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Gicquel C, Rossignol S, Cabrol S, et al. Epimutation of the telomeric imprinting center region on chromosome 11p15 in Silver-Russell syndrome

Laboratoire d'Explorations Fonctionnelles Endocriniennes, Inserm U515 et UPMC Paris 6, Hôpital Armand Trousseau, AP-HP, 26 avenue Arnold Netter, 75012 Paris, France.
Nature Genetics (Impact Factor: 29.65). 10/2005; 37(9):1003-7. DOI: 10.1038/ng1629
Source: PubMed

ABSTRACT Silver-Russell syndrome (SRS, OMIM 180860) is a congenital disorder characterized by severe intrauterine and postnatal growth retardation, dysmorphic facial features and body asymmetry. SRS is genetically heterogenous with maternal uniparental disomy with respect to chromosome 7 occurring in approximately 10% of affected individuals. Given the crucial role of the 11p15 imprinted region in the control of fetal growth, we hypothesized that dysregulation of genes at 11p15 might be involved in syndromic intrauterine growth retardation. We identified an epimutation (demethylation) in the telomeric imprinting center region ICR1 of the 11p15 region in several individuals with clinically typical SRS. This epigenetic defect is associated with, and probably responsible for, relaxation of imprinting and biallelic expression of H19 and downregulation of IGF2. These findings provide new insight into the pathogenesis of SRS and strongly suggest that the 11p15 imprinted region, in addition to those of 7p11.2-p13 and 7q31-qter, is involved in SRS.

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Available from: Véronique Dorine Barbu, Sep 03, 2015
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    • "Specific imprinted regions are affected by methylation changes in SRS SRS is one of several disorders associated with imprinted regions (Ishida and Moore 2013). Approximately, 50 % of SRS cases display hypomethylation at the H19 ICR1, while a further 5–10 % of SRS patients exhibit mUPD7 (Gicquel et al. 2005; Preece et al. 1997). We determined the prevalence of SRS-specific differences in methylation at imprinted loci in a genome-wide, systematic way. "
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    ABSTRACT: Silver–Russell syndrome (SRS) is a clinically heterogeneous disorder characterised by severe in utero growth restriction and poor postnatal growth, body asymmetry, irregular craniofacial features and several additional minor malformations. The aetiology of SRS is complex and current evidence strongly implicates imprinted genes. Approximately, half of all patients exhibit DNA hypomethylation at the H19/IGF2 imprinted domain, and around 10 % have maternal uniparental disomy of chromosome 7. We measured DNA methylation in 18 SRS patients at >485,000 CpG sites using DNA methylation microarrays. Using a novel bioinformatics methodology specifically designed to identify subsets of patients with a shared epimutation, we analysed methylation changes genome-wide as well as at known imprinted regions to identify SRS-associated epimutations. Our analysis identifies epimutations at the previously characterised domains of H19/IGF2 and at imprinted regions on chromosome 7, providing proof of principle that our methodology can detect DNA methylation changes at imprinted loci. In addition, we discovered two novel epimutations associated with SRS and located at imprinted loci previously linked to relevant mouse and human phenotypes. We identify RB1 as an additional imprinted locus associated with SRS, with a region near the RB1 differentially methylated region hypermethylated in 13/18 (~70 %) patients. We also report 6/18 (~33 %) patients were hypermethylated at a CpG island near the ANKRD11 gene. We do not observe consistent co-occurrence of epimutations at multiple imprinted loci in single SRS individuals. SRS is clinically heterogeneous and the absence of multiple imprinted loci epimutations reflects the heterogeneity at the molecular level. Further stratification of SRS patients by molecular phenotypes might aid the identification of disease causes.
    Human Genetics 01/2015; 134(3). DOI:10.1007/s00439-014-1526-1 · 4.52 Impact Factor
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    • "Loss of methylation at the H19/IGF2 ICR results in short body length and low birth weight, both in rodent models (DeChiara et al., 1990) as well as in humans, such as patients with Silver-Russell syndrome, a developmental disorder characterized by intrauterine and postnatal growth retardation (Gicquel et al., 2005). This has also been observed in humans who were periconceptually exposed to famine (Heijmans et al., 2008). "
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    ABSTRACT: Diabetes mellitus represents a group of complex metabolic diseases that result in impaired glucose homeostasis, which includes destruction of β-cells or the failure of these insulin-secreting cells to compensate for increased metabolic demand. Despite a strong interest in characterizing the transcriptome of the different human islet cell types to understand the molecular basis of diabetes, very little attention has been paid to the role of long non-coding RNAs (lncRNAs) and their contribution to this disease. Here we summarize the growing evidence for the potential role of these lncRNAs in β-cell function and dysregulation in diabetes, with a focus on imprinted genomic loci.
    Frontiers in Genetics 07/2014; 5:200. DOI:10.3389/fgene.2014.00200
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    • "The IGF2/H19 ICR contains several differentially methylated regions (DMRs), which are all predominantly methylated on the paternally inherited allele: the IGF2 DMR0 (located between exons 2 and 3 of IGF2), the IGF2 DMR2 (between exons 8 and 9) and the H19 DMR, located 4 kb upstream of the transcription start of H19[15], which are all methylated to a level of 40-50% [10,16,17]. The methylation status of the IGF2 DMR0 is more likely to be indicative of changes in IGF2 transcription from the active allele given it has been suggested to possess promoter activity [18]. "
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    ABSTRACT: Background There is a substantial genetic component for birthweight variation, and although there are known associations between fetal genotype and birthweight, the role of common epigenetic variation in influencing the risk for small for gestational age (SGA) is unknown. The two imprinting control regions (ICRs) located on chromosome 11p15.5, involved in the overgrowth disorder Beckwith-Wiedemann syndrome (BWS) and the growth restriction disorder Silver-Russell syndrome (SRS), are prime epigenetic candidates for regulating fetal growth. We investigated whether common variation in copy number in the BWS/SRS 11p15 region or altered methylation levels at IGF2/H19 ICR or KCNQ10T1 ICR was associated with SGA. Methods We used a methylation-specific multiplex-ligation-dependent probe amplification assay to analyse copy number variation in the 11p15 region and methylation of IGF2/H19 and KCNQ10T1 ICRs in blood samples from 153 children (including 80 SGA), as well as bisulfite pyrosequencing to measure methylation at IGF2 differentially methylated region (DMR)0 and H19 DMR. Results No copy number variants were detected in the analyzed cohort. Children born SGA had 2.7% lower methylation at the IGF2 DMR0. No methylation differences were detected at the H19 or KCNQ10T1 DMRs. Conclusions We confirm that a small hypomethylation of the IGF2 DMR0 is detected in peripheral blood leucocytes of children born SGA at term. Copy number variation within the 11p15 BWS/SRS region is not an important cause of non-syndromic SGA at term.
    BMC Medical Genetics 06/2014; 15(1):67. DOI:10.1186/1471-2350-15-67 · 2.45 Impact Factor
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