title: Hypomethylation at multiple maternally methylated imprinted regions including PLAGL1 and GNAS loci in Beckwith-Wiedemann syndrome.
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.
authors.affiliation: Department of Clinical Genetics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Jet
authors.initials: J
authors.lastname: Bliek
authors.forename: Gaetano
authors.initials: G
authors.lastname: Verde
authors.forename: Jonathan
authors.initials: J
authors.lastname: Callaway
authors.forename: Saskia M
authors.initials: SM
authors.lastname: Maas
authors.forename: Agostina
authors.initials: A
authors.lastname: De Crescenzo
authors.forename: Angela
authors.initials: A
authors.lastname: Sparago
authors.forename: Flavia
authors.initials: F
authors.lastname: Cerrato
authors.forename: Silvia
authors.initials: S
authors.lastname: Russo
authors.forename: Serena
authors.initials: S
authors.lastname: Ferraiuolo
authors.forename: Maria Michela
authors.initials: MM
authors.lastname: Rinaldi
authors.forename: Rita
authors.initials: R
authors.lastname: Fischetto
authors.forename: Faustina
authors.initials: F
authors.lastname: Lalatta
authors.forename: Lucio
authors.initials: L
authors.lastname: Giordano
authors.forename: Paola
authors.initials: P
authors.lastname: Ferrari
authors.forename: Maria Vittoria
authors.initials: MV
authors.lastname: Cubellis
authors.forename: Lidia
authors.initials: L
authors.lastname: Larizza
authors.forename: I Karen
authors.initials: IK
authors.lastname: Temple
authors.forename: Marcel M A M
authors.initials: MM
authors.lastname: Mannens
authors.forename: Deborah J G
authors.initials: DJ
authors.lastname: Mackay
authors.forename: Andrea
authors.initials: A
authors.lastname: Riccio
mesh_terms: D001506:Beckwith-Wiedemann Syndrome / Q000235:genetics* / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics*; D002864:Chromogranins; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D005260:Female; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics*; D018392:Genomic Imprinting; D006801:Humans; D008297:Male; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D014157:Transcription Factors / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D018797:Cell Cycle Proteins; D002864:Chromogranins; C106464:PLAGL1 protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C412484:DNMT3L protein, human; D004248:DNA (Cytosine-5-)-Methyltransferases; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs