-
Handbook of Clinical Neurology 2017Trinucleotide repeat disorders comprise a variable group of inherited neurodegenerative diseases, with a large range in prevalence figures. There is a broad range in... (Review)
Review
Trinucleotide repeat disorders comprise a variable group of inherited neurodegenerative diseases, with a large range in prevalence figures. There is a broad range in clinical presentations, but many of these diseases lead to some form of ataxia or other movement disorders, which are frequently combined with cognitive or psychiatric disturbances. This group can be divided into CAG- versus non-CAG-repeat diseases. Apart from spinocerebellar ataxia type 6 and 12 (SCA6 and SCA12), these CAG-repeat diseases, as well as Huntington disease-like 2 (HDL2) and SCA8, can be neuropathologically identified using 1C2 polyglutamine antibodies. In fragile X-associated tremor and ataxia, SCA6 and SCA12 ubiquitin/p62-positive and 1C2-negative inclusion bodies can be observed. In the other diseases proteinaceous inclusions are not found. For definite diagnosis genetic analysis is necessary.
Topics: Brain; Humans; Magnetic Resonance Imaging; Neurodegenerative Diseases; Neuropathology; Peptides; Trinucleotide Repeats
PubMed: 28987184
DOI: 10.1016/B978-0-12-802395-2.00027-4 -
DNA Repair Sep 2020Trinucleotide repeat (TNR) instability is the cause of over 40 human neurodegenerative diseases and certain types of cancer. TNR instability can result from DNA... (Review)
Review
Trinucleotide repeat (TNR) instability is the cause of over 40 human neurodegenerative diseases and certain types of cancer. TNR instability can result from DNA replication, repair, recombination, and gene transcription. Emerging evidence indicates that DNA base damage and base excision repair (BER) play an active role in regulating somatic TNR instability. These processes may potentially modulate the onset and progression of TNR-related diseases, given that TNRs are hotspots of DNA base damage that are present in mammalian cells with a high frequency. In this review, we discuss the recent advances in our understanding of the molecular mechanisms underlying BER-mediated TNR instability. We initially discuss the roles of the BER pathway and locations of DNA base lesions in TNRs and their interplay with non-B form DNA structures in governing repeat instability. We then discuss how the coordinated activities of BER enzymes can modulate a balance between the removal and addition of TNRs to regulate somatic TNR instability. We further discuss how this balance can be disrupted by the crosstalk between BER and DNA mismatch repair (MMR) machinery resulting in TNR expansion. Finally, we suggest future directions regarding BER-mediated somatic TNR instability and its association with TNR disease prevention and treatment.
Topics: Animals; DNA; DNA Damage; DNA Mismatch Repair; DNA Repair; Humans; Trinucleotide Repeat Expansion; Trinucleotide Repeats
PubMed: 33087278
DOI: 10.1016/j.dnarep.2020.102912 -
Trinucleotide repeat instability during double-strand break repair: from mechanisms to gene therapy.Current Genetics Feb 2019Trinucleotide repeats are a particular class of microsatellites whose large expansions are responsible for at least two dozen human neurological and developmental... (Review)
Review
Trinucleotide repeats are a particular class of microsatellites whose large expansions are responsible for at least two dozen human neurological and developmental disorders. Slippage of the two complementary DNA strands during replication, homologous recombination or DNA repair is generally accepted as a mechanism leading to repeat length changes, creating expansions and contractions of the repeat tract. The present review focuses on recent developments on double-strand break repair involving trinucleotide repeat tracts. Experimental evidences in model organisms show that gene conversion and break-induced replication may lead to large repeat tract expansions, while frequent contractions occur either by single-strand annealing between repeat ends or by gene conversion, triggering near-complete contraction of the repeat tract. In the second part of this review, different therapeutic approaches using highly specific single- or double-strand endonucleases targeted to trinucleotide repeat loci are compared. Relative efficacies and specificities of these nucleases will be discussed, as well as their potential strengths and weaknesses for possible future gene therapy of these dramatic disorders.
Topics: DNA; DNA Breaks, Double-Stranded; DNA Repair; Endonucleases; Genetic Therapy; Heredodegenerative Disorders, Nervous System; Humans; Models, Genetic; Trinucleotide Repeat Expansion; Trinucleotide Repeats
PubMed: 29974202
DOI: 10.1007/s00294-018-0865-1 -
Science China. Life Sciences Oct 2017Trinucleotide repeat expansions cause over 30 severe neuromuscular and neurodegenerative disorders, including Huntington's disease, myotonic dystrophy type 1, and... (Review)
Review
Trinucleotide repeat expansions cause over 30 severe neuromuscular and neurodegenerative disorders, including Huntington's disease, myotonic dystrophy type 1, and fragile X syndrome. Although previous studies have substantially advanced the understanding of the disease biology, many key features remain unknown. DNA mismatch repair (MMR) plays a critical role in genome maintenance by removing DNA mismatches generated during DNA replication. However, MMR components, particularly mismatch recognition protein MutSβ and its interacting factors MutLα and MutLγ, have been implicated in trinucleotide repeat instability. In this review, we will discuss the roles of these key MMR proteins in promoting trinucleotide repeat instability.
Topics: Animals; DNA Mismatch Repair; DNA-Binding Proteins; Genomic Instability; Humans; Huntington Disease; Models, Genetic; Myotonic Dystrophy; Trinucleotide Repeat Expansion; Trinucleotide Repeats
PubMed: 29075942
DOI: 10.1007/s11427-017-9186-7 -
Brain Pathology (Zurich, Switzerland) Jul 1997Trinucleotide repeat expansions are an important cause of inherited neurodegenerative disease. The expanded repeats are unstable, changing in size when transmitted from... (Review)
Review
Trinucleotide repeat expansions are an important cause of inherited neurodegenerative disease. The expanded repeats are unstable, changing in size when transmitted from parents to offspring (intergenerational instability, "meiotic instability") and often showing size variation within the tissues of an affected individual (somatic mosaicism, "mitotic instability"). Repeat instability is a clinically important phenomenon, as increasing repeat lengths correlate with an earlier age of onset and a more severe disease phenotype. The tendency of expanded trinucleotide repeats to increase in length during their transmission from parent to offspring in these diseases provides a molecular explanation for anticipation (increasing disease severity in successive affected generations). In this review, I explore the genetic and molecular basis of trinucleotide repeat instability. Studies of patients and families with trinucleotide repeat disorders have revealed a number of factors that determine the rate and magnitude of trinucleotide repeat change. Analysis of trinucleotide repeat instability in bacteria, yeast, and mice has yielded additional insights. Despite these advances, the pathways and mechanisms underlying trinucleotide repeat instability in humans remain largely unknown. There are many reasons to suspect that this uniquely human phenomenon will significantly impact upon our understanding of development, differentiation and neurobiology.
Topics: Animals; Humans; Meiosis; Mosaicism; Nerve Degeneration; Nucleic Acid Conformation; Sequence Homology, Nucleic Acid; Trinucleotide Repeats
PubMed: 9217977
DOI: 10.1111/j.1750-3639.1997.tb00895.x -
Archives of General Psychiatry Nov 1999Trinucleotide, or triplet, repeats consist of 3 nucleotides consecutively repeated (e.g., CCG CCG CCG CCG CCG) within a region of DNA, a not uncommon motif in the genome... (Review)
Review
Trinucleotide, or triplet, repeats consist of 3 nucleotides consecutively repeated (e.g., CCG CCG CCG CCG CCG) within a region of DNA, a not uncommon motif in the genome of humans and other species. In 1991, a new type of genetic mutation was discovered, known as a dynamic or expansion mutation, in which the number of triplets in a repeat increases and the length becomes unstable. During the past decade, nearly 20 diseases-including Huntington disease, 2 forms of the fragile X syndrome, and myotonic dystrophy-caused by trinucleotide repeat expansions have been identified. The unstable nature of the expanded repeat leads to remarkable patterns of inheritance in these diseases, distinctly at odds with traditional notions of mendelian genetics. We review the clinical and genetic features of these disorders, with a particular emphasis on their psychiatric manifestations. We also critically examine the hypothesis that expansion mutations may have an etiologic role in psychiatric diseases such as bipolar disorder, schizophrenia, and autism.
Topics: Autistic Disorder; Bipolar Disorder; Fragile X Syndrome; Genetic Predisposition to Disease; Humans; Huntington Disease; Mental Disorders; Mutation; Myotonic Dystrophy; Neurodegenerative Diseases; Schizophrenia; Trinucleotide Repeats
PubMed: 10565502
DOI: 10.1001/archpsyc.56.11.1019 -
Brain Research BulletinIt has long been known that bipolar disorder has a true but complex genetic background. Reports on genetic anticipation in bipolar disorder opened the way to a new... (Review)
Review
It has long been known that bipolar disorder has a true but complex genetic background. Reports on genetic anticipation in bipolar disorder opened the way to a new approach for genetic studies. Indeed, anticipation, a decreasing age at onset, and/or increasing disease severity in successive generations, were recently explained by an expansion of trinucleotide repeats in monogenic diseases like Huntington's disease and Fragile X syndrome. The involvement of trinucleotide repeat expansions in bipolar disorder received even more support when studies reported association of large CAG/CTG repeats with bipolar disorder. Even though a large number of studies have been conducted, this association is still unexplained. Here, we review the studies investigating the trinucleotide repeat expansion hypothesis in bipolar disorder. Studies on anticipation, on association of anonymous large CAG/CTG repeats and on specific trinucleotide repeats are critically analysed and discussed, showing a field with precipitate conclusions or inconclusive results. The analysis suggests that there are indications, though disputable, supporting the trinucleotide repeat expansion hypothesis in bipolar disorder, but no conclusive evidence has been hitherto provided.
Topics: Bipolar Disorder; Humans; Trinucleotide Repeat Expansion
PubMed: 11719258
DOI: 10.1016/s0361-9230(01)00657-8 -
Cells Apr 2021Trinucleotide repeats are a peculiar class of microsatellites whose expansions are responsible for approximately 30 human neurological or developmental disorders. The... (Review)
Review
Trinucleotide repeats are a peculiar class of microsatellites whose expansions are responsible for approximately 30 human neurological or developmental disorders. The molecular mechanisms responsible for these expansions in humans are not totally understood, but experiments in model systems such as yeast, transgenic mice, and human cells have brought evidence that the mismatch repair machinery is involved in generating these expansions. The present review summarizes, in the first part, the role of mismatch repair in detecting and fixing the DNA strand slippage occurring during microsatellite replication. In the second part, key molecular differences between normal microsatellites and those that show a bias toward expansions are extensively presented. The effect of mismatch repair mutants on microsatellite expansions is detailed in model systems, and in vitro experiments on mismatched DNA substrates are described. Finally, a model presenting the possible roles of the mismatch repair machinery in microsatellite expansions is proposed.
Topics: Animals; DNA; DNA Mismatch Repair; DNA Repair; Genotype; Humans; Meiosis; Mice; Mice, Transgenic; Microsatellite Repeats; Mitosis; MutL Proteins; MutS Proteins; Recombination, Genetic; Saccharomyces cerevisiae; Schizosaccharomyces; Trinucleotide Repeat Expansion; Trinucleotide Repeats
PubMed: 33925919
DOI: 10.3390/cells10051019 -
Yi Chuan = Hereditas Sep 2021The expansion and deletion instabilities shown by some trinucleotide repeated DNA sequences are associated with more than 50 neurodegenerative diseases in humans. The... (Review)
Review
The expansion and deletion instabilities shown by some trinucleotide repeated DNA sequences are associated with more than 50 neurodegenerative diseases in humans. The increase or decrease of the trinucleotide repeat units underlying the diseases are not yet clearly explained using any mechanism, but has been found to affect the expression of specific genes, or produces cytotoxic RNA and protein, which has now become a common pathological mechanism of the diseases. The ongoing studies have shown that the changes in the copy numbers of the disease-related trinucleotide repeats may result from abnormal DNA replication, repair, recombination, and gene transcription. Human genetical studies also suggest that abnormal DNA replication, repair, recombination, or gene transcription that occurred in the disease-related trinucleotide repeat DNA sites may play a key role in the trinucleotide repeat DNA instabilities. Based on the research experiences of our research group, this paper reviews the recent research progress on the mechanisms of the disease-associated trinucleotide repeat DNA instabilities including their base mutation instabilities, the amplification and deletion instabilities of the repeat units, to better understand the molecular mechanism of the disease-associated trinucleotide repeats instabilities.
Topics: DNA; DNA Repair; Humans; Neurodegenerative Diseases; Trinucleotide Repeat Expansion; Trinucleotide Repeats
PubMed: 34702697
DOI: 10.16288/j.yczz.21-182 -
Electrophoresis Sep 1995Trinucleotide repeat expansions have been identified as the underlying mutation in an increasing number of human genetic diseases, such as fragile site syndromes,... (Review)
Review
Trinucleotide repeat expansions have been identified as the underlying mutation in an increasing number of human genetic diseases, such as fragile site syndromes, myotonic dystrophy and several neurodegenerative disorders including Huntington's disease. By an unknown mechanism, polymorphic GC-rich triplet repeats expand in all these diseases. The expansions of a CCG repeat in fragile-site-associated disorders and the CTG repeat (in the 3'-untranslated region of the myotonin kinase gene) causing myotonic dystrophy are very large, whereas small expansions of CAG repeats have been identified in the open reading frame of genes in a number of neurological genetic disorders.
Topics: Age of Onset; Chromosome Fragile Sites; Chromosome Fragility; Female; Genetic Diseases, Inborn; Humans; Male; Myotonic Dystrophy; Nerve Degeneration; Sex Characteristics; Syndrome; Trinucleotide Repeats
PubMed: 8582359
DOI: 10.1002/elps.11501601282