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Reproductive Biomedicine Online Apr 2019FMR1 CGG trinucleotide repeat expansions are associated with Fragile X syndrome (full mutations) and primary ovarian insufficiency (premutation range); the effect of... (Meta-Analysis)
Meta-Analysis Review
FMR1 CGG trinucleotide repeat expansions are associated with Fragile X syndrome (full mutations) and primary ovarian insufficiency (premutation range); the effect of FMR1 on the success of fertility treatment is unclear. The effect of FMR1 CGG repeat lengths on IVF outcomes after ovarian stimulation was reviewed. PubMed was searched for studies on IVF-related outcomes reported by FMR1 trinucleotide repeat length published between 2002 and December 2017. For women with CGG repeats in the normal (<45 CGG), intermediate range (45-54 CGG), or both, research supports a minimal effect on IVF outcomes, including pregnancy rates; although one study reported lower oocyte yields after IVF stimulation in women with lower CGG repeat lengths and normal ovarian reserve. Meta-analysis revealed no association within subcategories of normal repeat length (<45 CGG) and IVF pregnancy rates (summary OR 1.0, 95% CI 0.87 to 1.15). Premutation carriers (CGG 55-200) may have reduced success with IVF treatment (lower oocyte yield) than women with a normal CGG repeat length or a full mutation, although findings are inconsistent. Direct implications of the repeat length on inheritance and the risk of Fragile X syndrome have been observed. Patients may require clinical and psychological counselling, and further preimplantation genetic testing options should be considered. Thus, there are clinical and psychological counseling implications for patients and potential further patient decisions regarding preimplantation genetic testing options.
Topics: Adult; Female; Fertility; Fertilization in Vitro; Fragile X Mental Retardation Protein; Fragile X Syndrome; Genotype; Heterozygote; Humans; Infertility, Female; Male; Maternal Age; Middle Aged; Oocyte Retrieval; Ovarian Reserve; Ovulation Induction; Pregnancy; Pregnancy Rate; Primary Ovarian Insufficiency; Treatment Outcome; Trinucleotide Repeat Expansion; Trinucleotide Repeats
PubMed: 30711457
DOI: 10.1016/j.rbmo.2018.11.009 -
Annual Review of Pathology Jan 2019Among the age-dependent protein aggregation disorders, nine neurodegenerative diseases are caused by expansions of CAG repeats encoding polyglutamine (polyQ) tracts. We... (Review)
Review
Among the age-dependent protein aggregation disorders, nine neurodegenerative diseases are caused by expansions of CAG repeats encoding polyglutamine (polyQ) tracts. We review the clinical, pathological, and biological features of these inherited disorders. We discuss insights into pathogenesis gleaned from studies of model systems and patients, highlighting work that informs efforts to develop effective therapies. An important conclusion from these analyses is that expanded CAG/polyQ domains are the primary drivers of neurodegeneration, with the biology of carrier proteins influencing disease-specific manifestations. Additionally, it has become apparent that CAG/polyQ repeat expansions produce neurodegeneration via multiple downstream mechanisms, involving both gain- and loss-of-function effects. This conclusion indicates that the likelihood of developing effective therapies targeting single nodes is reduced. The evaluation of treatments for premanifest disease will likely require new investigational approaches. We highlight the opportunities and challenges underlying ongoing work and provide recommendations related to the development of symptomatic and disease-modifying therapies and biomarkers that could inform future research.
Topics: Biomarkers; Humans; Neurodegenerative Diseases; Peptides; Trinucleotide Repeats
PubMed: 30089230
DOI: 10.1146/annurev-pathmechdis-012418-012857 -
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 -
DNA Repair Oct 2022Trinucleotide repeat instability is a driver of human disease. Large expansions of (GAA) repeats in the first intron of the FXN gene are the cause Friedreich's ataxia... (Review)
Review
Trinucleotide repeat instability is a driver of human disease. Large expansions of (GAA) repeats in the first intron of the FXN gene are the cause Friedreich's ataxia (FRDA), a progressive degenerative disorder which cannot yet be prevented or treated. (GAA) repeat instability arises during both replication-dependent processes, such as cell division and intergenerational transmission, as well as in terminally differentiated somatic tissues. Here, we provide a brief historical overview on the discovery of (GAA) repeat expansions and their association to FRDA, followed by recent advances in the identification of triplex H-DNA formation and replication fork stalling. The main body of this review focuses on the last decade of progress in understanding the mechanism of (GAA) repeat instability during DNA replication and/or DNA repair. We propose that the discovery of additional mechanisms of (GAA) repeat instability can be achieved via both comparative approaches to other repeat expansion diseases and genome-wide association studies. Finally, we discuss the advances towards FRDA prevention or amelioration that specifically target (GAA) repeat expansions.
Topics: DNA Replication; Friedreich Ataxia; Genome-Wide Association Study; Humans; Iron-Binding Proteins; Trinucleotide Repeat Expansion
PubMed: 35952488
DOI: 10.1016/j.dnarep.2022.103385 -
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 -
Molecular Neurobiology May 2019This review explores the presence and functions of polyglutamine (polyQ) in viral proteins. In mammals, mutations in polyQ segments (and CAG repeats at the nucleotide... (Review)
Review
This review explores the presence and functions of polyglutamine (polyQ) in viral proteins. In mammals, mutations in polyQ segments (and CAG repeats at the nucleotide level) have been linked to neural disorders and ataxias. PolyQ regions in normal human proteins have documented functional roles, in transcription factors and, more recently, in regulating autophagy. Despite the high frequency of polyQ repeats in eukaryotic genomes, little attention has been given to the presence or possible role of polyQ sequences in virus genomes. A survey described here revealed that polyQ repeats occur rarely in RNA viruses, suggesting that they have detrimental effects on virus replication at the nucleotide or protein level. However, there have been sporadic reports of polyQ segments in potyviruses and in reptilian nidoviruses (among the largest RNA viruses known). Conserved polyQ segments are found in the regulatory control proteins of many DNA viruses. Variable length polyQ tracts are found in proteins that contribute to transmissibility (cowpox A-type inclusion protein (ATI)) and control of latency (herpes viruses). New longer-read sequencing methods, using original biological samples, should reveal more details on the presence and functional role of polyQ in viruses, as well as the nucleotide regions that encode them. Given the known toxic effects of polyQ repeats, the role of these segments in neurovirulent and tumorigenic viruses should be further explored.
Topics: Amino Acid Sequence; Autophagy; Genome, Viral; Peptides; Trinucleotide Repeat Expansion; Viral Proteins; Viruses
PubMed: 30182336
DOI: 10.1007/s12035-018-1269-4 -
International Journal of Molecular... Jul 2019CRISPR/Cas technology holds promise for the development of therapies to treat inherited diseases. Myotonic dystrophy type 1 (DM1) is a severe neuromuscular disorder with... (Review)
Review
CRISPR/Cas technology holds promise for the development of therapies to treat inherited diseases. Myotonic dystrophy type 1 (DM1) is a severe neuromuscular disorder with a variable multisystemic character for which no cure is yet available. Here, we review CRISPR/Cas-mediated approaches that target the unstable (CTG•CAG)n repeat in the / gene pair, the autosomal dominant mutation that causes DM1. Expansion of the repeat results in a complex constellation of toxicity at the DNA level, an altered transcriptome and a disturbed proteome. To restore cellular homeostasis and ameliorate DM1 disease symptoms, CRISPR/Cas approaches were directed at the causative mutation in the DNA and the RNA. Specifically, the triplet repeat has been excised from the genome by several laboratories via dual CRISPR/Cas9 cleavage, while one group prevented transcription of the (CTG)n repeat through homology-directed insertion of a polyadenylation signal in . Independently, catalytically deficient Cas9 (dCas9) was recruited to the (CTG)n repeat to block progression of RNA polymerase II and a dCas9-RNase fusion was shown to degrade expanded (CUG)n RNA. We compare these promising developments in DM1 with those in other microsatellite instability diseases. Finally, we look at hurdles that must be taken to make CRISPR/Cas-mediated editing a therapeutic reality in patients.
Topics: Animals; CRISPR-Cas Systems; Cell- and Tissue-Based Therapy; Gene Editing; Gene Targeting; Genetic Association Studies; Genetic Loci; Genetic Predisposition to Disease; Genetic Therapy; Humans; Myotonic Dystrophy; Trinucleotide Repeat Expansion; Trinucleotide Repeats
PubMed: 31357652
DOI: 10.3390/ijms20153689 -
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 -
Emerging Topics in Life Sciences Dec 2023Neurodevelopmental disorders (NDDs) encompass a diverse group of disorders characterised by impaired cognitive abilities and developmental challenges. Short tandem... (Review)
Review
Neurodevelopmental disorders (NDDs) encompass a diverse group of disorders characterised by impaired cognitive abilities and developmental challenges. Short tandem repeats (STRs), repetitive DNA sequences found throughout the human genome, have emerged as potential contributors to NDDs. Specifically, the CGG trinucleotide repeat has been implicated in a wide range of NDDs, including Fragile X Syndrome (FXS), the most common inherited form of intellectual disability and autism. This review focuses on CGG STR expansions associated with NDDs and their impact on gene expression through repeat expansion-mediated epigenetic silencing. We explore the molecular mechanisms underlying CGG-repeat expansion and the resulting epigenetic modifications, such as DNA hypermethylation and gene silencing. Additionally, we discuss the involvement of other CGG STRs in neurodevelopmental diseases. Several examples, including FMR1, AFF2, AFF3, XYLT1, FRA10AC1, CBL, and DIP2B, highlight the complex relationship between CGG STR expansions and NDDs. Furthermore, recent advancements in this field are highlighted, shedding light on potential future research directions. Understanding the role of STRs, particularly CGG-repeats, in NDDs has the potential to uncover novel diagnostic and therapeutic strategies for these challenging disorders.
Topics: Humans; Trinucleotide Repeat Expansion; Fragile X Syndrome; Trinucleotide Repeats; DNA Methylation; Intellectual Disability; Fragile X Mental Retardation Protein; Nerve Tissue Proteins
PubMed: 37768318
DOI: 10.1042/ETLS20230021 -
Drug Discovery Today May 2012Expanded trinucleotide repeats cause Huntington's disease (HD) and many other neurodegenerative disorders. There are no cures for these devastating illnesses and... (Review)
Review
Expanded trinucleotide repeats cause Huntington's disease (HD) and many other neurodegenerative disorders. There are no cures for these devastating illnesses and treatments are urgently needed. Each trinucleotide repeat disorder is the result of the mutation of just one gene, and agents that block expression of the mutant gene offer a promising option for treatment. Therapies that block expression of both mutant and wild-type alleles can have adverse effects, challenging researchers to develop strategies to lower levels of mutant protein while leaving adequate wild-type protein levels. Here, we review approaches that use synthetic nucleic acids to inhibit expression of trinucleotide repeat genes.
Topics: Alleles; Animals; Gene Silencing; Humans; Neurodegenerative Diseases; Nucleic Acids; Polymorphism, Genetic; Trinucleotide Repeat Expansion
PubMed: 22285529
DOI: 10.1016/j.drudis.2012.01.006