DM1 Phenotype Variability and Triplet Repeat Instability: Challenges in the Development of New Therapies

Tomé, Stéphanie; Gourdon, Geneviève

doi:10.3390/ijms21020457

Cited by 27 publications

(35 citation statements)

References 65 publications

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“…Based on this feature, separate congenital, infantile, juvenile, adult and late-onset forms of DM1 are described, with respective mean repeat lengths of ~1000, 800, 600, 400, and 200 according to clinical records ( Figure 4 ) [ 3 , 69 ]. Noteworthily, DM1 patients display high levels of CTG instability between different tissues of the same individual that correlate with variations in hypermethylation and clinical variability ( Figure 4 ) [ 3 , 69 , 70 ]. In DM1-affected human embryonic stem cell (hESC) lines, it has been observed that hypermethylation varies in relation to expansion size [ 71 ].…”

Section: Unstable Gc-rich Repeats In 3′ Untranslated Region (3′utrmentioning

confidence: 99%

DNA Hypermethylation and Unstable Repeat Diseases: A Paradigm of Transcriptional Silencing to Decipher the Basis of Pathogenic Mechanisms

Poeta

Drongitis

Verrillo

et al. 2020

Genes

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Unstable repeat disorders comprise a variable group of incurable human neurological and neuromuscular diseases caused by an increase in the copy number of tandem repeats located in various regions of their resident genes. It has become clear that dense DNA methylation in hyperexpanded non-coding repeats induces transcriptional silencing and, subsequently, insufficient protein synthesis. However, the ramifications of this paradigm reveal a far more profound role in disease pathogenesis. This review will summarize the significant progress made in a subset of non-coding repeat diseases demonstrating the role of dense landscapes of 5-methylcytosine (5mC) as a common disease modifier. However, the emerging findings suggest context-dependent models of 5mC-mediated silencing with distinct effects of excessive DNA methylation. An in-depth understanding of the molecular mechanisms underlying this peculiar group of human diseases constitutes a prerequisite that could help to discover novel pathogenic repeat loci, as well as to determine potential therapeutic targets. In this regard, we report on a brief description of advanced strategies in DNA methylation profiling for the identification of unstable Guanine-Cytosine (GC)-rich regions and on promising examples of molecular targeted therapies for Fragile X disease (FXS) and Friedrich ataxia (FRDA) that could pave the way for the application of this technique in other hypermethylated expansion disorders.

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Section: Unstable Gc-rich Repeats In 3′ Untranslated Region (3′utrmentioning

confidence: 99%

DNA Hypermethylation and Unstable Repeat Diseases: A Paradigm of Transcriptional Silencing to Decipher the Basis of Pathogenic Mechanisms

Poeta

Drongitis

Verrillo

et al. 2020

Genes

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“…Individuals are classified into five categories based on the age at onset: congenital, infantile, juvenile, adult, and late-onset [39,40]. These are largely correlated with repeat size, but there is significant overlap between the categories [41]. Repeat lengths of 5-∼37 CTGs occur in the general population, and it is thought that alleles between 16 and 30 repeats are the source of rare de novo expansions [42].…”

Section: Introductionmentioning

confidence: 99%

“…Repeat lengths of 5-∼37 CTGs occur in the general population, and it is thought that alleles between 16 and 30 repeats are the source of rare de novo expansions [42]. Affected individuals can harbor from ∼50 to several thousand repeats, with congenital DM1 often presenting with alleles >1,000 CTGs [43,44], Repeats of ∼50-79 exhibit high levels of male germline expansion, whereas 80+ repeats tend to exhibit greater expansions in female transmissions [41]. Somatic instability can be detected in fetal tissues between 13 and 16 weeks of gestation, and in patients shows expansion-biased and tissue-dependent instability, with high levels seen in heart, skin, muscle and blood, as well as in brain tissues [41,45].…”

Section: Introductionmentioning

confidence: 99%

Modifiers of CAG/CTG Repeat Instability: Insights from Mammalian Models

Wheeler

Dion

2021

JHD

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At fifteen different genomic locations, the expansion of a CAG/CTG repeat causes a neurodegenerative or neuromuscular disease, the most common being Huntington’s disease and myotonic dystrophy type 1. These disorders are characterized by germline and somatic instability of the causative CAG/CTG repeat mutations. Repeat lengthening, or expansion, in the germline leads to an earlier age of onset or more severe symptoms in the next generation. In somatic cells, repeat expansion is thought to precipitate the rate of disease. The mechanisms underlying repeat instability are not well understood. Here we review the mammalian model systems that have been used to study CAG/CTG repeat instability, and the modifiers identified in these systems. Mouse models have demonstrated prominent roles for proteins in the mismatch repair pathway as critical drivers of CAG/CTG instability, which is also suggested by recent genome-wide association studies in humans. We draw attention to a network of connections between modifiers identified across several systems that might indicate pathway crosstalk in the context of repeat instability, and which could provide hypotheses for further validation or discovery. Overall, the data indicate that repeat dynamics might be modulated by altering the levels of DNA metabolic proteins, their regulation, their interaction with chromatin, or by direct perturbation of the repeat tract. Applying novel methodologies and technologies to this exciting area of research will be needed to gain deeper mechanistic insight that can be harnessed for therapies aimed at preventing repeat expansion or promoting repeat contraction.

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“…Among the trinucleotide repeat (TNR) diseases, Fragile X syndrome (FXS (MIM: 300624)), Huntington’s disease (HD (MIM: 143100)), several spinocerebellar ataxias (SCAs) and myotonic dystrophy type 1 (DM1 (MIM: 160900)) have been reported. DM1 is a highly multisystemic disorder caused by an unstable CTG repeat expansion within the 3′-untranslated region (UTR) of the myotonic dystrophy protein kinase ( DMPK ) gene that usually increases across generations and in tissues [ 2 , 3 ]. DM1 is mainly characterized by a broad clinical spectrum of symptoms such as myotonia, muscle weakness, cardiac conduction defect, respiratory insufficiency, dysphagia, gastrointestinal symptoms, somnolence or cataracts [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

“…However, many DM1 patients develop unusual DM1 symptoms or remain asymptomatic despite the presence of a large CTG repeat expansion in their cells. This suggests that contributing factors such as somatic mosaicism, gene modifiers and environmental factors may affect the evolution of the clinical and mutation aspects [ 3 , 6 , 7 ]. The somatic mosaicism observed in blood is strongly biased towards expansions and contributes not only to the progressive nature of the different symptoms in several DM1 ethnic groups, but also to the variation in the age of onset [ 6 , 8 , 9 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

Robust Detection of Somatic Mosaicism and Repeat Interruptions by Long-Read Targeted Sequencing in Myotonic Dystrophy Type 1

Mangin

Pontual

Tsai

et al. 2021

IJMS

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Myotonic dystrophy type 1 (DM1) is the most complex and variable trinucleotide repeat disorder caused by an unstable CTG repeat expansion, reaching up to 4000 CTG in the most severe cases. The genetic and clinical variability of DM1 depend on the sex and age of the transmitting parent, but also on the CTG repeat number, presence of repeat interruptions and/or on the degree of somatic instability. Currently, it is difficult to simultaneously and accurately determine these contributing factors in DM1 patients due to the limitations of gold standard methods used in molecular diagnostics and research laboratories. Our study showed the efficiency of the latest PacBio long-read sequencing technology to sequence large CTG trinucleotides, detect multiple and single repeat interruptions and estimate the levels of somatic mosaicism in DM1 patients carrying complex CTG repeat expansions inaccessible to most methods. Using this innovative approach, we revealed the existence of de novo CCG interruptions associated with CTG stabilization/contraction across generations in a new DM1 family. We also demonstrated that our method is suitable to sequence the DM1 locus and measure somatic mosaicism in DM1 families carrying more than 1000 pure CTG repeats. Better characterization of expanded alleles in DM1 patients can significantly improve prognosis and genetic counseling, not only in DM1 but also for other tandem DNA repeat disorders.

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DM1 Phenotype Variability and Triplet Repeat Instability: Challenges in the Development of New Therapies

Cited by 27 publications

References 65 publications

DNA Hypermethylation and Unstable Repeat Diseases: A Paradigm of Transcriptional Silencing to Decipher the Basis of Pathogenic Mechanisms

DNA Hypermethylation and Unstable Repeat Diseases: A Paradigm of Transcriptional Silencing to Decipher the Basis of Pathogenic Mechanisms

Modifiers of CAG/CTG Repeat Instability: Insights from Mammalian Models

Robust Detection of Somatic Mosaicism and Repeat Interruptions by Long-Read Targeted Sequencing in Myotonic Dystrophy Type 1

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