Fragile-X syndrome and myotonic dystrophy: parallels and paradoxes

Tapscott, Stephen J.; Klesert, Todd R.; Widrow, R.J.; Stöger, Reinhard; Laird, Charles D.

doi:10.1016/s0959-437x(98)80148-2

Cited by 18 publications

(15 citation statements)

References 99 publications

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“…54 Other syndromes postulated to have an epigenetic aetiology include: immunodeficiency, centromeric region instability, facial anomalies syndrome (ICF) which is caused by mutations in the DNA-methyltransferase 3B (DNMT3B) gene; 55 Rett syndrome, a neurological disorder that occurs in females and is caused by mutations in the methylcytosine-binding protein (MeCP2) gene; 56 X-linked a-thalassaemia/mental retardation (ATRX) Syndrome, caused by mutations in the X-chromosome gene ATR-X which result in the hypomethylation of repeat sequences; 57 and Fragile-X syndrome, which is caused by a combination of both genetic and epigenetic mechanisms. 58 It is becoming increasing clear that epigenetic processes are important in the development of cancer. In various cancers there is some degree of epigenetic misregulation, including both global genome-wide hypomethylation and the CpG island promoter hypermethylation of tumour suppressor genes.…”

Section: Epigenetic Factorsmentioning

confidence: 99%

Molecular studies of major depressive disorder: the epigenetic perspective

2007

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Major depressive disorder (MDD) is a common and highly heterogeneous psychiatric disorder encompassing a spectrum of symptoms involving deficits to a range of cognitive, psychomotor and emotional processes. As is the norm for aetiological studies into the majority of psychiatric phenotypes, particular focus has fallen on the interplay between genetic and environmental factors. There are, however, several epidemiological, clinical and molecular peculiarities associated with MDD that are hard to explain using traditional geneand environment-based approaches. Our goal in this study is to demonstrate the benefits of looking beyond conventional 'DNA þ environment' and 'DNA Â environment' aetiological paradigms. Epigenetic factors -inherited and acquired modifications of DNA and histones that regulate various genomic functions occurring without a change in nuclear DNA sequence -offer new insights about many of the non-Mendelian features of major depression, and provide a direct mechanistic route via which the environment can interact with the genome. The study of epigenetics, especially in complex diseases, is a relatively new field of research, and optimal laboratory techniques and analysis methods are still being developed. Incorporating epigenetic research into aetiological studies of MDD thus presents a number of methodological and interpretive challenges that need to be addressed. Despite these difficulties, the study of DNA methylation and histone modifications has the potential to transform our understanding about the molecular aetiology of complex diseases.

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Section: Epigenetic Factorsmentioning

confidence: 99%

Molecular studies of major depressive disorder: the epigenetic perspective

2007

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“…Chromatin structural changes and histone deacetylation are involved in various neurological diseases (Kernochan et al, 2005;Langley et al, 2005), including the triplet-repeat diseases myotonic dystrophy and Fragile X mental retardation (Cho et al, 2005;Tapscott et al, 1998), and in spinal muscular atrophy (Kernochan et al, 2005). Thus, HDAC inhibitors may revert silent heterochromain to an active chromatin conformation, and restore the normal function of genes that are silenced in these diseases (Di Prospero and Fischbeck, 2005).…”

Section: Histone Deacetylase Inhibitors As Potential Therapeutics Formentioning

confidence: 99%

Small molecules affecting transcription in Friedreich ataxia

Gottesfeld

2007

Pharmacology & Therapeutics

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This review concerns the development of small molecule therapeutics for the inherited neurodegenerative disease Friedreich ataxia (FRDA). FRDA is caused by transcriptional repression of the nuclear FXN gene, encoding the essential mitochondrial protein frataxin, and accompanying loss of frataxin protein. Frataxin insufficiency leads to mitochrondrial dysfunction and progressive neurodegeneration, along with scoliosis, diabetes and cardiomyopathy. Individuals with FRDA generally die in early adulthood from the associated heart disease, the most common cause of death in FRDA. While anti-oxidants and iron chelators have shown promise in ameliorating the symptoms of the disease, there is no effective therapy for FRDA that addresses the cause of the disease, the loss of frataxin protein. Gene therapy and protein replacement strategies for FRDA are promising approaches; however, current technology is not sufficiently advanced to envisage treatments for FRDA coming from these approaches in the near future. Since the FXN mutation in FRDA, expanded GAA·TTC triplets in an intron, does not alter the amino acid sequence of frataxin protein, gene reactivation would be of therapeutic benefit. Thus, a number of laboratories have focused on small molecule activators of FXN gene expression as potential therapeutics, and this review summarizes the current status of these efforts as well as the molecular basis for gene silencing in FRDA.

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“…DM1 and fragile X mental retardation syndrome (FMR1) share some peculiarities not present in the other triplet-repeat diseases: at both DM and FMR1 loci the expansion occurs in the transcribed non-translated regions embedding CpG islands, and it is associated with altered chromatin, aberrant methylation, and suppressed expression of DMPK and FMR1 genes (Tapscott et al, 1998). Furthermore, FMR1 is cytologically characterised by chromosome instability at the site of expanded trinucleotide repeats, which is the localisation of the fragile site FRAXA.…”

Section: Discussionmentioning

confidence: 99%

Spontaneous chromosome loss and colcemid resistance in lymphocytes from patients with myotonic dystrophy type 1

Casella

Lucarelli

Simili

et al. 2003

Cytogenet Genome Res

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Myotonic Dystrophy type 1 (DM1) is one of the many inherited human diseases whose molecular defect is the expansion of a trinucleotide DNA sequence. DM1 shares with fragile X syndrome (FMR1), another “unstable triplet syndrome”, several molecular features not present in the remaining triplet diseases. As FMR1 is also characterised by chromosome instability at the site of the expanded triplet, lymphocytes from DM1 patients and healthy donors were cultured for micronucleus (MN) analysis, in order to verify if DM1 is also prone to chromosome instability. A FISH analysis was also carried out to detect the presence of centromeric sequences in the observed MN. The data indicate that DM1 patients present a percentage of centromere-positive MN significantly higher than controls, suggesting that chromosome loss is the main mechanism underlying the origin of the increased spontaneous instability. To further assess the proneness to instability of cells of DM1 patients, cultures from patients and controls were treated in vitro with growing concentrations of two different mutagens: colcemid, a “pure” aneugen compound whose target is tubulin, and mytomicin C, a strong clastogen. The results show that the patient group is significantly less sensitive to colcemid. These data, together with FISH analysis, suggest the presence, in DM1 patients, of an already damaged tubulin, which becomes no more sensitive to the effect of colcemid and which could be the main defect underlying the aneugenic effects in DM1.

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Fragile-X syndrome and myotonic dystrophy: parallels and paradoxes

Cited by 18 publications

References 99 publications

Molecular studies of major depressive disorder: the epigenetic perspective

Molecular studies of major depressive disorder: the epigenetic perspective

Small molecules affecting transcription in Friedreich ataxia

Spontaneous chromosome loss and colcemid resistance in lymphocytes from patients with myotonic dystrophy type 1

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