Molecular genetics of congenital myotonic dystrophy

Lanni, Stella; Pearson, Christopher E.

doi:10.1016/j.nbd.2019.104533

Cited by 56 publications

(53 citation statements)

References 108 publications

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“…A handful of mosaic cases have been reported, including a case showing levels of methylated MLH1 alleles as low as 1% in blood and other tissues, which implies an opportunity to use very sensitive techniques [131]. The most commonly used method for MLH1 promoter methylation analysis is MS-MLPA, usually performed on peripheral leukocytes [135]. However, while this method is valuable for screening, it is semiquantitative.…”

Section: Lynch Syndromementioning

confidence: 99%

“…Myotonic dystrophy type 1 (DM1; OMIM#160900) is an autosomal dominant disease characterized by myopathy, progressive muscle weakness, and multisystem complications. The disease results from a CTG repeat expansion (50 to several thousand with tissue-specific differences) in a CpG island of the 3 untranslated region of the dystrophia myotonica protein kinase (DMPK) gene on chromosome 19q13.3 [135]. Several pathogenic mechanisms have been proposed for the repeat expansion including a cis-acting effect reducing DMPK gene transcription or translation, an alteration of the chromatin structure at the DMPK locus able to repress the expression of neighboring genes, and a toxic gain in the function of the resulting mRNA [136].…”

Section: Myotonic Dystrophy Typementioning

confidence: 99%

“…Several pathogenic mechanisms have been proposed for the repeat expansion including a cis-acting effect reducing DMPK gene transcription or translation, an alteration of the chromatin structure at the DMPK locus able to repress the expression of neighboring genes, and a toxic gain in the function of the resulting mRNA [136]. Based on the onset of the main symptoms, different clinical subtypes of the disease are recognized, including congenital (CDM1) and childhood onset cases, juvenile and adult onset ones, and late onset DM1 [135].…”

Section: Myotonic Dystrophy Typementioning

confidence: 99%

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DNA Methylation in the Diagnosis of Monogenic Diseases

Cerrato

Sparago

Ariani

et al. 2020

Genes

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DNA methylation in the human genome is largely programmed and shaped by transcription factor binding and interaction between DNA methyltransferases and histone marks during gamete and embryo development. Normal methylation profiles can be modified at single or multiple loci, more frequently as consequences of genetic variants acting in cis or in trans, or in some cases stochastically or through interaction with environmental factors. For many developmental disorders, specific methylation patterns or signatures can be detected in blood DNA. The recent use of high-throughput assays investigating the whole genome has largely increased the number of diseases for which DNA methylation analysis provides information for their diagnosis. Here, we review the methylation abnormalities that have been associated with mono/oligogenic diseases, their relationship with genotype and phenotype and relevance for diagnosis, as well as the limitations in their use and interpretation of results.

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Section: Lynch Syndromementioning

confidence: 99%

Section: Myotonic Dystrophy Typementioning

confidence: 99%

Section: Myotonic Dystrophy Typementioning

confidence: 99%

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DNA Methylation in the Diagnosis of Monogenic Diseases

Cerrato

Sparago

Ariani

et al. 2020

Genes

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“…Microsatellite repeat expansions are implicated in nearly 40 human genetic disorders, including various neurodevelopmental diseases such as Fragile X syndrome (FXS; Mendelian Inheritance in Man/MIM 309550) [ 1 ] and Early Infantile Epileptic Encephalopathy (EIEE; MIM 308350) [ 2 ], and several neuromuscular disorders such as myotonic dystrophy type 1 (DM1; MIM 160900) [ 3 ]. The vast majority of these unstable repeat disorders is caused by expansions of trinucleotide repeat sequences or other repeat tracts, including tetra-, penta-, and hexanucleotide repeats that typically are highly polymorphic and collectively account for about 3% of the human genome [ 4 , 5 , 6 ].…”

Section: Introductionmentioning

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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“…Myotonic dystrophy type 1 (DM1 [MIM: 160900]) is caused by an unstable CTG repeat expansion in the 3' UTR of the DMPK gene and mainly affects the neuronal and muscular systems 1 . Patients have an expanded and unstable CTG repeat tract sizing between 50 to 6500 repeats whereas unaffected individuals have a short and stable tract ranging from 5 to 37 CTG repeats 2,3 . Unusual DNA structures in the repetitive tract are suggested to serve as mutagenic intermediates explaining why repeat instability occurs whenever single stranded DNA is formed both in a replication-dependent or independent manner [4][5][6] .…”

Section: Introductionmentioning

confidence: 99%

MSH2knock-down shows CTG repeat stability and concomitant upstream demethylation at theDMPKlocus in myotonic dystrophy type 1 human embryonic stem cells

Franck

Barbé

Ardui

et al. 2020

Preprint

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Myotonic dystrophy type 1 (DM1) is caused by expansion of a CTG repeat in the DMPK gene, where expansion size and somatic mosaicism correlates with disease severity and age of onset. While it is known that the mismatch repair protein MSH2 contributes to the unstable nature of the repeat, its role on other disease-related features, such as CpG methylation upstream of the repeat, is unknown. In this study, we investigated the effect of an MSH2 knock-down (MSH2KD) on both CTG repeat dynamics and CpG methylation pattern in human embryonic stem cells (hESC) carrying the DM1 mutation. Repeat size in MSH2 wild type (MSH2WT) and MSH2KD DM1 hESC was determined by PacBio sequencing and CpG methylation by bisulfite massive parallel sequencing. We found stabilization of the CTG repeat concurrent with a gradual loss of methylation upstream of the repeat in MSH2KD cells, while the repeat continued to expand and upstream methylation remained unchanged in MSH2WT control lines. Repeat instability was re-established and biased towards expansions upon MSH2 transgenic re-expression in MSH2KD lines while upstream methylation was not consistently re-established. We hypothesize that the hypermethylation at the mutant DM1 locus is promoted by the MMR machinery and sustained by a constant DNA repair response, establishing a potential mechanistic link between CTG repeat instability and upstream CpG methylation. Our work represents a first step towards understanding how epigenetic alterations and repair pathways connect and contribute to the DM1 pathology.

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Molecular genetics of congenital myotonic dystrophy

Cited by 56 publications

References 108 publications

DNA Methylation in the Diagnosis of Monogenic Diseases

DNA Methylation in the Diagnosis of Monogenic Diseases

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

MSH2knock-down shows CTG repeat stability and concomitant upstream demethylation at theDMPKlocus in myotonic dystrophy type 1 human embryonic stem cells

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