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American Journal of Human Genetics May 2021Tandem repeats represent one of the most abundant class of variations in human genomes, which are polymorphic by nature and become highly unstable in a length-dependent... (Review)
Review
Tandem repeats represent one of the most abundant class of variations in human genomes, which are polymorphic by nature and become highly unstable in a length-dependent manner. The expansion of repeat length across generations is a well-established process that results in human disorders mainly affecting the central nervous system. At least 50 disorders associated with expansion loci have been described to date, with half recognized only in the last ten years, as prior methodological difficulties limited their identification. These limitations still apply to the current widely used molecular diagnostic methods (exome or gene panels) and thus result in missed diagnosis detrimental to affected individuals and their families, especially for disorders that are very rare and/or clinically not recognizable. Most of these disorders have been identified through family-driven approaches and many others likely remain to be identified. The recent development of long-read technologies provides a unique opportunity to systematically investigate the contribution of tandem repeats and repeat expansions to the genetic architecture of human disorders. In this review, we summarize the current and most recent knowledge about the genetics of repeat expansion disorders and the diversity of their pathophysiological mechanisms and outline the perspectives of developing personalized treatments in the future.
Topics: Anticipation, Genetic; Biomedical Research; Founder Effect; Genes, Dominant; Genes, Recessive; Genome, Human; Humans; Time Factors; Trinucleotide Repeat Expansion
PubMed: 33811808
DOI: 10.1016/j.ajhg.2021.03.011 -
Cell Aug 2019Variable, glutamine-encoding, CAA interruptions indicate that a property of the uninterrupted HTT CAG repeat sequence, distinct from the length of huntingtin's...
Variable, glutamine-encoding, CAA interruptions indicate that a property of the uninterrupted HTT CAG repeat sequence, distinct from the length of huntingtin's polyglutamine segment, dictates the rate at which Huntington's disease (HD) develops. The timing of onset shows no significant association with HTT cis-eQTLs but is influenced, sometimes in a sex-specific manner, by polymorphic variation at multiple DNA maintenance genes, suggesting that the special onset-determining property of the uninterrupted CAG repeat is a propensity for length instability that leads to its somatic expansion. Additional naturally occurring genetic modifier loci, defined by GWAS, may influence HD pathogenesis through other mechanisms. These findings have profound implications for the pathogenesis of HD and other repeat diseases and question the fundamental premise that polyglutamine length determines the rate of pathogenesis in the "polyglutamine disorders."
Topics: Adult; Age of Onset; Aged; Aged, 80 and over; Alleles; Base Sequence; Female; Genetic Loci; Genome-Wide Association Study; Haplotypes; Humans; Huntingtin Protein; Huntington Disease; Male; Middle Aged; Peptides; Phenotype; Polymorphism, Single Nucleotide; Trinucleotide Repeat Expansion; Young Adult
PubMed: 31398342
DOI: 10.1016/j.cell.2019.06.036 -
Journal of Huntington's Disease 2021Historically, Huntington's disease (HD; OMIM #143100) has played an important role in the enormous advances in human genetics seen over the past four decades. This... (Review)
Review
Historically, Huntington's disease (HD; OMIM #143100) has played an important role in the enormous advances in human genetics seen over the past four decades. This familial neurodegenerative disorder involves variable onset followed by consistent worsening of characteristic abnormal movements along with cognitive decline and psychiatric disturbances. HD was the first autosomal disease for which the genetic defect was assigned to a position on the human chromosomes using only genetic linkage analysis with common DNA polymorphisms. This discovery set off a multitude of similar studies in other diseases, while the HD gene, later renamed HTT, and its vicinity in chromosome 4p16.3 then acted as a proving ground for development of technologies to clone and sequence genes based upon their genomic location, with the growing momentum of such advances fueling the Human Genome Project. The identification of the HD gene has not yet led to an effective treatment, but continued human genetic analysis of genotype-phenotype relationships in large HD subject populations, first at the HTT locus and subsequently genome-wide, has provided insights into pathogenesis that divide the course of the disease into two sequential, mechanistically distinct components.
Topics: Genes, Modifier; Genetic Association Studies; Humans; Huntingtin Protein; Huntington Disease; Trinucleotide Repeat Expansion
PubMed: 33579862
DOI: 10.3233/JHD-200427 -
Molecular Neurobiology Mar 2023The pathogenic mechanisms of these diseases must be well understood for the treatment of neurological disorders such as Huntington's disease. Huntington's Disease (HD),... (Review)
Review
The pathogenic mechanisms of these diseases must be well understood for the treatment of neurological disorders such as Huntington's disease. Huntington's Disease (HD), a dominant and neurodegenerative disease, is characterized by the CAG re-expansion that occurs in the gene encoding the polyglutamine-expanded mutant Huntingtin (mHTT) protein. Genome editing approaches include zinc-finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs) and Clustered Regularly Interspaced Short Palindromic Repeats/Caspase 9 (CRISPR/Cas9) systems. CRISPR/Cas9 technology allows effective gene editing in different cell types and organisms. Through these systems are created isogenic control of human origin induced pluripotent stem cells (iPSCs). In human and mouse models, HD-iPSC lines can be continuously corrected using these systems. HD-iPSCs can be corrected through the CRISPR/Cas9 system and the cut-and-paste mechanism using isogenic control iPSCs. This mechanism is a piggyBac transposon-based selection system that can effectively switch between vectors and chromosomes. In studies conducted, it has been determined that in neural cells derived from HD-iPSC, there are isogenic controls as corrected lines recovered from phenotypic abnormalities and gene expression changes. It has been determined that trinucleotide repeat disorders occurring in HD can be cured by single-guide RNA (sgRNA) and normal exogenous DNA restoration, known as the single guideline RNA specific to Cas9. The purpose of this review in addition to give general information about HD, a neurodegenerative disorder is to explained the role of CRISPR/Cas9 system with iPSCs in HD treatment.
Topics: Mice; Animals; Humans; CRISPR-Cas Systems; Huntington Disease; Neurodegenerative Diseases; Gene Editing; Neurons
PubMed: 36482283
DOI: 10.1007/s12035-022-03150-5 -
Neurobiology of Disease Feb 2020Tandem repeat diseases include the neurodegenerative disorders known as polyglutamine (polyQ) diseases, caused by CAG repeat expansions in the coding regions of the... (Review)
Review
Tandem repeat diseases include the neurodegenerative disorders known as polyglutamine (polyQ) diseases, caused by CAG repeat expansions in the coding regions of the respective disease genes. The nine known polyQ disease include Huntington's disease (HD), dentatorubral-pallidoluysian atrophy (DRPLA), spinal bulbar muscular atrophy (SBMA), and six spinocerebellar ataxias (SCA1, SCA2, SCA3, SCA6, SCA7, and SCA17). The underlying disease mechanism in the polyQ diseases is thought principally to reflect dominant toxic properties of the disease proteins which, when harboring a polyQ expansion, differentially interact with protein partners and are prone to aggregate. Among the polyQ diseases, SCA3 is the most common SCA, and second to HD in prevalence worldwide. Here we summarize current understanding of SCA3 disease mechanisms within the broader context of the broader polyQ disease field. We emphasize properties of the disease protein, ATXN3, and new discoveries regarding three potential pathogenic mechanisms: 1) altered protein homeostasis; 2) DNA damage and dysfunctional DNA repair; and 3) nonneuronal contributions to disease. We conclude with an overview of the therapeutic implications of recent mechanistic insights.
Topics: Animals; Humans; Machado-Joseph Disease; Peptides; Trinucleotide Repeat Expansion
PubMed: 31669734
DOI: 10.1016/j.nbd.2019.104635 -
Progress in Retinal and Eye Research Mar 2021Fuchs endothelial corneal dystrophy (FECD) is a common cause for heritable visual loss in the elderly. Since the first description of an association between FECD and... (Review)
Review
Fuchs endothelial corneal dystrophy (FECD) is a common cause for heritable visual loss in the elderly. Since the first description of an association between FECD and common polymorphisms situated within the transcription factor 4 (TCF4) gene, genetic and molecular studies have implicated an intronic CTG trinucleotide repeat (CTG18.1) expansion as a causal variant in the majority of FECD patients. To date, several non-mutually exclusive mechanisms have been proposed that drive and/or exacerbate the onset of disease. These mechanisms include (i) TCF4 dysregulation; (ii) toxic gain-of-function from TCF4 repeat-containing RNA; (iii) toxic gain-of-function from repeat-associated non-AUG dependent (RAN) translation; and (iv) somatic instability of CTG18.1. However, the relative contribution of these proposed mechanisms in disease pathogenesis is currently unknown. In this review, we summarise research implicating the repeat expansion in disease pathogenesis, define the phenotype-genotype correlations between FECD and CTG18.1 expansion, and provide an update on research tools that are available to study FECD as a trinucleotide repeat expansion disease. Furthermore, ongoing international research efforts to develop novel CTG18.1 expansion-mediated FECD therapeutics are highlighted and we provide a forward-thinking perspective on key unanswered questions that remain in the field.
Topics: Fuchs' Endothelial Dystrophy; Gene Expression Regulation; Genetic Predisposition to Disease; Genotype; Humans; Polymorphism, Genetic; Transcription Factor 4; Trinucleotide Repeat Expansion
PubMed: 32735996
DOI: 10.1016/j.preteyeres.2020.100883 -
Nature Reviews. Neuroscience Apr 2021Fragile X mental retardation protein (FMRP) is the product of the fragile X mental retardation 1 gene (FMR1), a gene that - when epigenetically inactivated by a triplet... (Review)
Review
Fragile X mental retardation protein (FMRP) is the product of the fragile X mental retardation 1 gene (FMR1), a gene that - when epigenetically inactivated by a triplet nucleotide repeat expansion - causes the neurodevelopmental disorder fragile X syndrome (FXS). FMRP is a widely expressed RNA-binding protein with activity that is essential for proper synaptic plasticity and architecture, aspects of neural function that are known to go awry in FXS. Although the neurophysiology of FXS has been described in remarkable detail, research focusing on the molecular biology of FMRP has only scratched the surface. For more than two decades, FMRP has been well established as a translational repressor; however, recent whole transcriptome and translatome analyses in mouse and human models of FXS have shown that FMRP is involved in the regulation of nearly all aspects of gene expression. The emerging mechanistic details of the mechanisms by which FMRP regulates gene expression may offer ways to design new therapies for FXS.
Topics: Animals; Fragile X Mental Retardation Protein; Fragile X Syndrome; Humans; Mice; Neuronal Plasticity; Neurons; Trinucleotide Repeat Expansion
PubMed: 33608673
DOI: 10.1038/s41583-021-00432-0 -
Nature Genetics Feb 2020In many repeat diseases, such as Huntington's disease (HD), ongoing repeat expansions in affected tissues contribute to disease onset, progression and severity. Inducing...
In many repeat diseases, such as Huntington's disease (HD), ongoing repeat expansions in affected tissues contribute to disease onset, progression and severity. Inducing contractions of expanded repeats by exogenous agents is not yet possible. Traditional approaches would target proteins driving repeat mutations. Here we report a compound, naphthyridine-azaquinolone (NA), that specifically binds slipped-CAG DNA intermediates of expansion mutations, a previously unsuspected target. NA efficiently induces repeat contractions in HD patient cells as well as en masse contractions in medium spiny neurons of HD mouse striatum. Contractions are specific for the expanded allele, independently of DNA replication, require transcription across the coding CTG strand and arise by blocking repair of CAG slip-outs. NA-induced contractions depend on active expansions driven by MutSβ. NA injections in HD mouse striatum reduce mutant HTT protein aggregates, a biomarker of HD pathogenesis and severity. Repeat-structure-specific DNA ligands are a novel avenue to contract expanded repeats.
Topics: Animals; Corpus Striatum; DNA; DNA Mismatch Repair; DNA Replication; Disease Models, Animal; Humans; Huntingtin Protein; Huntington Disease; Male; Mice; Mice, Transgenic; Microsatellite Instability; Mutation; Naphthyridines; Quinolones; Ribonucleases; TATA-Box Binding Protein; Transcription, Genetic; Trinucleotide Repeat Expansion
PubMed: 32060489
DOI: 10.1038/s41588-019-0575-8 -
American Journal of Human Genetics Jan 2023Adult-onset cerebellar ataxias are a group of neurodegenerative conditions that challenge both genetic discovery and molecular diagnosis. In this study, we identified an...
Adult-onset cerebellar ataxias are a group of neurodegenerative conditions that challenge both genetic discovery and molecular diagnosis. In this study, we identified an intronic (GAA) repeat expansion in fibroblast growth factor 14 (FGF14). Genetic analysis of 95 Australian individuals with adult-onset ataxia identified four (4.2%) with (GAA) and a further nine individuals with (GAA). PCR and long-read sequence analysis revealed these were pure (GAA) repeats. In comparison, no control subjects had (GAA) and only 2/311 control individuals (0.6%) had a pure (GAA). In a German validation cohort, 9/104 (8.7%) of affected individuals had (GAA) and a further six had (GAA), whereas 10/190 (5.3%) control subjects had (GAA) but none were (GAA). The combined data suggest (GAA) are disease causing and fully penetrant (p = 6.0 × 10, OR = 72 [95% CI = 4.3-1,227]), while (GAA) is likely pathogenic with reduced penetrance. Affected individuals had an adult-onset, slowly progressive cerebellar ataxia with variable features including vestibular impairment, hyper-reflexia, and autonomic dysfunction. A negative correlation between age at onset and repeat length was observed (R = 0.44, p = 0.00045, slope = -0.12) and identification of a shared haplotype in a minority of individuals suggests that the expansion can be inherited or generated de novo during meiotic division. This study demonstrates the power of genome sequencing and advanced bioinformatic tools to identify novel repeat expansions via model-free, genome-wide analysis and identifies SCA50/ATX-FGF14 as a frequent cause of adult-onset ataxia.
Topics: Adult; Humans; Ataxia; Australia; Cerebellar Ataxia; Friedreich Ataxia; Trinucleotide Repeat Expansion; Fibroblast Growth Factors
PubMed: 36493768
DOI: 10.1016/j.ajhg.2022.11.015 -
International Journal of Molecular... Jun 2020The fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder seen in older premutation (55-200 CGG repeats) carriers of The premutation has... (Review)
Review
The fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder seen in older premutation (55-200 CGG repeats) carriers of The premutation has excessive levels of mRNA that lead to toxicity and mitochondrial dysfunction. The clinical features usually begin in the 60 s with an action or intention tremor followed by cerebellar ataxia, although 20% have only ataxia. MRI features include brain atrophy and white matter disease, especially in the middle cerebellar peduncles, periventricular areas, and splenium of the corpus callosum. Neurocognitive problems include memory and executive function deficits, although 50% of males can develop dementia. Females can be less affected by FXTAS because of a second X chromosome that does not carry the premutation. Approximately 40% of males and 16% of female carriers develop FXTAS. Since the premutation can occur in less than 1 in 200 women and 1 in 400 men, the FXTAS diagnosis should be considered in patients that present with tremor, ataxia, parkinsonian symptoms, neuropathy, and psychiatric problems. If a family history of a fragile X mutation is known, then DNA testing is essential in patients with these symptoms.
Topics: Age of Onset; Ataxia; Atrophy; Early Diagnosis; Female; Fragile X Mental Retardation Protein; Fragile X Syndrome; Humans; Magnetic Resonance Imaging; Male; Mutation; Sex Characteristics; Tremor; Trinucleotide Repeat Expansion
PubMed: 32575683
DOI: 10.3390/ijms21124391