Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004134 (ataxia)
 15,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Iraqi-Jewish optic atrophy plus is an autosomal recessive condition characterized by infantile optic atrophy, an early onset movement disorder, and 3-methylglutaconic aciduria. Other features include spastic paraplegia, mild ataxia, mild cognitive deficiency and dysarthria. This disorder was identified in inbred Iraqi-Jewish kindreds in which relationships between most of the affected individuals were unknown. In this study we identify linkage to chromosome 19q13.2-q13.3 by using a DNA pooling strategy to perform a genome wide screen followed by a high density search for shared segments among affected individuals in candidate regions identified in the initial genome wide screen. A significantly high positive lod score of 6.14 at zero recombination was obtained for the CTG repeat in the 3' untranslated region of the myotonic dystrophy protein kinase gene. The existence of multiple recombinant individuals indicates the disease interval can be further narrowed with additional markers. Linkage disequilibrium was seen in six polymorphic markers across a 1 Mb interval. This region is well characterized and contains several candidate genes.
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PMID:Iraqi-Jewish kindreds with optic atrophy plus (3-methylglutaconic aciduria type 3) demonstrate linkage disequilibrium with the CTG repeat in the 3' untranslated region of the myotonic dystrophy protein kinase gene. 909 59

Dominantly inherited diseases are generally caused by mutations resulting in gain of function protein alterations. However, a CTG expansion located in the 3' untranslated portion of a kinase gene was found to cause myotonic dystrophy type 1, a multisystemic dominantly inherited disorder. The recent discovery that an untranslated CCTG expansion causes the same constellation of clinical features in myotonic dystrophy type 2 (DM2), along with other recent discoveries on DM1 pathogenesis, have led to the understanding that both DM1 and DM2 mutations are pathogenic at the RNA level. These findings indicate the existence of a new category of disease wherein repeat expansions in RNA alter cellular function. Pathogenic repeat expansions in RNA may also be involved in spinocerebellar ataxia types 8, 10 and 12, and Huntington's disease-like type 2.
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PMID:Dominantly inherited, non-coding microsatellite expansion disorders. 1207 68

At least 15 human diseases have been associated with the length-dependent expansion of gene-specific (CTG).(CAG) repeats, including myotonic dystrophy (DM1) and spinocerebellar ataxia type 1 (SCA1). Repeat expansion is likely to involve unusual DNA structures. We have structurally characterized such DNA, with (CTG)(n).(CAG)(n) repeats of varying length (n=17-79), by high-resolution gel electrophoresis, and have probed their surfaces with anti-DNA antibodies of known specificities. We prepared homoduplex S-DNAs, which are (CTG)x.(CAG)y where x=y, and heteroduplex SI-DNAs, which are hybrids where x>y or x<y. S-DNAs formed many different species of slipped isomers, as indicated by its multiple electrophoretic species. In contrast, SI-DNAs formed distinct structures, as indicated by the limited electrophoretic species for all possible repeat length pairings. Sister SI-DNAs with an excess of CAG repeats always migrated slower than their sister SI-DNAs with an excess of CTG repeats. Strikingly, both the propensity to form slipped structures and the pattern of S-DNAs, but not SI-DNAs, varied for similar lengths of CTG/CAG repeats between the DM1 and SCA1 loci, highlighting a role for flanking cis-elements in S-DNA but not SI-DNA formation. Slipped structures bound structure and nucleotide-specific anti-DNA antibodies. Binding of anti-B-DNA antibodies was reduced for both S-DNAs and SI-DNAs relative to their linear forms. SI-DNAs bound anti-Z-DNA antibodies, while both S and SI-DNAs bound anti-cruciform antibodies, revealing shared characteristics between the corresponding DNA structures and slipped DNAs. Such features of the repeats may be recognized by cellular proteins known to bind such structures.
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PMID:Slipped (CTG).(CAG) repeats of the myotonic dystrophy locus: surface probing with anti-DNA antibodies. 1296 69

Myotonic dystrophy type 1 (DM1) is caused by a CTG expansion mutation located in the 3' untranslated portion of the dystrophica myotonin protein kinase gene. The identification and characterization of RNA-binding proteins that interact with expanded CUG repeats and the discovery that a similar transcribed but untranslated CCTG expansion in an intron causes myotonic dystrophy type 2 (DM2) have uncovered a new type of mechanism in which microsatellite expansion mutations cause disease through an RNA gain-of-function mechanism. This review discusses RNA pathogenesis in DM1 and DM2 and evidence that similar mechanisms may play a role in a growing number of dominant noncoding expansion disorders, including fragile X tremor ataxia syndrome (FXTAS), spinocerebellar ataxia type 8 (SCA8), SCA10, SCA12, and Huntington's disease-like 2 (HDL2).
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PMID:RNA-mediated neuromuscular disorders. 1677 86

We report two brothers with a progressive cerebellar syndrome due to spinocerebellar ataxia type 8 (SCA8). In addition to severe cerebellar atrophy, both had prominent white matter hyperintensities on cranial MRI. This is the first report of white matter hyperintensities on cranial MRI in patients with SCA8. A disorder due to a similar molecular basis, myotonic dystrophy 1 (DM1), is known to have white matter hyperintensities on cranial MRI. Cognitive impairment is well described in DM1 and is being recognized in SCA8. The significance of these associations is discussed.
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PMID:White matter hyperintense lesions in genetically proven spinocerebellar ataxia 8. 1792 Jan 87

Spinocerebellar ataxia type 8 (SCA8) is a dominantly inherited, slowly progressive neurodegenerative disorder caused by a CTG.CAG repeat expansion located on chromosome 13q21. The expansion mutation was isolated directly from the DNA of a single patient using RAPID cloning and subsequently shown to co-segregate with disease in additional ataxia families including a seven-generation kindred (the MN-A family). The size-dependent penetrance of the repeat found in the large MN-A kindred makes it appear as though some parts of the family have a dominant disorder while other parts of this same family have recessive or sporadic forms of ataxia. While the linkage and size-dependent penetrance of the SCA8 CTG.CAG expansion in the MN-A family argue that the SCA8 expansion causes ataxia, the reduced penetrance in other SCA8 families and the discovery of expansions in the general population have led to a controversy surrounding whether or not the SCA8 expansion is pathogenic. A recently reported mouse model in which SCA8 BAC-expansion but not BAC-control lines develop a progressive neurological phenotype now demonstrates the pathogenicity of the (CTG.CAG)(n) expansion. These mice show a loss of cerebellar GABAergic inhibition and, similar to human patients, have 1C2-positive intranuclear inclusions in Purkinje cells and other neurons. Additional studies demonstrate that the SCA8 expansion is expressed in both directions (CUG and CAG) and that a novel gene expressed in the CAG direction encodes a pure polyglutamine expansion protein (ataxin 8, ATXN8). Moreover, the expression of non-coding (CUG)(n) expansion transcripts (ataxin 8 opposite strand, ATXN8OS) and the discovery of intranuclear polyglutamine inclusions suggest SCA8 pathogenesis may involve toxic gain-of-function mechanisms at both the protein and RNA levels. Our data, combined with the recently reported antisense transcripts spanning the DM1 repeat expansion in the CAG direction and the growing number of reports of antisense transcripts expressed throughout the mammalian genome, raises the possibility that bidirectional expression across pathogenic microsatellite expansions may occur in other expansion disorders, and that potential pathogenic effects of mutations expressed from both strands should be considered.
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PMID:Bidirectional expression of the SCA8 expansion mutation: one mutation, two genes. 1841 92

The general model that dominant diseases are caused by mutations that result in a gain or change in function of the corresponding protein was challenged by the discovery that the myotonic dystrophy type 1 mutation is a CTG expansion located in the 3' untranslated portion of a kinase gene. The subsequent discovery that a similar transcribed but untranslated CCTG expansion in an intron causes the same multisystemic features in myotonic dystrophy type 2 (DM2), along with other developments in the DM1 field, demonstrate a mechanism in which these expansion mutations cause disease through a gain of function mechanism triggered by the accumulation of transcripts containing CUG or CCUG repeat expansions. A similar RNA gain of function mechanism has also been implicated in fragile X tremor ataxia syndrome (FXTAS) and may play a role in pathogenesis of other non-coding repeat expansion diseases, including spinocerebellar ataxia type 8 (SCA8), SCA10, SCA12 and Huntington disease-like 2.
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PMID:Dominant non-coding repeat expansions in human disease. 1872 54

Herein, we describe the design of high affinity ligands that bind expanded rCUG and rCAG repeat RNAs expressed in myotonic dystrophy type 1 (DM1) and spinocerebellar ataxia type 3. These ligands also inhibit, with nanomolar IC(50) values, the formation of RNA-protein complexes that are implicated in both disorders. The expanded rCUG and rCAG repeats form stable RNA hairpins with regularly repeating internal loops in the stem and have deleterious effects on cell function. The ligands that bind the repeats display a derivative of the bisbenzimidazole Hoechst 33258, which was identified by searching known RNA-ligand interactions for ligands that bind the internal loop displayed in these hairpins. A series of 13 modularly assembled ligands with defined valencies and distances between ligand modules was synthesized to target multiple motifs in these RNAs simultaneously. The most avid binder, a pentamer, binds the rCUG repeat hairpin with a K(d) of 13 nM. When compared to a series of related RNAs, the pentamer binds to rCUG repeats with 4.4- to >200-fold specificity. Furthermore, the affinity of binding to rCUG repeats shows incremental gains with increasing valency, while the background binding to genomic DNA is correspondingly reduced. Then, it was determined whether the modularly assembled ligands inhibit the recognition of RNA repeats by Muscleblind-like 1 (MBNL1) protein, the expanded-rCUG binding protein whose sequestration leads to splicing defects in DM1. Among several compounds with nanomolar IC(50) values, the most potent inhibitor is the pentamer, which also inhibits the formation of rCAG repeat-MBNL1 complexes. Comparison of the binding data for the designed synthetic ligands and MBNL1 to repeating RNAs shows that the synthetic ligand is 23-fold higher affinity and more specific to DM1 RNAs than MBNL1. Further studies show that the designed ligands are cell permeable to mouse myoblasts. Thus, cell permeable ligands that bind repetitive RNAs have been designed that exhibit higher affinity and specificity for binding RNA than natural proteins. These studies suggest a general approach to targeting RNA, including those that cause RNA dominant disease.
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PMID:Rational design of ligands targeting triplet repeating transcripts that cause RNA dominant disease: application to myotonic muscular dystrophy type 1 and spinocerebellar ataxia type 3. 1955 11

Trinucleotide expansions cause disease by both protein- and RNA-mediated mechanisms. Unexpectedly, we discovered that CAG expansion constructs express homopolymeric polyglutamine, polyalanine, and polyserine proteins in the absence of an ATG start codon. This repeat-associated non-ATG translation (RAN translation) occurs across long, hairpin-forming repeats in transfected cells or when expansion constructs are integrated into the genome in lentiviral-transduced cells and brains. Additionally, we show that RAN translation across human spinocerebellar ataxia type 8 (SCA8) and myotonic dystrophy type 1 (DM1) CAG expansion transcripts results in the accumulation of SCA8 polyalanine and DM1 polyglutamine expansion proteins in previously established SCA8 and DM1 mouse models and human tissue. These results have implications for understanding fundamental mechanisms of gene expression. Moreover, these toxic, unexpected, homopolymeric proteins now should be considered in pathogenic models of microsatellite disorders.
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PMID:Non-ATG-initiated translation directed by microsatellite expansions. 2117 21

Over 20 genetic loci with abnormal expansions of short tandem repeats have been associated with human hereditary neurological diseases. Of these, specific trinucleotide repeats located in non-coding and coding regions of individual genes implicated in these disorders are strongly overrepresented. Expansions of CTG, CGG and CAG repeats are linked to, respectively, myotonic dystrophy type 1 (DM1), fragile X-associated tremor/ataxia syndrome (FXTAS), as well as Huntington's disease (HD) and a number of spinocerebellar ataxias (SCAs). Expanded CAG repeats in translated exons trigger the most disorders for which a protein gain-of-function mechanism has been proposed to explain neurodegeneration by polyglutamine-rich (poly-Q) proteins. However, the results of last years showed that RNA composed of mutated CAG repeats can also be toxic and contribute to pathogenesis of polyglutamine disorders through an RNA-mediated gain-of-function mechanism. This mechanism has been best characterized in the non-coding repeat disorder DM1 and is also implicated in several other diseases, such as FXTAS, spinocerebellar ataxia type 8 (SCA8), Huntington's disease-like 2 (HDL2), as well as in myotonic dystrophy type 2 (DM2), spinocerebellar ataxia type 10 (SCA10) and type 31 (SCA31). In this review, we summarize recent findings that emphasize the participation of coding mutant CAG repeat RNA in the pathogenesis of polyglutamine disorders, and we discuss the basis of an RNA gain-of-function model in non-coding diseases such as DM1, FXTAS and SCA8.
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PMID:CAG repeat RNA as an auxiliary toxic agent in polyglutamine disorders. 2159 8


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