Comparison of Genomic and Epigenomic Expression in Monozygotic Twins Discordant for Rett Syndrome

Miyake, Kunio; Yang, Chunshu; Minakuchi, Yohei; Ohori, Kenta; Soutome, Masaki; Hirasawa, Takae; Kazuki, Yasuhiro; Adachi, Noboru; Suzuki, Shigenori; Itoh, Masayuki; Goto, Yu‐ichi; Andoh, Tomoko; Kurosawa, Hiroshi; Oshimura, Mitsuo; Sasaki, Masayuki; Toyoda, Atsushi; Kubota, Takeo

doi:10.1371/journal.pone.0066729

Cited by 55 publications

(27 citation statements)

References 62 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These results are consistent with a recent report of an increase in copy number variations (CNV) in F3 generation, but not F1 generation descendants of vinclozolin-exposed dams [48], and corroborate previous reports suggesting that disruption of epigenetic programming can predispose multiple types of genetic aberrations [49–58]. …”

Section: Discussionsupporting

confidence: 93%

Tertiary Epimutations – A Novel Aspect of Epigenetic Transgenerational Inheritance Promoting Genome Instability

et al. 2016

View full text Add to dashboard Cite

Exposure to environmental factors can induce the epigenetic transgenerational inheritance of disease. Alterations to the epigenome termed “epimutations” include “primary epimutations” which are epigenetic alterations in the absence of genetic change and “secondary epimutations” which form following an initial genetic change. To determine if secondary epimutations contribute to transgenerational transmission of disease following in utero exposure to the endocrine disruptor vinclozolin, we exposed pregnant female rats carrying the lacI mutation-reporter transgene to vinclozolin and assessed the frequency of mutations in kidney tissue and sperm recovered from F1 and F3 generation progeny. Our results confirm that vinclozolin induces primary epimutations rather than secondary epimutations, but also suggest that some primary epimutations can predispose a subsequent accelerated accumulation of genetic mutations in F3 generation descendants that have the potential to contribute to transgenerational phenotypes. We therefore propose the existence of “tertiary epimutations” which are initial primary epimutations that promote genome instability leading to an accelerated accumulation of genetic mutations.

show abstract

Section: Discussionsupporting

confidence: 93%

Tertiary Epimutations – A Novel Aspect of Epigenetic Transgenerational Inheritance Promoting Genome Instability

et al. 2016

View full text Add to dashboard Cite

show abstract

“…Our findings support the clinical observation that RTT patients present with a varied phenotype during childhood, and suggest that this may in part be related to the underlying genetic defect, in addition to X inactivation and other epigenetic factors which were not evaluated in this study. [19, 20]…”

Section: Discussionmentioning

confidence: 99%

Functional outcomes in Rett syndrome

Pidcock

Salorio

Bibat

et al. 2016

Brain and Development

View full text Add to dashboard Cite

Aim To relate functional outcomes to mutation type and age at evaluation in patients with Rett syndrome (RTT). Method We identified 96 RTT patients with mutations in the MECP2 (methyl-CpG-binding protein 2) gene. Chart analysis, clinical evaluation, and functional measures were completed. Results Among 11 mutation groups, a statistically significant group effect of mutation type was observed for self-care, upper extremity function, and mobility, on standardized measures administered by Occupational and Physical Therapists. Patients with R133C and uncommon mutations tended to perform best on upper extremity and self-care items, whereas patients with R133C, R306C and R294X had the highest scores on the mobility items. The worst performers on upper extremity and self-care items were patients with large deletions, R255X, R168X, and T158M mutations. The lowest scores for mobility were found in patients with T158M, R255X, R168X, and R270X mutations. On categorical variables as reported by parents at the time of initial evaluation, patients with R133C and R294X were most likely to have hand use, those with R133C, R294X, R306C and small deletions were most likely to be ambulatory, and those with R133C were most likely to be verbal. Interpretation Functional performance in RTT patients may relate to the type of mutation. Knowledge of these relationships is useful for developing appropriate rehabilitation strategies and prognosis.

show abstract

“…The binding of CTCF to this methylation boundary (−595 to −389) prevents MECP2 silencing in human neuronal cells (Nagarajan et al 2008). A comparison of MECP2 promoter methylation in RTT monozygotic twins had been conducted before, which indicated no differences in the MECP2 promoter methylation between the twins (Miyake et al 2013). However, to conclude that promoter methylation does not play a role in RTT, a direct comparison of RTT patients to age-and gendermatched healthy individuals is necessary.…”

Section: Promoter Dna Methylationmentioning

confidence: 99%

Rett Syndrome and MeCP2

2014

View full text Add to dashboard Cite

Rett syndrome (RTT) is a severe and progressive neurological disorder, which mainly affects young females. Mutations of the methyl-CpG binding protein 2 (MECP2) gene are the most prevalent cause of classical RTT cases. MECP2 mutations or altered expression are also associated with a spectrum of neurodevelopmental disorders such as autism spectrum disorders with recent links to fetal alcohol spectrum disorders. Collectively, MeCP2 relation to these neurodevelopmental disorders highlights the importance of understanding the molecular mechanisms by which MeCP2 impacts brain development, mental conditions, and compromised brain function. Since MECP2 mutations were discovered to be the primary cause of RTT, a significant progress has been made in the MeCP2 research, with respect to the expression, function and regulation of MeCP2 in the brain and its contribution in RTT pathogenesis. To date, there have been intensive efforts in designing effective therapeutic strategies for RTT benefiting from mouse models and cells collected from RTT patients. Despite significant progress in MeCP2 research over the last few decades, there is still a knowledge gap between the in vitro and in vivo research findings and translating these findings into effective therapeutic interventions in human RTT patients. In this review, we will provide a synopsis of Rett syndrome as a severe neurological disorder and will discuss the role of MeCP2 in RTT pathophysiology.

show abstract

Comparison of Genomic and Epigenomic Expression in Monozygotic Twins Discordant for Rett Syndrome

Cited by 55 publications

References 62 publications

Tertiary Epimutations – A Novel Aspect of Epigenetic Transgenerational Inheritance Promoting Genome Instability

Tertiary Epimutations – A Novel Aspect of Epigenetic Transgenerational Inheritance Promoting Genome Instability

Functional outcomes in Rett syndrome

Rett Syndrome and MeCP2

Contact Info

Product

Resources

About