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

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.
 ...
PMID:Dominantly inherited, non-coding microsatellite expansion disorders. 1207 68

The generation of long uninterrupted DNA repeats is important for the study of repeat instability associated with several human genetic diseases, including myotonic dystrophy type 1. However, obtaining defined lengths of long repeats in vitro has been problematic. Strand slippage and/or DNA secondary structure formation may prevent efficient ligation. For example, a purified (CTG)140.(CAG)140 repeat fragment containing 4-bp AGCA/TGCT overhanging ends ligated poorly using T4 or Escherichia coli DNA ligase, although limited repeat ligation occurred using thermostable DNA ligase. Here we describe a general procedure for ligating multimers of DNA repeats. Multimers are efficiently ligated when slippage is prevented or when DNA repeats contain a single G/C overhang. A cloning vector is designed from which pure repeat fragments containing a G/C overhang can be generated for further ligation. (CAG)n.(CTG)n DNA molecules longer than 800 bp were generated using this approach. This approach also worked for (GAA)n.(TTC)n, (CCTG)n-(CAGG)n, and (ATTCT)n.(AGAAT)n tracts associated with Friedreich ataxia, DM2, and spinocerebellar ataxia type 10, respectively.
 ...
PMID:Generation of long tracts of disease-associated DNA repeats. 1572 31

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).
 ...
PMID:RNA-mediated neuromuscular disorders. 1677 86

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.
 ...
PMID:Dominant non-coding repeat expansions in human disease. 1872 54

The DNA repeats (CTG).(CAG), (CGG).(CCG), (GAA).(TTC), (ATTCT).(AGAAT), and (CCTG).(CAGG), undergo expansion in humans leading to neurodegenerative disease. A genetic assay for repeat instability has revealed that the activities of RecA and RecB during replication restart are involved in a high rate of deletion of (CTG).(CAG) repeats in E. coli. This assay has been applied to (CCTG).(CAGG) repeats associated with myotonic dystrophy type 2 (DM2) that expand to 11 000 copies and to spinocerebellar ataxia type 10 (SCA10) (ATTCT).(AGAAT) repeats that expand to 4500 copies in affected individuals. DM2 (CCTG).(CAGG) repeats show a moderate rate of instability, less than that observed for the myotonic dystrophy type 1 (CTG).(CAG) repeats, while the SCA10 (ATTCT).(AGAAT) repeats were remarkably stable in E. coli. In contrast to (CTG).(CAG) repeats, deletions of the DM2 and SCA10 repeats were not dependent on RecA and RecB, suggesting that replication restart may not be a predominant mechanism by which these repeats undergo deletion. These results suggest that different molecular mechanisms, or pathways, are responsible for the instability of different disease-associated DNA repeats in E. coli. These pathways involve simple replication slippage and various sister strand exchange events leading to deletions or expansions, often associated with plasmid dimerization. The differences in the mechanisms of repeat deletion may result from the differential propensity of these repeats to form various DNA secondary structures and their differential proclivity for primer-template misalignment during replication.
 ...
PMID:Genetic instabilities of (CCTG).(CAGG) and (ATTCT).(AGAAT) disease-associated repeats reveal multiple pathways for repeat deletion. 1930 11

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.
 ...
PMID:CAG repeat RNA as an auxiliary toxic agent in polyglutamine disorders. 2159 8

Spinocerebellar ataxia type 31 (SCA31) is a relatively common degenerative ataxia in Japan. We recently discovered SCA31 mutation as a complex pentanucleotide repeat containing (TAAAA)(n), (TAGAA)(n), and (TGGAA)(n). The size of this repeat ranged from 2.8 to 3.5 kilo-base pairs (kb). Among these repeats, (TGGAA)(n) repeat appears crucial for SCA31 pathogenesis. The length of this complex repeat inversely correlated with ages of onset in patients. The mutation lies in an intron shared by two different genes, BEAN (brain expressed, associated with NEDD4) and TK2 (thymidine kinase 2), which are transcribed in opposite directions. Thus, the complex pentanucleotide sequence is predicted to be transcribed in both directions, but not necessarily translated into proteins. In situ hybridization analysis in patients' Purkinje cells demonstrated that pentanucleotide repeats transcribed in BEAN direction form RNA aggregates ("RNA foci"). We further found that splicing factors, SFRS1 and SFRS9, binds to (UGGAA)(n), the transcript of (TGGAA)(n) in vitro. These findings may imply that SCA31 conforms to pathogenic mechanisms underlying non-coding repeat disorders, such as myotonic dystrophies (DM1 & DM2), and that SFRS1 and SFRS9 are involved in SCA31 pathogenesis.
 ...
PMID:[Spinocerebellar ataxia type 31]. 2192 37

Myotonic dystrophy type 2 (DM2) is a subtype of the myotonic dystrophies, caused by expansion of a tetranucleotide CCTG repeat in intron 1 of the zinc finger protein 9 (ZNF9) gene. The expansions are extremely unstable and variable, ranging from 75-11,000 CCTG repeats. This unprecedented repeat size and somatic heterogeneity make molecular diagnosis of DM2 difficult, and yield variable clinical phenotypes. To better understand the mutational origin and instability of the ZNF9 CCTG repeat, we analyzed the repeat configuration and flanking regions in 26 primate species. The 3'-end of an AluSx element, flanked by target site duplications (5'-ACTRCCAR-3'or 5'-ACTRCCARTTA-3'), followed the CCTG repeat, suggesting that the repeat was originally derived from the Alu element insertion. In addition, our results revealed lineage-specific repetitive motifs: pyrimidine (CT)-rich repeat motifs in New World monkeys, dinucleotide (TG) repeat motifs in Old World monkeys and gibbons, and dinucleotide (TG) and tetranucleotide (TCTG and/or CCTG) repeat motifs in great apes and humans. Moreover, these di- and tetra-nucleotide repeat motifs arose from the poly (A) tail of the AluSx element, and evolved into unstable CCTG repeats during primate evolution. Alu elements are known to be the source of microsatellite repeats responsible for two other repeat expansion disorders: Friedreich ataxia and spinocerebellar ataxia type 10. Taken together, these findings raise questions as to the mechanism(s) by which Alu-mediated repeats developed into the large, extremely unstable expansions common to these three disorders.
 ...
PMID:The unstable CCTG repeat responsible for myotonic dystrophy type 2 originates from an AluSx element insertion into an early primate genome. 2272 57

RNA fluorescence in situ hybridization (FISH) is a widely used technique for detecting transcripts in fixed cells and tissues. Many variants of RNA FISH have been proposed to increase signal strength, resolution and target specificity. The current variants of this technique facilitate the detection of the subcellular localization of transcripts at a single molecule level. Among the applications of RNA FISH are studies on nuclear RNA foci in diseases resulting from the expansion of tri-, tetra-, penta- and hexanucleotide repeats present in different single genes. The partial or complete retention of mutant transcripts forming RNA aggregates within the nucleoplasm has been shown in multiple cellular disease models and in the tissues of patients affected with these atypical mutations. Relevant diseases include, among others, myotonic dystrophy type 1 (DM1) with CUG repeats, Huntington's disease (HD) and spinocerebellar ataxia type 3 (SCA3) with CAG repeats, fragile X-associated tremor/ataxia syndrome (FXTAS) with CGG repeats, myotonic dystrophy type 2 (DM2) with CCUG repeats, amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) with GGGGCC repeats and spinocerebellar ataxia type 32 (SCA32) with GGCCUG. In this article, we summarize the results obtained with FISH to examine RNA nuclear inclusions. We provide a detailed protocol for detecting RNAs containing expanded CAG and CUG repeats in different cellular models, including fibroblasts, lymphoblasts, induced pluripotent stem cells and murine and human neuronal progenitors. We also present the results of the first single-molecule FISH application in a cellular model of polyglutamine disease.
...
PMID:RNA FISH for detecting expanded repeats in human diseases. 2661 55

For nearly a century, the fruit fly, Drosophila melanogaster, has proven to be a valuable tool in our understanding of fundamental biological processes, and has empowered our discoveries, particularly in the field of neuroscience. In recent years, Drosophila has emerged as a model organism for human neurodegenerative and neuromuscular disorders. In this review, we highlight a number of recent studies that utilized the Drosophila model to study repeat-expansion associated diseases (READs), such as polyglutamine diseases, fragile X-associated tremor/ataxia syndrome (FXTAS), myotonic dystrophy type 1 (DM1) and type 2 (DM2), and C9ORF72-associated amyotrophic lateral sclerosis/frontotemporal dementia (C9-ALS/FTD). Discoveries regarding the possible mechanisms of RNA toxicity will be focused here. These studies demonstrate Drosophila as an excellent in vivo model system that can reveal novel mechanistic insights into human disorders, providing the foundation for translational research and therapeutic development.
 ...
PMID:Drosophila melanogaster As a Model Organism to Study RNA Toxicity of Repeat Expansion-Associated Neurodegenerative and Neuromuscular Diseases. 2837 94


1 2 Next >>