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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 -
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 -
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 -
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 -
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 -
NeuroRx : the Journal of the American... Apr 2004Huntington's disease (HD) is a dominantly transmitted neurodegenerative disorder with wide variation in onset age but with an average age at onset of 40 years. Children... (Review)
Review
Huntington's disease (HD) is a dominantly transmitted neurodegenerative disorder with wide variation in onset age but with an average age at onset of 40 years. Children of HD gene carriers have a 50% chance of inheriting the disease. The characteristic symptoms of HD are involuntary choreiform movements, cognitive impairment, mood disorders, and behavioral changes which are chronic and progressive over the course of the illness. HD is a "trinucleotide repeat" disorder, which is caused by an increase in the number of CAG repeats in the HD gene. Repeats of 40 or larger are associated with disease expression, whereas repeats of 26 and smaller are normal. Intermediate numbers of repeats, between 27 and 35, are not associated with disease expression but may expand in paternal transmission, resulting in the disease in descendents. Repeats of 36-39 are associated with reduced penetrance whereby some develop HD and others do not. The identification of the genetic defect in HD permits direct genetic testing for the presence of the gene alteration responsible for the disease. Tests may be performed in three circumstances: (1) confirmation of diagnosis, (2) predictive testing of persons at genetic risk for inheriting HD, and (3) prenatal testing. Testing is widely available and much experience has been gained with protocols that assist the individual in making an informed choice about test options, and minimize the occurrence of adverse emotional outcomes.
Topics: Humans; Huntingtin Protein; Huntington Disease; Nerve Tissue Proteins; Nuclear Proteins; Trinucleotide Repeats
PubMed: 15717026
DOI: 10.1602/neurorx.1.2.255 -
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 -
Journal of Materials Chemistry. B Jan 2020Trinucleotide repeat (TNR) sequences introduce sequence-directed flexibility in the genomic makeup of all living species leading to unique non-canonical structure...
Trinucleotide repeat (TNR) sequences introduce sequence-directed flexibility in the genomic makeup of all living species leading to unique non-canonical structure formation. In humans, the expansions of TNR sequences are responsible for almost 24 neurodegenerative and neuromuscular diseases because their unique structures disrupt cell functions. The biophysical studies of these sequences affect their electrophoretic mobility and spectroscopic signatures. Here, we demonstrate a novel strategy to characterize and discriminate the TNR sequences by monitoring their capillary flow in the absence of an external driving force using wax-on-plastic microchannels. The wax-on-plastic microfluidic system translates the sequence-directed flexibility of TNR into differential flow dynamics. Several variables were used to characterize sequences including concentration, single- vs. double-stranded samples, type of repeat sequence, length of the repeat sequence, presence of mismatches in duplex, and presence of metal ion. All these variables were found to influence the flow velocities of TNR sequences as these factors directly affect the structural flexibility of TNR at the molecular level. An overall trend was observed as the higher flexibility in the TNR structure leads to lower capillary flow. After testing samples derived from relevant cells harboring expanded TNR sequences, it is concluded that this approach may transform into a reagent-free and pump-free biosensing platform to detect microsatellite expansion diseases.
Topics: Humans; Materials Testing; Microfluidic Analytical Techniques; Trinucleotide Repeats; Waxes
PubMed: 31894829
DOI: 10.1039/c9tb02208b -
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