Polymerase Chain Reaction-Based Analysis Using Deaminated DNA of Dodecamer Expansions in <i>CSTB</i>, Associated with Unverricht-Lundborg Myoclonus Epilepsy

Horiuchi, Hidekazu; Osawa, Motoki; Furutani, R.; Morita, Motoki; Tian, Wei; Awatsu, Yumi; Shimazaki, Hideyuki; Umetsu, Kazuo

doi:10.1089/gte.2005.9.328

Cited by 9 publications

(8 citation statements)

References 20 publications

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“…Moreover, the presence of an unstable GC-rich tract suggests that, like other repeat diseases located in promoter or 5′untranslated regions (5′UTR), the surrounding CpG island could be hypermethylated, inducing transcriptional repression. However, in the peripheral blood of EPM1A patients, the CpG sites were found not to be subjected to de novo methylation in comparison to individual controls [ 30 , 31 ]. Noteworthily, since DNA methylation has tissue-specific landscapes, up to now, we cannot exclude that CSTB -expanded alleles could be specifically marked by hypermethylation in disease-affected tissues.…”

Section: Unstable Gc-rich Repeats In 5′ Regulatory Regionsmentioning

confidence: 99%

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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 5′ Regulatory Regionsmentioning

confidence: 99%

“… (?) [ 28 , 31 ] 5′ UTR (CGG)n FMR1 FXS XL Yes Yes [ 16 , 33 , 36 , 37 , 43 ] AFF2 FRAXE XL Yes (?) [ 46 ] AFF3 FRA2A AD Yes (?)…”

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

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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“…In detail, almost all (56 of 57) JME patients had normal alleles, with 2–3 dodecamer repeats (genotype 2/2: 12 of 57 [21.0%] patients; genotype 2/3: 14 of 57 [24.6%]; genotype 3/3: 30 of 57 [52.6%]). One affected individual carried an allele with four copies (genotype 3/4), which represents a very rare normal variant . In the healthy control individuals, the analysis revealed the commonly observed two and three copy repeat alleles (genotype 2/2: 16 of 75 [21.3%] subjects; genotype 2/3: 20 of 75 [26.7%]; genotype 3/3: 39 of 75 [52.0%]).…”

Section: Resultsmentioning

confidence: 99%

“…One affected individual carried an allele with four copies (genotype 3/4), which represents a very rare normal variant. 9 In the healthy control individuals, the analysis revealed the commonly observed two and three copy repeat alleles (genotype 2/2: 16 of 75 [21.3%] subjects; genotype 2/3: 20 of 75 [26.7%]; genotype 3/3: 39 of 75 [52.0%]).…”

Section: Resultsmentioning

confidence: 99%

No evidence of a role for cystatin B gene in juvenile myoclonic epilepsy

et al. 2015

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Laura Mumoli is a postdoctoral fellow with special interest in epilepsy. SUMMARYGenetic factors play a major role in the etiology of juvenile myoclonic epilepsy (JME), a common form of idiopathic generalized epilepsy, but so far, genes related to JME remain largely unknown. JME shares electroclinical features with Unverricht-Lundborg disease (progressive myoclonic epilepsy type 1; EPM1), a form of progressive myoclonus epilepsy characterized by myoclonus, epilepsy, and gradual neurologic deterioration. EPM1 is caused by mutations in the gene that codes for cystatin B (CSTB), an inhibitor of cysteine protease. In the present study, we wished to investigate the role of the CSTB gene in patients with JME. Fifty-seven unrelated patients (35 women; mean age AE standard deviation [SD], 24.1 AE 7.7; mean age AE SD at onset, 15.3 AE 2.4) with JME were enrolled. Twenty-three of 57 patients were the probands of families with JME. The molecular diagnosis was carried out to identify the common dodecamer repeat expansion mutation or other disease-causing mutations in the CSTB gene. The molecular analysis did not depict mutations in any of the 57 patients with JME. Our study did not support a role for the CSTB gene in patients with familial or sporadic JME.

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“…The majority of such patients carry repeat expansions of a dodecamer with high GC content in the promoter region of the stefin B gene (74). Although the regulatory role of these dodecamer has not been investigated in detail, these GC stretches are the site of methylation/demethylation regulating the expression of the downstream gene.…”

Section: α-Synuclein and Stefin B Are Candidate Pore-forming Proteinsmentioning

confidence: 99%

Pore-Forming Proteins as Mediators of Novel Epigenetic Mechanism of Epilepsy

et al. 2017

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Epilepsy is a disorder of the brain characterized by an enduring predisposition to generate epileptic seizures. In the last two decades, numerous gene defects underlying different forms of epilepsy have been identified with most of these genes encoding ion channel proteins. Despite these developments, the etiology of majority of non-familial epilepsies has no known associated genetic mutations and cannot be explained by defects in identified ion channels alone. We hypothesize that de novo formation of ion channels by naturally unfolded proteins (NUPs) increases neuronal excitability. Altered ionic homeostasis may initiate/contribute to cellular cascades related to epileptogenesis in susceptible individuals. Here, we consider two small proteins, namely, α-synuclein and stefin B, as prototypical candidates to illustrate the underlying mechanism(s). Previous work points to an association between epilepsy and α-synuclein or stefin B, but the mechanism(s) underlying such association remains elusive. We review the evidence to link the structure–function of these proteins with disease processes. Epigenetic mechanisms unrelated to altered DNA sequence(s) that may affect epileptogenesis include transcriptional or posttranscriptional regulation. Such epigenetic mechanisms or their combination(s) enhance the levels of these proteins and as a result the ability to form annular structures, which upon incorporation into membrane form novel ion channels and disturb intracellular ion homeostasis. Alternative epigenetic mechanisms may change amyloidogenic proteins by posttranslational modifications, thereby increasing their propensity to form channels. Further research elucidating the details about the formation of ion channels through these mechanisms and their role in epileptogenesis may define new molecular targets and guide the development of new drug targets.

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Polymerase Chain Reaction-Based Analysis Using Deaminated DNA of Dodecamer Expansions in CSTB, Associated with Unverricht-Lundborg Myoclonus Epilepsy

Cited by 9 publications

References 20 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

No evidence of a role for cystatin B gene in juvenile myoclonic epilepsy

Pore-Forming Proteins as Mediators of Novel Epigenetic Mechanism of Epilepsy

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