Effects of<i>MECP2</i>mutation type, location and X‐inactivation in modulating Rett syndrome phenotype

Weaving, Linda S.; Williamson, Sarah; Bennetts, Bruce; Davis, Mark; Ellaway, Carolyn; Leonard, Helen; Thong, Meow‐Keong; Delatycki, Martin B.; Thompson, Elizabeth; Laing, Nigel G.; Christodoulou, John

doi:10.1002/ajmg.a.10053

Cited by 109 publications

(110 citation statements)

References 60 publications

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“…The questionnaires provide information about background demographic data, developmental history, medical conditions, healthcare service utilisation, functional ability, and clinical severity. Further, the MECP2 genotype was available for most cases [12].…”

Section: Methodsmentioning

confidence: 99%

Sleep problems in Rett syndrome

Young

Nagarajan

Klerk

et al. 2007

Brain and Development

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121

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Rett syndrome (RTT) is a severe neurological disorder, affecting mainly females. It is generally caused by mutations in the MECP2 gene. Sleep problems are thought to occur commonly in Rett syndrome, but there has been little research on prevalence or natural history. An Australian population-based registry of cases born since 1976 has been operating since 1993, with current ascertainment at 300. The Australian Rett Syndrome Database (ARSD) consists of information about Rett syndrome cases including their functional ability, behaviour, sleep patterns, medical conditions and genotype. The cases range in age from two to 29 years.The aim of this study was to investigate the type and frequency of sleep problems, relationships with age and MECP2 mutation type and to evaluate changes over time.Parents or carers of the subjects with Rett syndrome were asked to complete a questionnaire about sleep problems on three separate occasions (2000, 2002 and 2004). Regression modelling was used to investigate the relationships between sleep problems, age and mutation type. Sleep problems were identified in over 80% of cases. The prevalence of night-time laughter decreased with age and the prevalence of reported night-time seizures and daytime napping increased with age. The prevalence of sleep problems was highest in cases with a large deletion of the MECP2 gene and in those with the p.R294X or p.R306C mutations.Sleep problems are common in Rett syndrome and there is some variation with age and mutation type.

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Section: Methodsmentioning

confidence: 99%

Sleep problems in Rett syndrome

Young

Nagarajan

Klerk

et al. 2007

Brain and Development

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121

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“…Most acquired an independent gait (94.1%), but this was both ataxic and rigid; they regressed at a median age of 18 months (13-26), and 52.9% had epilepsy. Their median severity score was 11 (range, [8][9][10][11][12][13][14]; 68.8% of the patients with this presentation had missense mutations, particularly T158M.…”

Section: Clinical Presentation Among Mecp2 Positive Rtt Patients (Gromentioning

confidence: 97%

“…The results, however, were not conclusive, as different methodologies were applied in the various studies, concerning clinical and mutation classifications and severity score systems [4][5][6]. Nevertheless, the larger studies pointed to a broad correlation between type of mutation and phenotype, patients with truncating mutations having a more severe phenotype, than those with missense mutations [5][6][7][8][9][10][11][12].…”

Section: Introductionmentioning

confidence: 95%

Rett syndrome with and without detected MECP2 mutations: An attempt to redefine phenotypes

Temudo

Santos

Ramos

et al. 2011

Brain and Development

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Background: The diagnosis of Rett syndrome (RTT) is based on a set of clinical criteria, irrespective of mutation status. The aims of this study were (1) to define the clinical differences existing between patients with Rett syndrome with (Group I) and without a MECP2 mutation (Group II), and (2) to characterize the phenotypes associated with the more common MECP2 mutations. Patients and methods: We analyzed 87 patients fulfilling the clinical criteria for RTT. All were observed and videotaped by the same paediatric neurologist. Seven common mutations were considered separately, and associated clinical features analysed. Results: Comparing Group I and II, we found differences concerning psychomotor development prior to onset, acquisition of propositive manipulation and language, and evolving autistic traits. Based on age at observation, we found differences in eye pointing, microcephaly, growth, number of stereotypies, rigidity, ataxia and ataxic-rigid gait, and severity score. Patients with truncating differed from those with missense mutations regarding acquisition of propositive words and independent gait, before the beginning of the disease, and microcephaly, growth, foot length, dystonia, rigidity and severity score, at the time of observation. Patients with the R168X mutation had a more severe phenotype, whereas those with R133C showed a less severe one. Patients with R294X had a hyperactive behaviour, and those with T158M seemed to be particularly ataxic and rigid. Conclusion: A clear regressive period (with loss of prehension and language, deceleration of growth) and the presence of more than three different stereotypies, rigidity and ataxic-rigid gait seemed to be very helpful in differentiating Group I from Group II.

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“…The involvement of MBPs in gene imprinting (14), X inactivation (15), and transcriptional silencing of genes possessing hypermethylated CpG islands in cancer cells (16) is now well documented. MBPs includes 5 isoforms of Mecp2, MBD1, MBD2, MBD3, and MBD4.…”

Section: Introductionmentioning

confidence: 99%

Methyl-CpG binding protein MBD2 is implicated in methylation-mediated suppression of miR-373 in hilar cholangiocarcinoma

Chen

Gao²,

Luo³

et al. 2011

Oncol Rep

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Abstract. Aberrant expression of miRNAs is associated with particular cancers showing tissue-and clinical-featurespecificity patterns. Some miRNA genes harboring or being embedded in CpG islands undergo methylation mediated silencing. MBP, methyl CpG binding protein, suppresses transcription through binding to methylated CpG dinucleotides. Expression of miR-373 has been reported to be suppressed in malignant bile duct cell lines. Bioinformatic prediction reveals that the transcription start site (TSS) of miR-373 is implanted in a 402 bp canonical CpG island containing 26 CpG dinucleotides. In this study, we aim to determine the epigenetic regulation of miR-373 gene in hilar cholangiocarcinoma. TaqMan microRNA assay shows that downregulation of miR-373 is closely associated with poor cell differentiation, advanced clinical stage and shorter overall and disease-free survival in hilar cholangiocarcinomas. Methylation analysis shows that the promoter-associated CpG island is hypermethylated which is consistent with the inhibition of miR-373. Chromatin immunoprecipitation (ChIP) assay indicates that down-regulation of miR-373 resultes from the selective recruitment of MBD2 to methylated CpG islands. In contrast, MBD2 knock-down by use of a specific siRNA promoted the expression of miR-373. Reactivation of miR-373 by pharmacologic induction of 5-aza-CdR and trichostatin A (TSA) led to decreased enrichment of MBD2 at CpG island regions. Enhanced expression of exogenous MBD2 in stable QBC 939 cells which stably express pGL4-m373-prom induces strengthened recruitment of MBD2. Our findings suggest that miR-373 is a methylationmediated gene and the implication of MBD2 in methylationmediated suppression of miR-373 plays an important role in tumourigenesis and development in hilar cholangiocarcinoma.

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Effects ofMECP2mutation type, location and X‐inactivation in modulating Rett syndrome phenotype

Cited by 109 publications

References 60 publications

Sleep problems in Rett syndrome

Sleep problems in Rett syndrome

Rett syndrome with and without detected MECP2 mutations: An attempt to redefine phenotypes

Methyl-CpG binding protein MBD2 is implicated in methylation-mediated suppression of miR-373 in hilar cholangiocarcinoma

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