Beckwith–Wiedemann syndrome caused by maternally inherited mutation of an OCT-binding motif in the IGF2/H19-imprinting control region, ICR1

Poole, Rebecca L; Leith, Donald J; Docherty, Louise E; Shmela, Mansur E; Gicquel, Christine; Splitt, Miranda; Temple, I. Karen; Mackay, Deborah J G

doi:10.1038/ejhg.2011.166

Cited by 61 publications

(58 citation statements)

References 10 publications

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“…It was reported that dyad Oct-binding sequences located in the ICR21 region mediated the maintenance of DNA hypomethylation at the H19 ICR in cultured cells (44,45). Curiously, the binding sequences are conserved in humans and were found to be mutated in Beckwith-Wiedemann syndrome (BWS) patients with ICR gain-of-methylation phenotypes, even though they have intact CTCF sites (46,47). Therefore, the binding of CTCF as well as other factors, including Oct proteins, to the maternal H19 ICR may be required to fully protect its CpG sites from de novo DNA methylation.…”

Section: Discussionmentioning

confidence: 99%

The H19 Imprinting Control Region Mediates Preimplantation Imprinted Methylation of Nearby Sequences in Yeast Artificial Chromosome Transgenic Mice

Okamura

Matsuzaki

Sakaguchi

et al. 2013

Molecular and Cellular Biology

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cIn the mouse Igf2/H19 imprinted locus, differential methylation of the imprinting control region (H19 ICR) is established during spermatogenesis and is maintained in offspring throughout development. Previously, however, we observed that the paternal H19 ICR, when analyzed in yeast artificial chromosome transgenic mice (YAC-TgM), was preferentially methylated only after fertilization. To identify the DNA sequences that confer methylation imprinting, we divided the H19 ICR into two fragments (1.7 and 1.2 kb), ligated them to both ends of a DNA fragment into which CTCF binding sites had been inserted, and analyzed this in YAC-TgM. The maternally inherited sequence, normally methylated after implantation in the absence of H19 ICR sequences, became hypomethylated, demonstrating protective activity against methylation within the ICR. Meanwhile, the paternally inherited sequence was hypermethylated before implantation only when a 1.7-kb fragment was ligated. Consistently, when two subfragments of the H19 ICR were individually investigated for their activities in YAC-TgM, only the 1.7-kb fragment was capable of introducing paternal allele-specific DNA methylation. These results show that postfertilization methylation imprinting is conferred by a paternal allele-specific methylation activity present in a 1.7-kb DNA fragment of the H19 ICR, while maternal allele-specific activities protect the allele from de novo DNA methylation.

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Section: Discussionmentioning

confidence: 99%

The H19 Imprinting Control Region Mediates Preimplantation Imprinted Methylation of Nearby Sequences in Yeast Artificial Chromosome Transgenic Mice

Okamura

Matsuzaki

Sakaguchi

et al. 2013

Molecular and Cellular Biology

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“…However, singlenucleotide mutations were shown to prevent binding of pluripotency factors (OCT4 and SOX2) to the H19 ICR. Interestingly, these mutations induced aberrant acquisition of DNA methylation at this ICR and biallelic expression of the locus' IGF2 gene, resulting in an overgrowth upon maternal, but not upon paternal, transmission (Demars et al, 2010;Poole et al, 2012). Mouse studies have shown that Igf2 overexpression induces fetal and postnatal overgrowth, and Peg1 overexpression leads to reduced growth and fat mass expansion.…”

Section: Genetic Polymorphisms and The Control Of Mono-allelic Gene Ementioning

confidence: 99%

Imprinted gene expression in hybrids: perturbed mechanisms and evolutionary implications

2014

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Diverse mechanisms contribute to the evolution of reproductive barriers, a process that is critical in speciation. Amongst these are alterations in gene products and in gene dosage that affect development and reproductive success in hybrid offspring. Because of its strict parent-of-origin dependence, genomic imprinting is thought to contribute to the aberrant phenotypes observed in interspecies hybrids in mammals and flowering plants, when the abnormalities depend on the directionality of the cross. In different groups of mammals, hybrid incompatibility has indeed been linked to loss of imprinting. Aberrant expression levels have been reported as well, including imprinted genes involved in development and growth. Recent studies in humans emphasize that genetic diversity within a species can readily perturb imprinted gene expression and phenotype as well. Despite novel insights into the underlying mechanisms, the full extent of imprinted gene perturbation still remains to be determined in the different hybrid systems. Here we review imprinted gene expression in intra-and interspecies hybrids and examine the evolutionary scenarios under which imprinting could contribute to hybrid incompatibilities. We discuss effects on development and reproduction and possible evolutionary implications.

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“…However, data for adult height are inconclusive because of lack of information due to the discontinuation of follow-up after the usual period of surveillance for the occurrence of tumors. Several studies have reported patients in small cohorts to have a final height in the normal range [8,9,10,11], whereas others have reported adult heights exceeding +2 SDS [12,13,14,15,16,17,18] (table 1). …”

Section: Introductionmentioning

confidence: 99%

Beckwith-Wiedemann Syndrome: Growth Pattern and Tumor Risk according to Molecular Mechanism, and Guidelines for Tumor Surveillance

Brioude¹,

Lacoste

Netchine³

et al. 2013

Horm Res Paediatr

141

216

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Background: Beckwith-Wiedemann syndrome (BWS) is an overgrowth syndrome associated with an increased risk of pediatric tumors. The underlying molecular abnormalities may be genetic (CDKN1C mutations or 11p15 paternal uniparental isodisomy, pUPD) or epigenetic (imprinting center region 1, ICR1, gain of methylation, ICR1 GOM, or ICR2 loss of methylation, ICR2 LOM). Aim: We aimed to describe a cohort of 407 BWS patients with molecular defects of the 11p15 domain followed prospectively after molecular diagnosis. Results: Birth weight and length were significantly higher in patients with ICR1 GOM than in the other groups. ICR2 LOM and CDKN1C mutations were associated with a higher prevalence of exomphalos. Mean adult height (regardless of molecular subtype, n = 35) was 1.8 ± 1.2 SDS, with 18 patients having a final height above +2 SDS. The prevalence of tumors was 8.6% in the whole population; 28.6 and 17.3% of the patients with ICR1 GOM (all Wilms tumors) and 11p15 pUPD, respectively, developed a tumor during infancy. Conversely, the prevalence of tumors in patients with ICR2 LOM and CDKN1C mutations were 3.1 and 8.8%, respectively, with no Wilms tumors. Conclusion: Based on these results for a large cohort, we formulated guidelines for the follow-up of these patients according to the molecular subtype of BWS.

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Beckwith–Wiedemann syndrome caused by maternally inherited mutation of an OCT-binding motif in the IGF2/H19-imprinting control region, ICR1

Cited by 61 publications

References 10 publications

The H19 Imprinting Control Region Mediates Preimplantation Imprinted Methylation of Nearby Sequences in Yeast Artificial Chromosome Transgenic Mice

The H19 Imprinting Control Region Mediates Preimplantation Imprinted Methylation of Nearby Sequences in Yeast Artificial Chromosome Transgenic Mice

Imprinted gene expression in hybrids: perturbed mechanisms and evolutionary implications

Beckwith-Wiedemann Syndrome: Growth Pattern and Tumor Risk according to Molecular Mechanism, and Guidelines for Tumor Surveillance

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