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Nature Reviews. Genetics Nov 2010Trinucleotide expansion underlies several human diseases. Expansion occurs during multiple stages of human development in different cell types, and is sensitive to the... (Review)
Review
Trinucleotide expansion underlies several human diseases. Expansion occurs during multiple stages of human development in different cell types, and is sensitive to the gender of the parent who transmits the repeats. Repair and replication models for expansions have been described, but we do not know whether the pathway involved is the same under all conditions and for all repeat tract lengths, which differ among diseases. Currently, researchers rely on bacteria, yeast and mice to study expansion, but these models differ substantially from humans. We need now to connect the dots among human genetics, pathway biochemistry and the appropriate model systems to understand the mechanism of expansion as it occurs in human disease.
Topics: Animals; Chromosomal Instability; Female; Growth and Development; Human Development; Humans; Male; Mice; Models, Biological; Saccharomyces cerevisiae; Spermatogonia; Trinucleotide Repeat Expansion; Trinucleotide Repeats
PubMed: 20953213
DOI: 10.1038/nrg2828 -
Advances in Neurobiology 2018RNA metabolism impacts different steps of mRNA life cycle including splicing, polyadenylation, nucleo-cytoplasmic export, translation, and decay. Growing evidence... (Review)
Review
RNA metabolism impacts different steps of mRNA life cycle including splicing, polyadenylation, nucleo-cytoplasmic export, translation, and decay. Growing evidence indicates that defects in any of these steps lead to devastating diseases in humans. This chapter reviews the various RNA metabolic mechanisms that are disrupted in Myotonic Dystrophy-a trinucleotide repeat expansion disease-due to dysregulation of RNA-Binding Proteins. We also compare Myotonic Dystrophy to other microsatellite expansion disorders and describe how some of these mechanisms commonly exert direct versus indirect effects toward disease pathologies.
Topics: Humans; Microsatellite Repeats; Myotonic Dystrophy; RNA; RNA Splicing; Trinucleotide Repeat Expansion
PubMed: 29916021
DOI: 10.1007/978-3-319-89689-2_8 -
Acta Ophthalmologica Aug 2022Fuchs' endothelial corneal dystrophy (FECD) has been considered a genetically heterogeneous disease but is increasingly associated with the transcription factor 4 (TCF4)...
PURPOSE
Fuchs' endothelial corneal dystrophy (FECD) has been considered a genetically heterogeneous disease but is increasingly associated with the transcription factor 4 (TCF4) gene. This study investigates the prevalence of the cytosine-thymine-guanine (CTG) repeat expansion in TCF4 among FECD patients in northern Sweden coupled to the phenotype.
METHODS
Blood samples were collected from 85 FECD cases at different stages. Short tandem repeat PCR and triplet repeat-primed PCR were applied in order to determine TCF4 (CTG) genotype.
RESULTS
A (CTG) repeat expansion (n > 50) in TCF4 was identified in 76 of 85 FECD cases (89.4%) and in four of 102 controls (3.9%). The median (CTG) repeat length was 81 (IQR 39.3) in mild FECD and 87 (IQR 13.0) in severe FECD (p = 0.01). A higher number of (CTG) repeats in an expanded TCF4 allele increased the probability of severe FECD. Other ocular surgery was overrepresented in FECD cases without a (CTG) repeat expansion (44.4%, n = 4) compared with 3.9% (n = 3) in FECD cases with an (CTG) repeat expansion (p < 0.001).
CONCLUSION
In northern Sweden, the FECD phenotype is associated with (CTG) expansion in the TCF4 gene, with nearly 90% of patients being hetero- or homozygous for (CTG) expansion over 50 repeats. Furthermore, the severity of FECD was associated with the repeat length in the TCF4 gene. Ocular surgery might act as an environmental factor explaining the clinical disease in FECD without a repeat expansion in TCF4.
Topics: Fuchs' Endothelial Dystrophy; Genetic Predisposition to Disease; Humans; Sweden; Transcription Factor 4; Trinucleotide Repeat Expansion
PubMed: 34644448
DOI: 10.1111/aos.15032 -
Nature Communications Apr 2023Expanded CAG/CTG repeats are sites of DNA damage, leading to repeat length changes. Homologous recombination (HR) is one cause of repeat instability and we hypothesized...
Expanded CAG/CTG repeats are sites of DNA damage, leading to repeat length changes. Homologous recombination (HR) is one cause of repeat instability and we hypothesized that gap filling was a driver of repeat instability during HR. To test this, we developed an assay such that resection and ssDNA gap fill-in would occur across a (CAG) or (CTG) repeat tract. When the ssDNA template was a CTG sequence, there were increased repeat contractions and a fragile site was created leading to large-scale deletions. When the CTG sequence was on the resected strand, resection was inhibited, resulting in repeat expansions. Increased nucleolytic processing by deletion of Rad9, the ortholog of 53BP1, rescued repeat instability and chromosome breakage. Loss of Rad51 increased contractions implicating a protective role for Rad51 on ssDNA. Together, our work implicates structure-forming repeats as an impediment to resection and gap-filling which can lead to mutations and large-scale deletions.
Topics: Humans; Chromosome Breakage; Mutation; DNA Damage; Trinucleotide Repeat Expansion
PubMed: 37120647
DOI: 10.1038/s41467-023-37901-2 -
Japanese Journal of Radiology Feb 2023Triplet repeat diseases (TRDs) refer to a group of diseases caused by three nucleotide repeats elongated beyond a pathologic threshold. TRDs are divided into the... (Review)
Review
Triplet repeat diseases (TRDs) refer to a group of diseases caused by three nucleotide repeats elongated beyond a pathologic threshold. TRDs are divided into the following four groups depending on the pathomechanisms, although the pathomechanisms of several diseases remain unelucidated: polyglutamine disorders, caused by a pathologic repeat expansion of CAG (coding the amino acid glutamine) located within the exon; loss-of-function repeat disorders, characterized by the common feature of a loss of function of the gene within which they occur; RNA gain-of-function disorders, involving the production of a toxic RNA species; and polyalanine disorders, caused by a pathologic repeat expansion of GCN (coding the amino acid alanine) located within the exon. Many of these TRDs manifest through neurologic symptoms; moreover, neuroimaging, especially brain magnetic resonance imaging, plays a pivotal role in the detection of abnormalities, differentiation, and management of TRDs. In this article, we reviewed the clinical and neuroimaging features of TRDs. An early diagnosis of TRDs through clinical and imaging approaches is important and may contribute to appropriate medical intervention for patients and their families.
Topics: Humans; Trinucleotide Repeats; RNA; Amino Acids; Neuroimaging
PubMed: 36169768
DOI: 10.1007/s11604-022-01343-5 -
Annals of Human Genetics Mar 2012Fragile X syndrome (FXS) is characterized by moderate to severe intellectual disability, which is accompanied by macroorchidism and distinct facial morphology. FXS is... (Review)
Review
Fragile X syndrome (FXS) is characterized by moderate to severe intellectual disability, which is accompanied by macroorchidism and distinct facial morphology. FXS is caused by the expansion of the CGG trinucleotide repeat in the 5' untranslated region of the fragile X mental retardation 1 (FMR1) gene. The syndrome has been studied in ethnically diverse populations around the world and has been extensively characterized in several populations. Similar to other trinucleotide expansion disorders, the gene-specific instability of FMR1 is not accompanied by genomic instability. Currently we do not have a comprehensive understanding of the molecular underpinnings of gene-specific instability associated with tandem repeats. Molecular evidence from in vitro experiments and animal models supports several pathways for gene-specific trinucleotide repeat expansion. However, whether the mechanisms reported from other systems contribute to trinucleotide repeat expansion in humans is not clear. To understand how repeat instability in humans could occur, the CGG repeat expansion is explored through molecular analysis and population studies which characterized CGG repeat alleles of FMR1. Finally, the review discusses the relevance of these studies in understanding the mechanism of trinucleotide repeat expansion in FXS.
Topics: Fragile X Mental Retardation Protein; Fragile X Syndrome; Genetics, Population; Genomic Instability; Humans; Mutation; Prevalence; Trinucleotide Repeat Expansion; Trinucleotide Repeats
PubMed: 22188182
DOI: 10.1111/j.1469-1809.2011.00694.x -
Neurobiology of Aging Mar 2017We investigated a CAG trinucleotide repeat expansion in the ATXN2 gene in amyotrophic lateral sclerosis (ALS). Two new case-control studies, a British dataset of 1474... (Meta-Analysis)
Meta-Analysis
We investigated a CAG trinucleotide repeat expansion in the ATXN2 gene in amyotrophic lateral sclerosis (ALS). Two new case-control studies, a British dataset of 1474 ALS cases and 567 controls, and a Dutch dataset of 1328 ALS cases and 691 controls were analyzed. In addition, to increase power, we systematically searched PubMed for case-control studies published after 1 August 2010 that investigated the association between ATXN2 intermediate repeats and ALS. We conducted a meta-analysis of the new and existing studies for the relative risks of ATXN2 intermediate repeat alleles of between 24 and 34 CAG trinucleotide repeats and ALS. There was an overall increased risk of ALS for those carrying intermediate sized trinucleotide repeat alleles (odds ratio 3.06 [95% confidence interval 2.37-3.94]; p = 6 × 10), with an exponential relationship between repeat length and ALS risk for alleles of 29-32 repeats (R = 0.91, p = 0.0002). No relationship was seen for repeat length and age of onset or survival. In contrast to trinucleotide repeat diseases, intermediate ATXN2 trinucleotide repeat expansion in ALS does not predict age of onset but does predict disease risk.
Topics: Age of Onset; Alleles; Amyotrophic Lateral Sclerosis; Ataxin-2; Case-Control Studies; Female; Genetic Association Studies; Humans; Male; Risk; Trinucleotide Repeat Expansion; Trinucleotide Repeats
PubMed: 28017481
DOI: 10.1016/j.neurobiolaging.2016.11.010 -
Trends in Genetics : TIG Jun 2014DNA must constantly be repaired to maintain genome stability. Although it is clear that DNA repair reactions depend on cell type and developmental stage, we know... (Review)
Review
DNA must constantly be repaired to maintain genome stability. Although it is clear that DNA repair reactions depend on cell type and developmental stage, we know surprisingly little about the mechanisms that underlie this tissue specificity. This is due, in part, to the lack of adequate study systems. This review discusses recent progress toward understanding the mechanism leading to varying rates of instability at expanded trinucleotide repeats (TNRs) in different tissues. Although they are not DNA lesions, TNRs are hotspots for genome instability because normal DNA repair activities cause changes in repeat length. The rates of expansions and contractions are readily detectable and depend on cell identity, making TNR instability a particularly convenient model system. A better understanding of this type of genome instability will provide a foundation for studying tissue-specific DNA repair more generally, which has implications in cancer and other diseases caused by mutations in the caretakers of the genome.
Topics: Animals; DNA Damage; DNA Repair; Genomic Instability; Humans; Organ Specificity; Trinucleotide Repeats
PubMed: 24842550
DOI: 10.1016/j.tig.2014.04.005 -
R-loops promote trinucleotide repeat deletion through DNA base excision repair enzymatic activities.The Journal of Biological Chemistry Oct 2020Trinucleotide repeat (TNR) expansion and deletion are responsible for over 40 neurodegenerative diseases and associated with cancer. TNRs can undergo somatic instability...
Trinucleotide repeat (TNR) expansion and deletion are responsible for over 40 neurodegenerative diseases and associated with cancer. TNRs can undergo somatic instability that is mediated by DNA damage and repair and gene transcription. Recent studies have pointed toward a role for R-loops in causing TNR expansion and deletion, and it has been shown that base excision repair (BER) can result in CAG repeat deletion from R-loops in yeast. However, it remains unknown how BER in R-loops can mediate TNR instability. In this study, using biochemical approaches, we examined BER enzymatic activities and their influence on TNR R-loops. We found that AP endonuclease 1 incised an abasic site on the nontemplate strand of a TNR R-loop, creating a double-flap intermediate containing an RNA:DNA hybrid that subsequently inhibited polymerase β (pol β) synthesis of TNRs. This stimulated flap endonuclease 1 (FEN1) cleavage of TNRs engaged in an R-loop. Moreover, we showed that FEN1 also efficiently cleaved the RNA strand, facilitating pol β loop/hairpin bypass synthesis and the resolution of TNR R-loops through BER. Consequently, this resulted in fewer TNRs synthesized by pol β than those removed by FEN1, thereby leading to repeat deletion. Our results indicate that TNR R-loops preferentially lead to repeat deletion during BER by disrupting the balance between the addition and removal of TNRs. Our discoveries open a new avenue for the treatment and prevention of repeat expansion diseases and cancer.
Topics: DNA Polymerase beta; DNA Repair; DNA-(Apurinic or Apyrimidinic Site) Lyase; Flap Endonucleases; Humans; R-Loop Structures; Trinucleotide Repeats
PubMed: 32763971
DOI: 10.1074/jbc.RA120.014161 -
The Journal of Clinical Investigation Nov 2023Expansion of CAG and CTG (CWG) triplet repeats causes several inherited neurological diseases. The CWG repeat diseases are thought to involve complex pathogenic...
Expansion of CAG and CTG (CWG) triplet repeats causes several inherited neurological diseases. The CWG repeat diseases are thought to involve complex pathogenic mechanisms through expanded CWG repeat-derived RNAs in a noncoding region and polypeptides in a coding region, respectively. However, an effective therapeutic approach has not been established for the CWG repeat diseases. Here, we show that a CWG repeat DNA-targeting compound, cyclic pyrrole-imidazole polyamide (CWG-cPIP), suppressed the pathogenesis of coding and noncoding CWG repeat diseases. CWG-cPIP bound to the hairpin form of mismatched CWG DNA, interfering with transcription elongation by RNA polymerase through a preferential activity toward repeat-expanded DNA. We found that CWG-cPIP selectively inhibited pathogenic mRNA transcripts from expanded CWG repeats, reducing CUG RNA foci and polyglutamine accumulation in cells from patients with myotonic dystrophy type 1 (DM1) and Huntington's disease (HD). Treatment with CWG-cPIP ameliorated behavioral deficits in adeno-associated virus-mediated CWG repeat-expressing mice and in a genetic mouse model of HD, without cytotoxicity or off-target effects. Together, we present a candidate compound that targets expanded CWG repeat DNA independently of its genomic location and reduces both pathogenic RNA and protein levels. CWG-cPIP may be used for the treatment of CWG repeat diseases and improvement of clinical outcomes.
Topics: Humans; Animals; Mice; RNA; Trinucleotide Repeat Expansion; Nylons; Myotonic Dystrophy; Trinucleotide Repeats; Huntington Disease; DNA; Imidazoles
PubMed: 37707954
DOI: 10.1172/JCI164792