Hypomethylation at multiple maternally methylated imprinted regions including PLAGL1 and GNAS loci in Beckwith-Wiedemann syndrome - PubMed (original) (raw)

doi: 10.1038/ejhg.2008.233. Epub 2008 Dec 17.

Gaetano Verde, Jonathan Callaway, Saskia M Maas, Agostina De Crescenzo, Angela Sparago, Flavia Cerrato, Silvia Russo, Serena Ferraiuolo, Maria Michela Rinaldi, Rita Fischetto, Faustina Lalatta, Lucio Giordano, Paola Ferrari, Maria Vittoria Cubellis, Lidia Larizza, I Karen Temple, Marcel M A M Mannens, Deborah J G Mackay, Andrea Riccio

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Hypomethylation at multiple maternally methylated imprinted regions including PLAGL1 and GNAS loci in Beckwith-Wiedemann syndrome

Jet Bliek et al. Eur J Hum Genet. 2009 May.

Abstract

Genomic imprinting is an epigenetic phenomenon restricting gene expression in a manner dependent on parent of origin. Imprinted gene products are critical regulators of growth and development, and imprinting disorders are associated with both genetic and epigenetic mutations, including disruption of DNA methylation within the imprinting control regions (ICRs) of these genes. It was recently reported that some patients with imprinting disorders have a more generalised imprinting defect, with hypomethylation at a range of maternally methylated ICRs. We report a cohort of 149 patients with a clinical diagnosis of Beckwith-Wiedemann syndrome (BWS), including 81 with maternal hypomethylation of the KCNQ1OT1 ICR. Methylation analysis of 11 ICRs in these patients showed that hypomethylation affecting multiple imprinted loci was restricted to 17 patients with hypomethylation of the KCNQ1OT1 ICR, and involved only maternally methylated loci. Both partial and complete hypomethylation was demonstrated in these cases, suggesting a possible postzygotic origin of a mosaic imprinting error. Some ICRs, including the PLAGL1 and GNAS/NESPAS ICRs implicated in the aetiology of transient neonatal diabetes and pseudohypoparathyroidism type 1b, respectively, were more frequently affected than others. Although we did not find any evidence for mutation of the candidate gene DNMT3L, these results support the hypotheses that trans-acting factors affect the somatic maintenance of imprinting at multiple maternally methylated loci and that the clinical presentation of these complex cases may reflect the loci and tissues affected with the epigenetic abnormalities.

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Figures

Figure 1

Figure 1

Examples of the assays used for the methylation analysis. The methylation of nine maternally methylated ICRs was analysed by MS-PCR (a) and COBRA (b) in the DNAs of a normal individual and two BWS patients with multiple methylation defects (BWS1 and BWS2). The peaks of the MS-PCR corresponding to unmethylated and methylated DNA are indicated by blue and red filled circles, respectively, and the bands of the COBRA corresponding to the unmethylated and methylated DNA are indicated at the right side of the panels. The area of the MS-PCR peaks and the non-normalised unme/me ratios of intensities of the COBRA bands are also indicated below each panel. Details are given in Patients and methods and Supplementary Tables 1 and 2. Note that the results obtained with the two techniques are highly concordant.

Figure 2

Figure 2

Multiple hypomethylated ICRs, as analysed by bisulphite sequencing. The methylation of the three maternally methylated ICRs was analysed by bisulphite sequencing in the DNAs of a normal individual and two BWS patients with multiple methylation defects (BWS1 and BWS2). Twenty-five CpGs of the KCNQ1OT1 ICR, 26 CpGs of the PLAGL1 ICR and 59 CpGs (only the first 25 CpGs are shown) of the MEST ICR were analysed. Each line corresponds to a single template DNA molecule cloned; each circle corresponds to a CpG dinucleotide. Filled circles designate methylated cytosines; open circles, unmethylated cytosines. Numbers at the right border of the CpG circles indicate multiple sequenced clones with identical methylation pattern. Note that the hypomethylation extends over the entire amplicons sequenced.

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