32 research outputs found

    Microdeletion of target sites for insulator protein CTCF in a chromosome 11p15 imprinting center in Beckwith-Wiedemann syndrome and Wilms' tumor

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    We have analyzed several cases of Beckwith-Wiedemann syndrome (BWS) with Wilms' tumor in a familial setting, which give insight into the complex controls of imprinting and gene expression in the chromosome 11p15 region. We describe a 2.2-kbp microdeletion in the H19/insulin-like growth factor 2 (IGF2)-imprinting center eliminating three target sites of the chromatin insulator protein CTCF that we believe here is necessary, but not sufficient, to cause BWS and Wilms' tumor. Maternal inheritance of the deletion is associated with IGF2 loss of imprinting and up-regulation of IGF2 mRNA. However, in at least one affected family member a second genetic lesion (a duplication of maternal 11p15) was identified and accompanied by a further increase in IGF2 rnRNA levels 35-fold higher than control values. Our results suggest that the combined effects of the H19//GF2-imprinting center microdeletion and 11p15 chromosome duplication were necessary for manifestation of BWS

    Stability and change the role of keepsakes and family homes in the lives of parentally bereaved young adults in the Netherlands 1

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    This paper examines the loss of a parent in young adulthood, showing how this emergent and distinctive life stage shapes Dutch young people’s experience of bereavement. Youth material cultures have commonly been analysed in terms of the construction and expression of youth identities, for example, through style, music and leisure. In this research, we highlight three themes in young people’s relationship to material culture as part of their everyday lived experience of parental loss: first, the parental home as a space of departure, memory and return, and the potential for conflict, destabilisation and misunderstanding when the remaining parent transforms the home or embarks on a new relationship; second, the different strategies young adults use to commemorate their parent in their own temporary or shared accommodation and online space; and third, the role of small, portable but effective keepsakes and adornment, such as jewellery or tattoos, that meet their need for the emotional experience of closeness with the memory of their parent. A focus on the material trajectories of grief grants insights into how young adults cope with loss in their everyday life, generating understanding of the ways young people may support themselves and be supported by others in the context of parental bereavement

    An 11p15 Imprinting Centre Region 2 Deletion in a Family with Beckwith Wiedemann Syndrome Provides Insights into Imprinting Control at CDKN1C

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    We report a three generation family with Beckwith Wiedemann syndrome (BWS) in whom we have identified a 330 kb deletion within the KCNQ1 locus, encompassing the 11p15.5 Imprinting Centre II (IC2). The deletion arose on the paternal chromosome in the first generation and was only associated with BWS when transmitted maternally to subsequent generations. The deletion on the maternal chromosome was associated with a lower median level of CDKN1C expression in the peripheral blood of affected individuals when compared to a cohort of unaffected controls (p<0.05), however was not significantly different to the expression levels in BWS cases with loss of methylation (LOM) within IC2 (p<0.78). Moreover the individual with a deletion on the paternal chromosome did not show evidence of elevated CDKN1C expression or features of Russell Silver syndrome. These observations support a model invoking the deletion of enhancer elements required for CDKN1C expression lying within or close to the imprinting centre and importantly extend and validate a single observation from an earlier study. Analysis of 94 cases with IC2 loss of methylation revealed that KCNQ1 deletion is a rare cause of loss of maternal methylation, occurring in only 3% of cases, or in 1.5% of BWS overall

    Differential Differences in Methylation Status of Putative Imprinted Genes among Cloned Swine Genomes

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    DNA methylation is a major epigenetic modification in the mammalian genome that regulates crucial aspects of gene function. Mammalian cloning by somatic cell nuclear transfer (SCNT) often results in gestational or neonatal failure with only a small proportion of manipulated embryos producing live births. Many of the embryos that survive to term later succumb to a variety of abnormalities that are likely due to inappropriate epigenetic reprogramming. Aberrant methylation patterns of imprinted genes in cloned cattle and mice have been elucidated, but few reports have analyzed the cloned pig genome. Four surviving cloned sows that were created by ear fibroblast nuclear transfer, each with a different life span and multiple organ defects, such as heart defects and bone growth delay, were used as epigenetic study materials. First, we identified four putative differential methylation regions (DMR) of imprinted genes in the wild-type pig genome, including two maternally imprinted loci (INS and IGF2) and two paternally imprinted loci (H19 and IGF2R). Aberrant DNA methylation, either hypermethylation or hypomethylation, commonly appeared in H19 (45% of imprinted loci hypermethylated vs. 30% hypomethylated), IGF2 (40% vs. 0%), INS (50% vs. 5%), and IGF2R (15% vs. 45%) in multiple tissues from these four cloned sows compared with wild-type pigs. Our data suggest that aberrant epigenetic modifications occur frequently in the genome of cloned swine. Even with successful production of cloned swine that avoid prenatal or postnatal death, the perturbation of methylation in imprinted genes still exists, which may be one of reason for their adult pathologies and short life. Understanding the aberrant pattern of gene imprinting would permit improvements in future cloning techniques

    The modified Manchester Fothergill procedure compared with vaginal hysterectomy with low uterosacral ligament suspension in patients with pelvic organ prolapse: long-term outcome

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    INTRODUCTION AND HYPOTHESIS: The objective of this study was to compare the long-term outcome between vaginal hysterectomy with low uterosacral ligament suspension (VH) and the modified Manchester Fothergill procedure (MF) as surgical treatment in patients with pelvic organ prolapse (POP). We hypothesize that MF is non-inferior to VH in the long term. METHODS: In this single-center retrospective cohort study patients who underwent MF or VH for primary apical compartment prolapse between 2003 and 2009 were eligible for inclusion. The primary outcome was subjective recurrence of POP. Secondary outcomes included number and type of reinterventions, time to reintervention and the degree of complaints. RESULTS: One hundred sixty of 398 patients (53 MF, 107 VH) returned the questionnaires (40%). The mean follow-up was 12.97 years for MF and 13.24 years for VH (p = 0.38). There were similar rates of subjective POP recurrence (51% in both groups). The reintervention rate in the MF group was higher but reached no statistical significance [19/53 (36%) versus 29/107 (27%), p = 0.26]. Kaplan-Meier curve showed no statistically significant difference in risk of reintervention after MF at the maximum follow-up of 16.5 years [HR 1.830 (95% CI 0.934-3.586), p = 0.08]. The mean time to reintervention was 3 years shorter in the MF group (p = 0.03). CONCLUSIONS: The subjective recurrence after MF is similar to VH in treatment of POP at the long term. MF appears to be non-inferior to VH when comparing the risk of reintervention. However, the small sample size precludes a definitive conclusion of non-inferiority, and future studies are needed

    The molecular function and clinical phenotype of partial deletions of the IGF2/H19 imprinting control region depends on the spatial arrangement of the remaining CTCF binding sites

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    At chromosome 11p15.5, the imprinting centre 1 (IC1) controls the parent of origin-specific expression of the IGF2 and H19 genes. The 5 kb IC1 region contains multiple target sites (CTS) for the zinc-finger protein CTCF, whose binding on the maternal chromosome prevents the activation of IGF2 and allows that of H19 by common enhancers. CTCF binding helps maintaining the maternal IC1 methylation-free, whereas on the paternal chromosome gamete-inherited DNA methylation inhibits CTCF interaction and enhancer-blocking activity resulting in IGF2 activation and H19 silencing. Maternally inherited 1.4-2.2 kb deletions are associated with methylation of the residual CTSs and Beckwith-Wiedemann syndrome, although with different penetrance and expressivity. We explored the relationship between IC1 microdeletions and phenotype by analysing a number of previously described and novel mutant alleles. We used a highly quantitative assay based on next generation sequencing to measure DNA methylation in affected families and analysed enhancer-blocking activity and CTCF binding in cultured cells. We demonstrate that the microdeletions mostly affect IC1 function and CTCF binding by changing CTS spacing. Thus, the extent of IC1 inactivation and the clinical phenotype are influenced by the arrangement of the residual CTSs. A CTS spacing similar to the wild-type allele results in moderate IC1 inactivation and is associated with stochastic DNA methylation of the maternal IC1 and incomplete penetrance. Microdeletions with different CTS spacing display severe IC1 inactivation and are associated with IC1 hypermethylation and complete penetrance. Careful characterization of the IC1 microdeletions is therefore needed to predict recurrence risks and phenotypical outcomes. © The Author 2012. Published by Oxford University Press

    A Transient Receptor Potential Channel Expressed in Taste Receptor Cells

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    We used differential screening of cDNAs from individual taste receptor cells to identify candidate taste transduction elements in mice. Among the differentially expressed clones, one encoded Trpm5, a member of the mammalian family of transient receptor potential (TRP) channels. We found Trpm5 to be expressed in a restricted manner, with particularly high levels in taste tissue. In taste cells, Trpm5 was coexpressed with taste-signaling molecules such as -gustducin, G13, phospholipase C-2 (PLC-2) and inositol 1,4,5-trisphosphate receptor type III (IP3R3). Our heterologous expression studies of Trpm5 indicate that it functions as a cationic channel that is gated when internal calcium stores are depleted. Trpm5 may be responsible for capacitative calcium entry in taste receptor cells that respond to bitter and/or sweet compounds
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