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Статті в журналах з теми "Triplet repeat diseases"

Автор: Grafiati

Опубліковано: 19 жовтня 2024

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1

Pan, Feng, Pengning Xu, Christopher Roland, Celeste Sagui, and Keith Weninger. "Structural and Dynamical Properties of Nucleic Acid Hairpins Implicated in Trinucleotide Repeat Expansion Diseases." Biomolecules 14, no. 10 (October 10, 2024): 1278. http://dx.doi.org/10.3390/biom14101278.

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Анотація:

Dynamic mutations in some human genes containing trinucleotide repeats are associated with severe neurodegenerative and neuromuscular disorders—known as Trinucleotide (or Triplet) Repeat Expansion Diseases (TREDs)—which arise when the repeat number of triplets expands beyond a critical threshold. While the mechanisms causing the DNA triplet expansion are complex and remain largely unknown, it is now recognized that the expandable repeats lead to the formation of nucleotide configurations with atypical structural characteristics that play a crucial role in TREDs. These nonstandard nucleic acid forms include single-stranded hairpins, Z-DNA, triplex structures, G-quartets and slipped-stranded duplexes. Of these, hairpin structures are the most prolific and are associated with the largest number of TREDs and have therefore been the focus of recent single-molecule FRET experiments and molecular dynamics investigations. Here, we review the structural and dynamical properties of nucleic acid hairpins that have emerged from these studies and the implications for repeat expansion mechanisms. The focus will be on CAG, GAC, CTG and GTC hairpins and their stems, their atomistic structures, their stability, and the important role played by structural interrupts.

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2

Monckton, Darren G., and C. Thomas Caskey. "Unstable Triplet Repeat Diseases." Circulation 91, no. 2 (January 15, 1995): 513–20. http://dx.doi.org/10.1161/01.cir.91.2.513.

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3

Jasinska, Anna J., Piotr Kozlowski, and Wlodzimierz J. Krzyzosiak. "Expression characteristics of triplet repeat-containing RNAs and triplet repeat-interacting proteins in human tissues." Acta Biochimica Polonica 55, no. 1 (January 30, 2008): 1–8. http://dx.doi.org/10.18388/abp.2008_3090.

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Numerous human transcripts contain tandem repeats of trinucleotide motifs, the function of which remains unknown. In this study we used the available gene expression EST data to characterize the abundance of a large group of these transcripts in different tissues and determine the mRNAs which had the highest contribution to the observed levels of transcripts containing different types of the CNG repeats. A more extensive characteristics was performed for transcripts containing the CUG repeats, and those encoding the repeat-binding proteins. The scarcity of double-stranded CUG repeats as well as various proportions of the single-stranded and double-stranded CUG repeat-binding proteins were revealed in the studied transcriptomes. The observed correlated levels of transcripts containing single-stranded CUG repeats and of proteins binding single-stranded CUG repeats may imply that in addition to transcripts which only provide binding sites for these proteins there may be a substantial portion of the transcripts whose metabolism is directly regulated by such proteins. Our results showing a highly variable composition of triplet repeat-containing transcripts and their interacting proteins in different tissues may contribute to a better understanding of the mechanism of RNA-mediated pathogenesis in triplet repeat expansion diseases.

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4

Bates, Gillian P., and Roman Gonitel. "Mouse Models of Triplet Repeat Diseases." Molecular Biotechnology 32, no. 2 (2006): 147–58. http://dx.doi.org/10.1385/mb:32:2:147.

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5

Di Prospero, Nicholas A., and Kenneth H. Fischbeck. "Therapeutics development for triplet repeat expansion diseases." Nature Reviews Genetics 6, no. 10 (October 2005): 756–66. http://dx.doi.org/10.1038/nrg1690.

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6

Li, Rena, and Rif S. El-Mallakh. "Triplet Repeat Gene Sequences in Neuropsychiatric Diseases." Harvard Review of Psychiatry 5, no. 2 (January 1997): 66–74. http://dx.doi.org/10.3109/10673229709034729.

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7

Gorbunova, Vera, Andrei Seluanov, Vincent Dion, Zoltan Sandor, James L. Meservy, and John H. Wilson. "Selectable System for Monitoring the Instability of CTG/CAG Triplet Repeats in Mammalian Cells." Molecular and Cellular Biology 23, no. 13 (July 1, 2003): 4485–93. http://dx.doi.org/10.1128/mcb.23.13.4485-4493.2003.

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ABSTRACT Despite substantial progress in understanding the mechanism by which expanded CTG/CAG trinucleotide repeats cause neurodegenerative diseases, little is known about the basis for repeat instability itself. By taking advantage of a novel phenomenon, we have developed a selectable assay to detect contractions of CTG/CAG triplets. When inserted into an intron in the APRT gene or the HPRT minigene, long tracts of CTG/CAG repeats (more than about 33 repeat units) are efficiently incorporated into mRNA as a new exon, thereby rendering the encoded protein nonfunctional, whereas short repeat tracts do not affect the phenotype. Therefore, contractions of long repeats can be monitored in large cell populations, by selecting for HPRT+ or APRT+ clones. Using this selectable system, we determined the frequency of spontaneous contractions and showed that treatments with DNA-damaging agents stimulate repeat contractions. The selectable system that we have developed provides a versatile tool for the analysis of CTG/CAG repeat instability in mammalian cells. We also discuss how the effect of long CTG/CAG repeat tracts on splicing may contribute to the progression of polyglutamine diseases.

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8

Sinnreich, Michael, Eric J. Sorenson, and Christopher J. Klein. "Neurologic Course, Endocrine Dysfunction and Triplet Repeat Size in Spinal Bulbar Muscular Atrophy." Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques 31, no. 3 (August 2004): 378–82. http://dx.doi.org/10.1017/s0317167100003486.

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Objective:To study the role of diabetes, gynecomastia and CAG triplet repeat size as disease modifying factors of neurologic expression in spinal bulbar muscular atrophy (SBMA, Kennedy's disease).Methods:Twenty unrelated SBMApatients with confirmatory genetic testing were reviewed. Patterns of neurologic involvement were assessed (e.g. bulbar, asymmetric, proximal, distal, motor and sensory). Slopes of disease progression were calculated from serial quantified neurologic examinations. Patterns of neurologic involvement and course were correlated to the presence of diabetes, gynecomastia and triplet repeat size.Results:Diabetes or glucose impairment occurred in nine and 11 had gynecomastia. Patterns of neurologic involvement and rates of progression did not correlate with these endocrine diseases or triplet repeat sizes. Correlation was seen between number of CAG repeats and age of onset weakness (r = -0.53, r2 = 29%, p = 0.01).Conclusion:The specific neurotoxic effect of expanded CAGs appears limited to age of onset weakness in SBMA. Although significant, only 29% of the variability in onset age could be accounted for by polyglutamine size suggesting the importance of other unidentified factors. In this series diabetes or glucose impairment was more common than previously reported and, like gynecomastia, did not correlate with size of triplet repeats, severity or patterns of neurologic involvement. Modifying factors other than diabetes, gynecomastia or triplet repeat size are suggested in disease expression.

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9

Olejniczak, Marta, Martyna O. Urbanek, and Wlodzimierz J. Krzyzosiak. "The Role of the Immune System in Triplet Repeat Expansion Diseases." Mediators of Inflammation 2015 (2015): 1–11. http://dx.doi.org/10.1155/2015/873860.

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Анотація:

Trinucleotide repeat expansion disorders (TREDs) are a group of dominantly inherited neurological diseases caused by the expansion of unstable repeats in specific regions of the associated genes. Expansion of CAG repeat tracts in translated regions of the respective genes results in polyglutamine- (polyQ-) rich proteins that form intracellular aggregates that affect numerous cellular activities. Recent evidence suggests the involvement of an RNA toxicity component in polyQ expansion disorders, thus increasing the complexity of the pathogenic processes. Neurodegeneration, accompanied by reactive gliosis and astrocytosis is the common feature of most TREDs, which may suggest involvement of inflammation in pathogenesis. Indeed, a number of immune response markers have been observed in the blood and CNS of patients and mouse models, and the activation of these markers was even observed in the premanifest stage of the disease. Although inflammation is not an initiating factor of TREDs, growing evidence indicates that inflammatory responses involving astrocytes, microglia, and the peripheral immune system may contribute to disease progression. Herein, we review the involvement of the immune system in the pathogenesis of triplet repeat expansion diseases, with particular emphasis on polyglutamine disorders. We also present various therapeutic approaches targeting the dysregulated inflammation pathways in these diseases.

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10

Servadio, Antonio, Angelo Poletti, Antonio Servadio, and Franco Taroni. "Triplet repeat diseases: from basic to clinical aspects." Brain Research Bulletin 56, no. 3-4 (November 2001): 159. http://dx.doi.org/10.1016/s0361-9230(01)00750-x.

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11

Galka-Marciniak, Paulina, Martyna O. Urbanek, and Wlodzimierz J. Krzyzosiak. "Triplet repeats in transcripts: structural insights into RNA toxicity." Biological Chemistry 393, no. 11 (November 1, 2012): 1299–315. http://dx.doi.org/10.1515/hsz-2012-0218.

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Abstract Tandem repeats of various trinucleotide motifs are frequent entities in transcripts, and RNA structures formed by these sequences depend on the motif type and number of reiterations. The functions performed by normal triplet repeats in transcripts are poorly understood, but abnormally expanded repeats of certain types trigger pathogenesis in several human genetic disorders known as the triplet repeat expansion diseases (TREDs). The diseases caused by expanded non-coding CUG and CGG repeats in transcripts include myotonic dystrophy type 1 and fragile X-associated tremor ataxia syndrome. Another group of disorders in which transcripts containing translated CAG repeats play an auxiliary role in pathogenesis include Huntington’s disease and several spinocerebellar ataxias. In this review, we gathered existing knowledge regarding the structural features of triplet repeats in transcripts and discussed this in the context of various pathogenic mechanisms assigned to toxic RNA repeats. These mechanisms include aberrant alternative splicing, the inhibition of nuclear transport and export, induction of the innate immune response, alteration of a microRNA biogenesis pathway and abnormal activation of an RNA interference pathway. We also provide ideas for future investigations to reveal further mechanisms of pathogenesis directly triggered by mutant RNA repeats in TREDs.

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12

Randall, Teri. "Triplet Repeat Mutations: Amplification Within Pedigrees Generates Three Human Diseases." JAMA: The Journal of the American Medical Association 269, no. 5 (February 3, 1993): 558. http://dx.doi.org/10.1001/jama.1993.03500050016004.

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13

Randall, T. "Triplet repeat mutations: amplification within pedigrees generates three human diseases." JAMA: The Journal of the American Medical Association 269, no. 5 (February 3, 1993): 558. http://dx.doi.org/10.1001/jama.269.5.558.

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14

Williams, Gregory M., Vasileios Paschalis, Janice Ortega, Frederick W. Muskett, James T. Hodgkinson, Guo-Min Li, John W. R. Schwabe та Robert S. Lahue. "HDAC3 deacetylates the DNA mismatch repair factor MutSβ to stimulate triplet repeat expansions". Proceedings of the National Academy of Sciences 117, № 38 (8 вересня 2020): 23597–605. http://dx.doi.org/10.1073/pnas.2013223117.

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Trinucleotide repeat (TNR) expansions cause nearly 20 severe human neurological diseases which are currently untreatable. For some of these diseases, ongoing somatic expansions accelerate disease progression and may influence age of onset. This new knowledge emphasizes the importance of understanding the protein factors that drive expansions. Recent genetic evidence indicates that the mismatch repair factor MutSβ (Msh2-Msh3 complex) and the histone deacetylase HDAC3 function in the same pathway to drive triplet repeat expansions. Here we tested the hypothesis that HDAC3 deacetylates MutSβ and thereby activates it to drive expansions. The HDAC3-selective inhibitor RGFP966 was used to examine its biological and biochemical consequences in human tissue culture cells. HDAC3 inhibition efficiently suppresses repeat expansion without impeding canonical mismatch repair activity. Five key lysine residues in Msh3 are direct targets of HDAC3 deacetylation. In cells expressing Msh3 in which these lysine residues are mutated to arginine, the inhibitory effect of RGFP966 on expansions is largely bypassed, consistent with the direct deacetylation hypothesis. RGFP966 treatment does not alter MutSβ subunit abundance or complex formation but does partially control its subcellular localization. Deacetylation sites in Msh3 overlap a nuclear localization signal, and we show that localization of MutSβ is partially dependent on HDAC3 activity. Together, these results indicate that MutSβ is a key target of HDAC3 deacetylation and provide insights into an innovative regulatory mechanism for triplet repeat expansions. The results suggest expansion activity may be druggable and support HDAC3-selective inhibition as an attractive therapy in some triplet repeat expansion diseases.

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15

Gonzalez-Alegre, Pedro. "Recent advances in molecular therapies for neurological disease: triplet repeat disorders." Human Molecular Genetics 28, R1 (June 22, 2019): R80—R87. http://dx.doi.org/10.1093/hmg/ddz138.

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AbstractTriplet repeat diseases (TRDs) are caused by pathogenic expansions of trinucleotide sequence repeats within coding and non-coding regions of different genes. They are typically progressive, very disabling and frequently involve the nervous system. Currently available symptomatic therapies provide modest benefit at best. The development of interventions that interfere with the natural history of these diseases is a priority. A common pathogenic process shared by most TRDs is the presence of toxicity from the messenger RNA or protein encoded by the gene harboring the abnormal expansion. Strategies to interfere with the expression of these genes using different molecular approaches are being pursued and have reached the clinical stage. This review will summarize the significant progress made in this field in the last few years, focusing on three main areas: the discovery of biomarkers of disease progression and target engagement, advances in preclinical studies for the polyglutamine ataxias and the initial clinical application in myotonic dystrophy type 1 and Huntington’s disease.

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16

Nahalka, Jozef. "1-L Transcription in Prion Diseases." International Journal of Molecular Sciences 25, no. 18 (September 15, 2024): 9961. http://dx.doi.org/10.3390/ijms25189961.

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Understanding the pathogenesis and mechanisms of prion diseases can significantly expand our knowledge in the field of neurodegenerative diseases. Prion biology is increasingly recognized as being relevant to the pathophysiology of Alzheimer’s disease and Parkinson’s disease, both of which affect millions of people each year. This bioinformatics study used a theoretical protein-RNA recognition code (1-L transcription) to reveal the post-transcriptional regulation of the prion protein (PrPC). The principle for this method is directly elucidated on PrPC, in which an octa-repeat can be 1-L transcribed into a GGA triplet repeat RNA aptamer known to reduce the misfolding of normal PrPC into abnormal PrPSc. The identified genes/proteins are associated with mitochondria, cancer, COVID-19 and ER-stress, and approximately half are directly or indirectly associated with prion diseases. For example, the octa-repeat supports CD44, and regions of the brain with astrocytic prion accumulation also display high levels of CD44.

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17

Truant, Ray, Lynn A. Raymond, Jianrun Xia, Deborah Pinchev, Anjee Burtnik, and Randy Singh Atwal. "Canadian Association of Neurosciences Review: Polyglutamine Expansion Neurodegenerative Diseases." Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques 33, no. 3 (August 2006): 278–91. http://dx.doi.org/10.1017/s031716710000514x.

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ABSTRACT:Since the early 1990s, DNA triplet repeat expansions have been found to be the cause in an ever increasing number of genetic neurologic diseases. A subset of this large family of genetic diseases has the expansion of a CAG DNA triplet in the open reading frame of a coding exon. The result of this DNA expansion is the expression of expanded glutamine amino acid repeat tracts in the affected proteins, leading to the term, Polyglutamine Diseases, which is applied to this sub-family of diseases. To date, nine distinct genes are known to be linked to polyglutamine diseases, including Huntington's disease, Machado-Joseph Disease and spinobulbar muscular atrophy or Kennedy's disease. Most of the polyglutamine diseases are characterized clinically as spinocerebellar ataxias. Here we discuss recent successes and advancements in polyglutamine disease research, comparing these different diseases with a common genetic flaw at the level of molecular biology and early drug design for a family of diseases where many new research tools for these genetic disorders have been developed. Polyglutamine disease research has successfully used interdisciplinary collaborative efforts, informative multiple mouse genetic models and advanced tools of pharmaceutical industry research to potentially serve as the prototype model of therapeutic research and development for rare neurodegenerative diseases.

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18

Völker, Plum, Gindikin, and Breslauer. "Dynamic DNA Energy Landscapes and Substrate Complexity in Triplet Repeat Expansion and DNA Repair." Biomolecules 9, no. 11 (November 6, 2019): 709. http://dx.doi.org/10.3390/biom9110709.

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DNA repeat domains implicated in DNA expansion diseases exhibit complex conformational and energy landscapes that impact biological outcomes. These landscapes include ensembles of entropically driven positional interchanges between isoenergetic, isomeric looped states referred to as rollamers. Here, we present evidence for the position-dependent impact on repeat DNA energy landscapes of an oxidative lesion (8oxodG) and of an abasic site analogue (tetrahydrofuran, F), the universal intermediate in base excision repair (BER). We demonstrate that these lesions modulate repeat bulge loop distributions within the wider dynamic rollamer triplet repeat landscapes. We showed that the presence of a lesion disrupts the energy degeneracy of the rollameric positional isomers. This lesion-induced disruption leads to the redistribution of loop isomers within the repeat loop rollamer ensemble, favoring those rollameric isomers where the lesion is positioned to be energetically least disruptive. These dynamic ensembles create a highly complex energy/conformational landscape of potential BER enzyme substrates to select for processing or to inhibit processing. We discuss the implications of such lesion-induced alterations in repeat DNA energy landscapes in the context of potential BER repair outcomes, thereby providing a biophysical basis for the intriguing in vivo observation of a linkage between pathogenic triplet repeat expansion and DNA repair.

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19

Kelley, Karen, Shin-Ju E. Chang, and Shi-Lung Lin. "Mechanism of Repeat-Associated MicroRNAs in Fragile X Syndrome." Neural Plasticity 2012 (2012): 1–10. http://dx.doi.org/10.1155/2012/104796.

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The majority of the human genome is comprised of non-coding DNA, which frequently contains redundant microsatellite-like trinucleotide repeats. Many of these trinucleotide repeats are involved in triplet repeat expansion diseases (TREDs) such as fragile X syndrome (FXS). After transcription, the trinucleotide repeats can fold into RNA hairpins and are further processed byDicerendoribonuclases to form microRNA (miRNA)-like molecules that are capable of triggering targeted gene-silencing effects in the TREDs. However, the function of these repeat-associated miRNAs (ramRNAs) is unclear. To solve this question, we identified the first native ramRNA in FXS and successfully developed a transgenic zebrafish model for studying its function. Our studies showed that ramRNA-induced DNA methylation of theFMR15′-UTR CGG trinucleotide repeat expansion is responsible for both pathological and neurocognitive characteristics linked to the transcriptionalFMR1gene inactivation and the deficiency of its protein product FMRP. FMRP deficiency often causes synapse deformity in the neurons essential for cognition and memory activities, whileFMR1inactivation augments metabotropic glutamate receptor (mGluR)-activated long-term depression (LTD), leading to abnormal neuronal responses in FXS. Using this novel animal model, we may further dissect the etiological mechanisms of TREDs, with the hope of providing insights into new means for therapeutic intervention.

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20

Bhattacharyya, Saumitri, Michael L. Rolfsmeier, Michael J. Dixon, Kara Wagoner, and Robert S. Lahue. "Identification of RTG2 as a Modifier Gene for CTG·CAG Repeat Instability in Saccharomyces cerevisiae." Genetics 162, no. 2 (October 1, 2002): 579–89. http://dx.doi.org/10.1093/genetics/162.2.579.

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Abstract Trinucleotide repeats (TNRs) undergo frequent mutations in families affected by TNR diseases and in model organisms. Much of the instability is conferred in cis by the sequence and length of the triplet tract. Trans-acting factors also modulate TNR instability risk, on the basis of such evidence as parent-of-origin effects. To help identify trans-acting modifiers, a screen was performed to find yeast mutants with altered CTG·CAG repeat mutation frequencies. The RTG2 gene was identified as one such modifier. In rtg2 mutants, expansions of CTG·CAG repeats show a modest increase in rate, depending on the starting tract length. Surprisingly, contractions were suppressed in an rtg2 background. This creates a situation in a model system where expansions outnumber contractions, as in humans. The rtg2 phenotype was apparently specific for CTG·CAG repeat instability, since no changes in mutation rate were observed for dinucleotide repeats or at the CAN1 reporter gene. This feature sets rtg2 mutants apart from most other mutants that affect genetic stability both for TNRs and at other DNA sequences. It was also found that RTG2 acts independently of its normal partners RTG1 and RTG3, suggesting a novel function of RTG2 that helps modify CTG·CAG repeat mutation risk.

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21

Volker, J., N. Makube, G. E. Plum, H. H. Klump, and K. J. Breslauer. "Conformational energetics of stable and metastable states formed by DNA triplet repeat oligonucleotides: Implications for triplet expansion diseases." Proceedings of the National Academy of Sciences 99, no. 23 (November 4, 2002): 14700–14705. http://dx.doi.org/10.1073/pnas.222519799.

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22

Hasan, Qurratulain, Ravindra Varma Alluri, Pragna Rao, and Yog Raj Ahuja. "Role of Glutamine Deamidation in Neurodegenerative Diseases Associated With Triplet Repeat Expansions: A Hypothesis." Journal of Molecular Neuroscience 29, no. 1 (2006): 29–34. http://dx.doi.org/10.1385/jmn:29:1:29.

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23

Hoffman-Zacharska, Dorota, and Anna Sulek. "The New Face of Dynamic Mutation—the CAA [CAG]n CAA CAG Motif as a Mutable Unit in the TBP Gene Causative for Spino-Cerebellar Ataxia Type 17." International Journal of Molecular Sciences 25, no. 15 (July 26, 2024): 8190. http://dx.doi.org/10.3390/ijms25158190.

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Since 1991, several genetic disorders caused by unstable trinucleotide repeats (TNRs) have been identified, collectively referred to as triplet repeat diseases (TREDs). They share a common mutation mechanism: the expansion of repeats (dynamic mutations) due to the propensity of repeated sequences to form unusual DNA structures during replication. TREDs are characterized as neurodegenerative diseases or complex syndromes with significant neurological components. Spinocerebellar ataxia type 17 (SCA17) falls into the former category and is caused by the expansion of mixed CAA/CAG repeats in the TBP gene. To date, a five-unit organization of this region [(CAG)3 (CAA)3] [(CAG)n] [CAA CAG CAA] [(CAG)n] [CAA CAG], with expansion in the second [(CAG)n] unit being the most common, has been proposed. In this study, we propose an alternative organization scheme for the repeats. A search of the PubMed database was conducted to identify articles reporting both the number and composition of GAC/CAA repeats in TBP alleles. Nineteen reports were selected. The sequences of all identified CAG/CAA repeats in the TBP locus, including 67 cases (probands and b relatives), were analyzed in terms of their repetition structure and stability in inheritance, if possible. Based on the analysis of three units [(CAG)3 (CAA)2] [CAA (CAG)n CAA CAG] [CAA (CAG)n CAA CAG], the organization of repeats is proposed. Detailed analysis of the CAG/CAA repeat structure, not just the number of repeats, in TBP-expanded alleles should be performed, as it may have a prognostic value in the prediction of stability/instability during transmission and the possible anticipation of the disease.

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24

Shen, Tao, Yukari Nagai, M. Udayakumar, K. Narasimhan, R. K. Arvind Shriram, N. Mohanraj, and V. Elamaran. "Automated Genomic Signal Processing for Diseased Gene Identification." Journal of Medical Imaging and Health Informatics 9, no. 6 (August 1, 2019): 1254–61. http://dx.doi.org/10.1166/jmihi.2019.2726.

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Genomic signal processing (GSP) is the engineering discipline for the analysis, processing, and use of genomic signals to gain biological knowledge, and the translation of that knowledge into systems-based applications that can be used to diagnose and treat genetic diseases. Statistical Computations on DNA Sequences is one of key areas in which GSP can be applied. In this paper, we apply DSP tools on trinucleotide repeat disorders (too many copies of a certain nucleotide triplet in the DNA) to classify any gene sequence into diseased/non-diseased state. Intially, we collected the Gene sequences responsible for trinucleotide repeat disorders from NCBI. Then, we applied GSP techniques to convert the given gene sequence into an indicator sequence, and furthermore we apply Fast Fourier transforms (FFTs) and Discrete Wavelet Transforms (DWTs), followed by statistical feature extraction and the obtained statistical features, fed into an Artificial Neural Network to predict the state of the input genomic sequence.

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25

Raaijmakers, Renée H. L., Lise Ripken, C. Rosanne M. Ausems, and Derick G. Wansink. "CRISPR/Cas Applications in Myotonic Dystrophy: Expanding Opportunities." International Journal of Molecular Sciences 20, no. 15 (July 27, 2019): 3689. http://dx.doi.org/10.3390/ijms20153689.

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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 DMPK/DM1-AS 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 DMPK. 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.

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26

KIMMEL, MAREK. "WHY MATHEMATICS IS NEEDED TO UNDERSTAND COMPLEX GENETICS DISEASES." Journal of Biological Systems 10, no. 04 (December 2002): 359–80. http://dx.doi.org/10.1142/s0218339002000688.

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Анотація:

We discuss mathematical approaches to population genetics and evolutionary theory in the context of complex genetic disease. Mechanisms, which we discuss, include gene-environment interaction in lung cancer as well as classical mechanisms of stabilization of genetic disease such as overdominance, antagonistic pleiotropy and recurring mutations. Specific modeling approaches discussed include: (1) Mathematical model of the evolution of disease chromosome applied to mapping of a disease gene. (2) Iterated Galton–Watson branching process applied to modeling of trinucleotide expansion in triplet-repeat diseases. (3) Application of Ewens' sampling formula to analysis of Single Nucleotide Polymorphism haplotypes at disease-related genes. The aim of this paper is not to present an exhaustive review, but rather to advocate mathematical modeling approaches in a field of current interest.

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27

Wells, Robert D., Pawel Parniewski, Anna Pluciennik, Albino Bacolla, Robert Gellibolian, and Adam Jaworski. "Small Slipped Register Genetic Instabilities inEscherichia coliin Triplet Repeat Sequences Associated with Hereditary Neurological Diseases." Journal of Biological Chemistry 273, no. 31 (July 31, 1998): 19532–41. http://dx.doi.org/10.1074/jbc.273.31.19532.

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28

Shimizu, M., R. Fujita, N. Tomita, H. Shindo, and R. D. Wells. "Chromatin structure of yeast minichromosomes containing triplet repeat sequences associated with human hereditary neurological diseases." Nucleic Acids Symposium Series 1, no. 1 (November 1, 2001): 71–72. http://dx.doi.org/10.1093/nass/1.1.71.

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29

Matsuo, Kazuya, Susumu Ikenoshita, Yasushi Yabuki, Kosuke Kawakubo, Sefan Asamitsu, Hiroshi Sugiyama, and Norifumi Shioda. "Development of a mutant allele-specific transcriptional repressive agent in CAG/CTG triplet repeat diseases." Proceedings for Annual Meeting of The Japanese Pharmacological Society 96 (2022): YIA08–1. http://dx.doi.org/10.1254/jpssuppl.96.0_yia08-1.

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30

Kawakubo, Kosuke, Susumu Ikenoshita, Kazuya Matsuo, Sefan Asamitsu, Yasushi Yabuki, Hiroshi Sugiyama, and Norifumi Shioda. "Therapeutic targeting expanded DNA using cyclic pyrrole-imidazole polyamide in CAG/CTG triplet repeat neurological diseases." Proceedings for Annual Meeting of The Japanese Pharmacological Society 95 (2022): 1—SS—27. http://dx.doi.org/10.1254/jpssuppl.95.0_1-ss-27.

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31

Hou, M. H. "Crystal structure of actinomycin D bound to the CTG triplet repeat sequences linked to neurological diseases." Nucleic Acids Research 30, no. 22 (November 15, 2002): 4910–17. http://dx.doi.org/10.1093/nar/gkf619.

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32

Volker, J., H. H. Klump, and K. J. Breslauer. "DNA energy landscapes via calorimetric detection of microstate ensembles of metastable macrostates and triplet repeat diseases." Proceedings of the National Academy of Sciences 105, no. 47 (November 17, 2008): 18326–30. http://dx.doi.org/10.1073/pnas.0810376105.

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33

SERMON, K. "PGD in the lab for triplet repeat diseases ? myotonic dystrophy, Huntington's disease and Fragile-X syndrome." Molecular and Cellular Endocrinology 183 (October 2001): S77—S85. http://dx.doi.org/10.1016/s0303-7207(01)00572-x.

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34

Maduro, Maria Rosa, Roberto Casella, Alex G. Smith, and Dolores J. Lamb. "Increased incidence of triplet repeat diseases expanded alleles in azoospermic men: a new concern for ICSI?" Fertility and Sterility 78 (September 2002): S32. http://dx.doi.org/10.1016/s0015-0282(02)03465-9.

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35

White, Peter J., Rhona H. Borts, and Mark C. Hirst. "Stability of the Human Fragile X (CGG)n Triplet Repeat Array inSaccharomyces cerevisiae Deficient in Aspects of DNA Metabolism." Molecular and Cellular Biology 19, no. 8 (August 1, 1999): 5675–84. http://dx.doi.org/10.1128/mcb.19.8.5675.

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ABSTRACT Expanded trinucleotide repeats underlie a growing number of human diseases. The human FMR1 (CGG) n array can exhibit genetic instability characterized by progressive expansion over several generations leading to gene silencing and the development of the fragile X syndrome. While expansion is dependent upon the length of uninterrupted (CGG) n , instability occurs in a limited germ line and early developmental window, suggesting that lineage-specific expression of other factors determines the cellular environment permissive for expansion. To identify these factors, we have established normal- and premutation-length human FMR1 (CGG) n arrays in the yeast Saccharomyces cerevisiae and assessed the frequency of length changes greater than 5 triplets in cells deficient in various DNA repair and replication functions. In contrast to previous studies withEscherichia coli, we observed a low frequency of orientation-dependent large expansions in arrays carrying long uninterrupted (CGG) n arrays in a wild-type background. This frequency was unaffected by deletion of several DNA mismatch repair genes or deletion of the EXO1 andDIN7 genes and was not enhanced through meiosis in a wild-type background. Array contraction occurred in an orientation-dependent manner in most mutant backgrounds, but loss of the Sgs1p resulted in a generalized increase in array stability in both orientations. In contrast, FMR1 arrays had a 10-fold-elevated frequency of expansion in a rad27 background, providing evidence for a role in lagging-strand Okazaki fragment processing in (CGG) n triplet repeat expansion.

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36

Huntley, Melanie A., Sanaa Mahmood, and G. Brian Golding. "Simple sequence in brain and nervous system specific proteins." Genome 48, no. 2 (April 1, 2005): 291–301. http://dx.doi.org/10.1139/g04-124.

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We examined sequences expressed in the brain and nervous system using EST data. A previous study including sequences thought to have neurological function found a deficiency of simple sequence within such sequences. This was despite many examples of neurodegenerative diseases, such as Huntington disease, which are thought to be caused by expansions of polyglutamine tracts within associated protein sequences. It may be that many of the sequences thought to have neurological function have other additional, non-neurological roles. For this reason, we examined sequences with specific expression in the brain and nervous system, using EST expression data to determine if they too are deficient of simple, repetitive sequences. Indeed, we find this class of sequences to be deficient. Unexpectedly, however, we find sequences expressed in the brain and nervous system to be consistently enriched for histidine-enriched simple sequence. Determining the function of these histidine-rich regions within brain-specific proteins requires more experimental data.Key words: amino acid repeats, homopeptides, simple sequence, triplet repeat diseases, nervous system proteins, brain-specific proteins.

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37

Liu, Yuan, Haihua Zhang, Janaki Veeraraghavan, Robert A. Bambara, and Catherine H. Freudenreich. "Saccharomyces cerevisiae Flap Endonuclease 1 Uses Flap Equilibration To Maintain Triplet Repeat Stability." Molecular and Cellular Biology 24, no. 9 (May 1, 2004): 4049–64. http://dx.doi.org/10.1128/mcb.24.9.4049-4064.2004.

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ABSTRACT Flap endonuclease 1 (FEN1) is a central component of Okazaki fragment maturation in eukaryotes. Genetic analysis of Saccharomyces cerevisiae FEN1 (RAD27) also reveals its important role in preventing trinucleotide repeat (TNR) expansion. In humans such expansion is associated with neurodegenerative diseases. In vitro, FEN1 can inhibit TNR expansion by employing its endonuclease activity to compete with DNA ligase I. Here we employed two yeast FEN1 nuclease mutants, rad27-G67S and rad27-G240D, to further define the mechanism by which FEN1 prevents TNR expansion. Using a yeast artificial chromosome system that can detect both TNR instability and fragility, we demonstrate that the G240D but not the G67S mutation increases both the expansion and fragility of a CTG tract in vivo. In vitro, the G240D nuclease is proficient in cleaving a fixed nonrepeat double flap; however, it exhibits severely impaired cleavage of both nonrepeat and CTG-containing equilibrating flaps. In contrast, wild-type FEN1 and the G67S mutant exhibit more efficient cleavage on an equilibrating flap than on a fixed CTG flap. The degree of TNR expansion and the amount of chromosome fragility observed in the mutant strains correlate with the severity of defective flap cleavage in vitro. We present a model to explain how flap equilibration and the unique tracking mechanism of FEN1 can collaborate to remove TNR flaps and prevent repeat expansion.

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38

Saido, T. C. "Involvement of polyglutamine endolysis followed by pyroglutamate formation in the pathogenesis of triplet repeat/polyglutamine-expansion diseases." Medical Hypotheses 54, no. 3 (March 2000): 427–29. http://dx.doi.org/10.1054/mehy.1999.0866.

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39

Thirugnanasambandam, Arunachalam, Selvam Karthik, Pradeep Kumar Mandal, and Namasivayam Gautham. "The novel double-folded structure of d(GCATGCATGC): a possible model for triplet-repeat sequences." Acta Crystallographica Section D Biological Crystallography 71, no. 10 (September 30, 2015): 2119–26. http://dx.doi.org/10.1107/s1399004715013930.

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The structure of the decadeoxyribonucleotide d(GCATGCATGC) is presented at a resolution of 1.8 Å. The decamer adopts a novel double-folded structure in which the direction of progression of the backbone changes at the two thymine residues. Intra-strand stacking interactions (including an interaction between the endocylic O atom of a ribose moiety and the adjacent purine base), hydrogen bonds and cobalt-ion interactions stabilize the double-folded structure of the single strand. Two such double-folded strands come together in the crystal to form a dimer. Inter-strand Watson–Crick hydrogen bonds form four base pairs. This portion of the decamer structure is similar to that observed in other previously reported oligonucleotide structures and has been dubbed a `bi-loop'. Both the double-folded single-strand structure, as well as the dimeric bi-loop structure, serve as starting points to construct models for triplet-repeat DNA sequences, which have been implicated in many human diseases.

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40

Fischer, K. M. "Etiology of (CAG)n triplet repeat neurodegenerative diseases such as Huntington's disease is connected to stimulation of glutamate receptors." Medical Hypotheses 48, no. 5 (May 1997): 393–98. http://dx.doi.org/10.1016/s0306-9877(97)90034-7.

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41

Freudenreich, C. H., J. B. Stavenhagen, and V. A. Zakian. "Stability of a CTG/CAG trinucleotide repeat in yeast is dependent on its orientation in the genome." Molecular and Cellular Biology 17, no. 4 (April 1997): 2090–98. http://dx.doi.org/10.1128/mcb.17.4.2090.

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Trinucleotide repeat expansion is the causative mutation for a growing number of diseases including myotonic dystrophy, Huntington's disease, and fragile X syndrome. A (CTG/CAG)130 tract cloned from a myotonic dystrophy patient was inserted in both orientations into the genome of Saccharomyces cerevisiae. This insertion was made either very close to the 5' end or very close to the 3' end of a URA3 transcription unit. Regardless of its orientation, no evidence was found for triplet-mediated transcriptional repression of the nearby gene. However, the stability of the tract correlated with its orientation on the chromosome. In one orientation, the (CTG/CAG)130 tract was very unstable and prone to deletions. In the other orientation, the tract was stable, with fewer deletions and two possible cases of expansion detected. Analysis of the direction of replication through the region showed that in the unstable orientation the CTG tract was on the lagging-strand template and that in the stable orientation the CAG tract was on the lagging-strand template. The orientation dependence of CTG/CAG tract instability seen in this yeast system supports models involving hairpin-mediated polymerase slippage previously proposed for trinucleotide repeat expansion.

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42

Bichara, M., S. Schumacher, and R. P. Fuchs. "Genetic instability within monotonous runs of CpG sequences in Escherichia coli." Genetics 140, no. 3 (July 1, 1995): 897–907. http://dx.doi.org/10.1093/genetics/140.3.897.

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Abstract Genetic information can be altered by base substitutions, frameshift mutations, and addition or deletion of nucleotides. Deletions represent an important class of genetic aberration occurring at DNA sequences where it is often possible to predict the existence of intermediates of mutation. Instability within tracts of repetitive sequence have recently been associated with several genetic disorders, including the so-called triplet repeat diseases and certain forms of colorectal cancers. In Escherichia coli, (GpC)n repetitive sequences have been shown to be deletion prone, but the precise mechanism of this mutagenic pathway is still unknown. We show here that interrupting the monotony of the (GpC)n run with an ApT or a GpT dinucleotide decreases the rate of deletions within these sequences. On the other hand, introducing purine-pyrimidine alternating sequences beside the GpC insert results in an increased rate of deletion. Two pathways can be envisioned: (1) (GpC)n tracts can be seen as potential Z-forming DNA sequences, and this unusual DNA structure can be processed by an unknown cellular mechanism to give rise to the observed deletions and (2) (GpC)n monotonous runs can be considered as a succession of direct or palindromic repeats, allowing formation of DNA structures that are known to participate to frameshift mutagenesis. The results presented in this article are discussed in the light of these two alternative pathways.

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43

Szwarocka, Sylwia T., Paweł Stączek, and Paweł Parniewski. "Chromosomal model for analysis of a long CTG/CAG tract stability in wild-type Escherichia coli and its nucleotide excision repair mutants." Canadian Journal of Microbiology 53, no. 7 (July 2007): 860–68. http://dx.doi.org/10.1139/w07-047.

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Many human hereditary neurological diseases, including fragile X syndrome, myotonic dystrophy, and Friedreich’s ataxia, are associated with expansions of the triplet repeat sequences (TRS) (CGG/CCG, CTG/CAG, and GAA/TTC) within or near specific genes. Mechanisms that mediate mutations of TRS include DNA replication, repair, and gene conversion and (or) recombination. The involvement of the repair systems in TRS instability was investigated in Escherichia coli on plasmid models, and the results showed that the deficiency of some nucleotide excision repair (NER) functions dramatically affects the stability of long CTG inserts. In such models in which there are tens or hundreds of plasmid molecules in each bacterial cell, repetitive sequences may interact between themselves and according to a recombination hypothesis, which may lead to expansions and deletions within such repeated tracts. Since one cannot control interaction between plasmids, it is also sometimes difficult to give precise interpretation of the results. Therefore, using modified lambda phage (λInCh), we have constructed a chromosomal model to study the instability of trinucleotide repeat sequences in E. coli. We have shown that the stability of (CTG/CAG)68 tracts in the bacterial chromosome is influenced by mutations in NER genes in E. coli. The absence of the uvrC or uvrD gene products greatly enhances the instability of the TRS in the chromosome, whereas the lack of the functional UvrA or UvrB proteins causes substantial stabilization of (CTG/CAG) tracts.

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44

Lee, Suman, and Min S. Park. "Human FEN-1 can process the 5'-flap DNA of CTG/CAG triplet repeat derived from human genetic diseases by length and sequence dependent manner." Experimental & Molecular Medicine 34, no. 4 (September 2002): 313–17. http://dx.doi.org/10.1038/emm.2002.44.

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45

Shimada, Makoto K. "Splicing Modulators Are Involved in Human Polyglutamine Diversification via Protein Complexes Shuttling between Nucleus and Cytoplasm." International Journal of Molecular Sciences 24, no. 11 (June 1, 2023): 9622. http://dx.doi.org/10.3390/ijms24119622.

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Length polymorphisms of polyglutamine (polyQs) in triplet-repeat-disease-causing genes have diversified during primate evolution despite them conferring a risk of human-specific diseases. To explain the evolutionary process of this diversification, there is a need to focus on mechanisms by which rapid evolutionary changes can occur, such as alternative splicing. Proteins that can bind polyQs are known to act as splicing factors and may provide clues about the rapid evolutionary process. PolyQs are also characterized by the formation of intrinsically disordered (ID) regions, so I hypothesized that polyQs are involved in the transportation of various molecules between the nucleus and cytoplasm to regulate mechanisms characteristic of humans such as neural development. To determine target molecules for empirical research to understand the evolutionary change, I explored protein–protein interactions (PPIs) involving the relevant proteins. This study identified pathways related to polyQ binding as hub proteins scattered across various regulatory systems, including regulation via PQBP1, VCP, or CREBBP. Nine ID hub proteins with both nuclear and cytoplasmic localization were found. Functional annotations suggested that ID proteins containing polyQs are involved in regulating transcription and ubiquitination by flexibly changing PPI formation. These findings explain the relationships among splicing complex, polyQ length variations, and modifications in neural development.

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46

McDonough, Paul G. "Triple repeat diseases and unstable gonadal function." Fertility and Sterility 88, no. 5 (November 2007): 1477–78. http://dx.doi.org/10.1016/j.fertnstert.2007.07.021.

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47

Pastore, Lisa M., JoAnn V. Pinkerton, and Christopher D. Williams. "Triple repeat diseases and unstable gonadal function." Fertility and Sterility 88, no. 5 (November 2007): 1477. http://dx.doi.org/10.1016/j.fertnstert.2007.07.023.

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48

Wittenberger, Michael D., and Lawrence M. Nelson. "Reply: Triple repeat diseases and unstable gonadal function." Fertility and Sterility 88, no. 5 (November 2007): 1477. http://dx.doi.org/10.1016/j.fertnstert.2007.07.022.

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49

TSUJI, Shoji. "Molecular Genetics of Triplet Repeats: Unstable Expansion of Triplet Repeats as a New Mechanism for Neurodegenerative Diseases." Internal Medicine 36, no. 1 (1997): 3–8. http://dx.doi.org/10.2169/internalmedicine.36.3.

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50

Usdin, K. "NGG-triplet repeats form similar intrastrand structures: implications for the triplet expansion diseases." Nucleic Acids Research 26, no. 17 (September 1, 1998): 4078–85. http://dx.doi.org/10.1093/nar/26.17.4078.

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