009 45

The expansion of triplet repeat sequences is an initial step in the disease etiology of a number of hereditary neurological disorders in humans. Diseases such as myotonic dystrophy, Huntington's, several spinocerebellar ataxias, fragile X syndrome, and Friedreich's ataxia are caused by the expansions of CTG.CAG, CGG.CCG, or GAA.TTC repeats. The mechanisms of the expansion process have been investigated intensely in E. coli, yeast, transgenic mice, mammalian cell culture, and in human clinical cases. Whereas studies from 1994-1999 have implicated DNA replication and repair at the paused synthesis sites due to the unusual conformations of the triplet repeat sequences, recent work has shown that homologous recombination (gene conversion) is a powerful mechanism for generating massive expansions, in addition to, or in concert with, replication and repair.
 ...
PMID:Genetic instabilities of triplet repeat sequences by recombination. 1132 7

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.
 ...
PMID:Fragile X syndrome and Friedreich's ataxia: two different paradigms for repeat induced transcript insufficiency. 1171 74

To date several neurodegenerative disorders including myotonic dystrophy, Huntington's disease, Kennedy's disease, fragile X syndrome, spinocerebellar ataxias or Friedreich's ataxia have been linked to the expanding trinucleotide sequences. Although phenotypic features vary among these debilitating diseases, the structural abnormalities of the triplet repeat containing DNA sequences is the primary cause for all of these disorders. Expansions of the CAG repeat within coding regions of miscellaneous genes result in the synthesis of aberrant proteins containing enormously long polyglutamine stretches. Such proteins acquire toxic functions and/or may direct cells into the apoptotic cycle. On the other hand, massive expansions of various triplet repeats (i.e., CTG/CAG, CGG/CCG/, GAA/TTC) inside the noncoding regions lead to the silencing of transcription and therefore affect expression of the adjacent genes. The repetitive character of TRS allows stretches of such tracts to form slipped-stranded structures, self-complementary hairpins, triplexes or more complex configurations called "sticky DNA", which are not equally processed by some cellular mechanisms, as compared to random DNA. It is likely that the instability of the short TRS (below the threshold level) occurs due to the SILC pathway, which is driven by the DNA slippage. Accumulation of the short expansions leads to the disease premutation state where the MLC pathway becomes predominant. Independent of which mechanism is involved in the MLC pathway (replication, transcription, repair or recombination) the process of complementary strand synthesis is crucial for the TRS instability. Generally, dependent on the location of the tract which has higher potential to form secondary DNA structure, further processing of such tract may result in expansions (secondary structure formed at the newly synthesized strand) or deletions (structure present on the template strand). Analyses of molecular mechanisms of the TRS genetic instability using bacteria, yeast, cell lines and transgenic animals as models allowed the scientists to better understand the role of some major cellular processes in the development of neurodegenerative disorders in humans. However, it is necessary to remember that most of these investigations were focused on the involvement of each particular process separately. Much less of this work though was dedicated to the search for the interactions between such cellular systems that in effect could result in different rate of TRS expansions. Thus, more intensive studies are necessary in order to fully understand the phenomenon ofthe dynamic mutations leading to the human hereditary neurodegenerative diseases.
 ...
PMID:Molecular mechanisms of TRS instability. 1261 33

The influence of negative superhelical density on the genetic instabilities of long GAA.TTC, CGG.CCG, and CTG.CAG repeat sequences was studied in vivo in topologically constrained plasmids in Escherichia coli. These repeat tracts are involved in the etiologies of Friedreich ataxia, fragile X syndrome, and myotonic dystrophy type 1, respectively. The capacity of these DNA tracts to undergo deletions-expansions was explored with three genetic-biochemical approaches including first, the utilization of topoisomerase I and/or DNA gyrase mutants, second, the specific inhibition of DNA gyrase by novobiocin, and third, the genetic removal of the HU protein, thus lowering the negative supercoil density (-sigma). All three strategies revealed that higher -sigma in vivo enhanced the formation of deleted repeat sequences. The effects were most pronounced for the Friedreich ataxia and the fragile X triplet repeat sequences. Higher levels of -sigma stabilize non-B DNA conformations (i.e. triplexes, sticky DNA, flexible and writhed DNA, slipped structures) at appropriate repeat tracts; also, numerous prior genetic instability investigations invoke a role for these structures in promoting the slippage of the DNA complementary strands. Thus, we propose that the in vivo modulation of the DNA structure, localized to the repeat tracts, is responsible for these behaviors. Presuming that these interrelationships are also found in humans, dynamic alterations in the chromosomal nuclear matrix may modulate the -sigma of certain DNA regions and, thus, stabilize/destabilize certain non-B conformations which regulate the genetic expansions-deletions responsible for the diseases.
 ...
PMID:Increased negative superhelical density in vivo enhances the genetic instability of triplet repeat sequences. 1616 72

Triplet repeat expansions were first discovered in 1991 and since then have been found to be the mutation underlying a range of neurodegenerative, neuromuscular, and cognitive disorders including fragile X syndrome, myotonic dystrophy, Friedreich's ataxia, and the polyglutamine disorders that include Huntington's disease. The repeats exert their detrimental effects through different molecular mechanisms dependent on whether they are located in coding or noncoding regions of the gene in question. During the past 10 yr, a wide range of strategies have been used to successfully establish mouse models for all of these disorders. This review presents an overview of these mouse models, discusses the insights into the molecular pathogenesis of these disorders that have been gained from their analysis and the strategies that are being used to uncover novel therapeutic options.
 ...
PMID:Mouse models of triplet repeat diseases. 1644 16

A mounting number of inherited human disorders, including Huntington disease, myotonic dystrophy, fragile X syndrome, Friedreich ataxia and several spinocerebellar ataxias, have been associated with the expansion of unstable simple sequence DNA repeats. Despite a similar genetic basis, pathogenesis in these disorders is mediated by a variety of both loss and gain of function pathways. Thus, therapies targeted at downstream pathology are likely to be disease specific. Characteristically, disease-associated expanded alleles in these disorders are highly unstable in the germline and somatic cells, with a tendency towards further expansion. Whereas germline expansion accounts for the phenomenon of anticipation, tissue-specific, age-dependent somatic expansion may contribute towards the tissue-specificity and progressive nature of the symptoms. Thus, somatic expansion presents as a novel therapeutic target in these disorders. Suppression of somatic expansion should be therapeutically beneficial, whilst reductions in repeat length could be curative. It is well established that both cis- and trans-acting genetic modifiers play key roles in the control of repeat dynamics. Importantly, recent data have revealed that expanded CAG.CTG repeats are also sensitive to a variety of trans-acting chemical modifiers. These data provide an exciting proof of principle that drug induced suppression of somatic expansion might indeed be feasible. Moreover, as our understanding of the mechanism of expansion is refined more rational approaches to chemical intervention in the expansion pathway can be envisioned. For instance, the demonstration that expansion of CAG.CTG repeats is dependent on the Msh2, Msh3 and Pms2 genes, highlights components of the DNA mismatch repair pathway as therapeutic targets. In addition to potential therapeutic applications, the response of expanded simple repeats to genotoxic assault suggests such sequences could also have utility as bio-monitors of environmentally induced genetic damage in the soma.
 ...
PMID:Chemical modifiers of unstable expanded simple sequence repeats: what goes up, could come down. 1650 Jun 84

Expansions of simple DNA repeats are responsible for more than two dozen hereditary disorders in humans, including fragile X syndrome, myotonic dystrophy, Huntington's disease, various spinocerebellar ataxias, Friedreich's ataxia and others. During the past decade, it became clear that unusual structural features of expandable repeats greatly contribute to their instability and could lead to their expansion. Furthermore, DNA replication, repair and recombination are implicated in the formation of repeat expansions, as shown in various experimental systems. The replication model of repeat expansion stipulates that unusual structures of expandable repeats stall replication fork progression, whereas extra repeats are added during replication fork restart. It also explains the bias toward repeat expansion or contraction that was observed in different organisms.
 ...
PMID:DNA structures, repeat expansions and human hereditary disorders. 1671 48

A substantial portion of the human genome has been found to consist of simple sequence repeats, including microsatellites and minisatellites. Microsatellites, tandem repeats of 1-6 nucleotides, form the template for dynamic mutations, which involve heritable changes in the lengths of repeat sequences. In recent years, a large number of human disorders have been found to be caused by dynamic mutations, the most common of which are trinucleotide repeat expansion diseases. Dynamic mutations are common to numerous nervous system disorders, including Huntington's disease, various spinocerebellar ataxias, fragile X syndrome, fragile X tremor/ataxia syndrome, Friedreich ataxia and other neurodegenerative disorders. The involvement of dynamic mutations in brain disorders will be reviewed, with a focus on the large group caused by CAG/glutamine repeat expansions. We will also outline a proposed role of tandem repeat polymorphisms (TRPs), with unique 'digital' genetic distributions, in modulating brain development and normal function, so as to generate additional mutational diversity upon which natural selection may act.
 ...
PMID:Dynamic mutations as digital genetic modulators of brain development, function and dysfunction. 1750 92

Many human hereditary neurological diseases, including fragile X syndrome, myotonic dystrophy, and Friedreich's ataxia, are associated with expansions of the triplet repeat sequences (TRS) (CGG/CCG, CTG/CAG, and GAA/TTC) within or near specific genes. Mechanisms that mediate mutations of TRS include DNA replication, repair, and gene conversion and (or) recombination. The involvement of the repair systems in TRS instability was investigated in Escherichia coli on plasmid models, and the results showed that the deficiency of some nucleotide excision repair (NER) functions dramatically affects the stability of long CTG inserts. In such models in which there are tens or hundreds of plasmid molecules in each bacterial cell, repetitive sequences may interact between themselves and according to a recombination hypothesis, which may lead to expansions and deletions within such repeated tracts. Since one cannot control interaction between plasmids, it is also sometimes difficult to give precise interpretation of the results. Therefore, using modified lambda phage (lambdaInCh), we have constructed a chromosomal model to study the instability of trinucleotide repeat sequences in E. coli. We have shown that the stability of (CTG/CAG)68 tracts in the bacterial chromosome is influenced by mutations in NER genes in E. coli. The absence of the uvrC or uvrD gene products greatly enhances the instability of the TRS in the chromosome, whereas the lack of the functional UvrA or UvrB proteins causes substantial stabilization of (CTG/CAG) tracts.
 ...
PMID:Chromosomal model for analysis of a long CTG/CAG tract stability in wild-type Escherichia coli and its nucleotide excision repair mutants. 1789 41


<< Previous 1 2 3 4 Next >>