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)

Several human disorders are now known to be caused by expansion of unstable trinucleotide repeat sequences, including fragile X syndrome (FRAX), myotonic dystrophy (DM), spinal and bulbar muscular atrophy (SBMA, also known as Kennedy disease), Huntington disease (HD), dentatorubral-pallidoluysian atrophy (DRPLA), spinocerebellar ataxia type 1 (SCA1), Machado-Joseph disease (MJD), and Friedreich ataxia. As these diseases are studied in more detail, important differences have emerged in the nature of the unstable repeats and the mechanism by which the repeat expansions cause disease symptoms. There are already animal models of some of these disorders, and these are important resources for studying pathology and therapeutic strategies. Diagnostic procedures for these disorders are only beginning to be standardized, and effective therapy will have to wait for further information on disease mechanisms. Much has been learned since discovery of the fragile X syndrome gene in 1991, but much remains to be done.
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PMID:Trinucleotide repeat disorders in humans: discussions of mechanisms and medical issues. 900 50

Expansion of trinucleotide repeats has been identified as a common mechanism of hereditary neurodegenerative diseases including spinal and bulbar muscular atrophy (SBMA), Huntington's disease, dentatorubral-pallidoluysian atrophy (DRPLA), Machado-Joseph disease (MJD), fragile X syndrome, myotonic dystrophy and Friedreich's ataxia. These diseases share unique features, which are difficult to explain based on Mendelian inheritance. These unique clinical genetic features include genetic anticipation and a broad spectrum of clinical presentations, which have been shown to be associated with the instability of the trinucleotide repeats. Recent studies suggest that gene products with expanded polyglutamine tracts may be toxic to neuronal cells, and the mechanisms of neurotoxicity should be thoroughly investigated. To develop therapeutic measures, creation of animal models or cell culture systems for the investigation of neurotoxicity will be indispensable.
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PMID:Molecular genetics of triplet repeats: unstable expansion of triplet repeats as a new mechanism for neurodegenerative diseases. 905 92

Friedreich's ataxia, the most frequent inherited ataxia, is caused, in the vast majority of cases, by large GAA repeat expansions in the first intron of the frataxin gene. The normal sequence corresponds to a moderately polymorphic trinucleotide repeat with bimodal size distribution. Small normal alleles have approximately eight to nine repeats whereas a more heterogeneous mode of large normal alleles ranges from 16 to 34 GAA. The latter class accounts for approximately 17% of normal alleles. To identify the origin of the expansion mutation, we analyzed linkage disequilibrium between expansion mutations or normal alleles and a haplotype of five polymorphic markers within or close to the frataxin gene; 51% of the expansions were associated with a single haplotype, and the other expansions were associated with haplotypes that could be related to the major one by mutation at a polymorphic marker or by ancient recombination. Of interest, the major haplotype associated with expansion is also the major haplotype associated with the larger alleles in the normal size range and was almost never found associated with the smaller normal alleles. The results indicate that most if not all large normal alleles derive from a single founder chromosome and that they represent a reservoir for larger expansion events, possibly through "premutation" intermediates. Indeed, we found two such alleles (42 and 60 GAA) that underwent cataclysmic expansion to pathological range in a single generation. This stepwise evolution to large trinucleotide expansions already was suggested for myotonic dystrophy and fragile X syndrome and may relate to a common mutational mechanism, despite sequence motif differences.
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PMID:Evolution of the Friedreich's ataxia trinucleotide repeat expansion: founder effect and premutations. 920 12

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

The human genome has many nucleotide repeat sequences. These range from a single repeating base to entire duplicated genes. Expansion of repeating triplets of nucleotides in the genome has recently been associated with nine degenerative and developmental neuropsychiatric diseases: fragile X syndrome, fragile X-linked mental retardation, myotonic dystrophy, Friedreich's ataxia, spinal and bulbar muscular atrophy, Huntington's disease, spinocerebellar ataxia type 1, dentatorubral-pallidoluysian atrophy, and Machado-Joseph disease. These diseases are all conditions of the central nervous system; in all of them, the inheritance pattern usually exhibits the phenomenon of anticipation (defined as progressively earlier age of onset or a worsening disease severity over successive generations), and the severity of the phenotypic expression and penetrance appears to be related to the extent of the triplet expansion. Identification of this pathological genetic phenomenon solves several of the mysteries that surrounded these conditions but raises many important questions regarding pathogenic mechanisms that may be shared. There is some indication that triplet expansions may also underlie other neuropsychiatric conditions such as schizophrenia or bipolar disorder.
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PMID:Triplet repeat gene sequences in neuropsychiatric diseases. 938 23

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

Unstable (CAG)n trinucleotide repeat microsatellites are hypothesized to cause schizophrenia. The (CAG)n microsatellite of dominant spinal cerebellar ataxia type 1 (SCA1) is a candidate schizophrenia gene. Autism results from expansions of (CGG)n and (GAA)n trinucleotide repeat stretches at fragile X syndrome (FRAXA), and the recessive Friedreich's ataxia (FA). Dominant ataxia genes may cause schizophrenia and recessive ataxia genes may cause autism. Syndromes with autism show purine synthesis defects (PSDs) and/or pigmentation defects (PDs). Autism is caused by very lengthy expansions of (CAG)n, (CGG)n and (GAA)n repeats, while schizophrenia results from much smaller (CAG)n and (CGG)n repeat expansions.
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PMID:Expanded (CAG)n, (CGG)n and (GAA)n trinucleotide repeat microsatellites, and mutant purine synthesis and pigmentation genes cause schizophrenia and autism. 979

The influence of nucleotide excision repair (NER), the principal in vivo repair system for DNA damages, was investigated in Escherichia coli with uvrA, uvrB and uvrAuvrB mutants with the triplet repeat sequences (TRS) involved in myotonic dystrophy, the fragile X syndrome and Friedreich's ataxia. (CTG*CAG)175was more stable when the (CTG) strand was transcribed than when the (CAG) strand was transcribed in the alternate orientation. A lack of the UvrA protein dramatically increases the instability of this TRS in vivo as compared with the stability of the same sequence in uvrB mutant, which produces an intact UvrA protein. We propose that transcription transiently dissociates the triplet repeat complementary strands enabling the non-transcribed strand to fold into a hairpin conformation which is then sufficiently stable that replication bypasses the hairpin to give large deletions. If the TRS was not transcribed, fewer deletions were observed. Alternatively, in the uvrA-mutant, the hairpins existing on the lagging strand will suffer bypass DNA synthesis to generate deleted molecules. Hence, NER, functionally similar in both prokaryotes and eukaryotes, is an important factor in the genetic instabilities of long transcribed TRS implicated in human hereditary neuro-logical diseases.
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PMID:Nucleotide excision repair affects the stability of long transcribed (CTG*CAG) tracts in an orientation-dependent manner in Escherichia coli. 986 88

The discovery of unstable DNA sequences as the cause of genetic disease is a fascinating new area in human genetics, raising a number of important questions addressing the understanding of both the mechanisms and the effects of this new type of mutation. Trinucleotide repeat expansion mutations have been identified in a number of neurodegenerative diseases, including spinal and bulbar muscular atrophy (SBMA), fragile X syndrome (FRAXA and FRAXE), myotonic dystrophy (DM), Huntington's disease (HD), spinocerebellar ataxia types 1, 2, 3, 6, 7 (SCA1, SCA2, SCA3, SCA6, SCA7), dentatorubral-pallidoluysian atrophy (DRPLA), Friedreich's ataxia (FRDA) and autosomal dominant pure spastic paraplegia (ADPSP). They have been traced to genetic variation in the length of (CTG)n/(CAG)n, (CGG)n/(CCG)n, or (GAA)n/(TTC)n triplet repeats in DNA. In normal individuals these loci contain a short length of triplet repeats (usually 5-40), which is polymorphic within the population. Increases in the lengths of the translated triplet repeats to 40-100 are associated with disease symptoms, whereas the untranslated triplet repeats to 200-3000 are associated with the disease. We concentrated on repeat expansions in myotonic dystrophy. In this symposium, we outline the molecular aspects of myotonic dystrophy including DNA diagnosis and anticipation, and review the similarities and differences among these triplet repeat diseases.
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PMID:[Genomic instability and neurodegenerative disease]. 1006 64

A growing number of hereditary neurodegenerative disorders have been found to be caused by expansion of trinucleotide repeats. A smaller number of diseases such as fragile X syndrome, myotonic dystrophy, and Friedreich's ataxia, have been found to be due to expansions in non-coding DNA. In a large group of diseases, the expansion consists of CAG repeats in the coding region of the gene, producing an expanded polyglutamine sequence in the protein. Nine diseases have so far been identified as belonging to this group: Huntington's disease, spinobulbar muscular atrophy (SBMA), dentatorubral pallidoluysian atrophy (DRPLA), autosomal dominant "pure" spastic paraplegia (ADPSP), and five forms of spinocerebellar ataxia (SCA 1,2,3,6 and 7). Except for SBMA, all of the CAG repeat disorders are characterised by autosomal dominant heredity and anticipation (i.e., earlier onset age and increasing severity in successive generations). The mutated protein causes disease via an as yet unidentified gain-of-function mechanism in specific subsets of neurones. Today, DNA analysis permits the diagnosis of a trinucleotide disease in individual cases.
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PMID:[Growing genes cause neurological diseases]. 1008 35


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