caa a22 4500 397574495 CHVBK 20180308164851.0 cr unu---uuuuu 161202e199612 xx s 000 0 eng 10.1093/hmg/5.12.2027 doi (NATIONALLICENCE)oxford-10.1093/hmg/5.12.2027 Imprinting Mutation in the Beckwith-Wiedemann Syndrome Leads to Biallelic IGF2 expression through an H19-Independent Pathway [Elektronische Daten] [Keith W. Brown, Angela J. Villar, Wendy Bickmore, Jill Clayton-Smith, Daniel Catchpoole, Eamonn R. Maher, Wolf Reik] The Beckwith-Wiedemann syndrome (BWS) is genetically linked to chromosome 11p15.5, and a variety of observations suggest that deregulation of imprinted genes in this region is causally involved in the patho-genesis of the disease. It has been shown that in some patients without cytogenetic abnormalities the otherwise repressed maternal copy of the insulin-like growth factor 2 (IGF2) gene is expressed, leading to biallelic expression of IGF2. In some of these cases, this is accompanied by repression and DNA methylation of the maternal (otherwise active) copy of the neighbouring H19 gene. Hence, it is attractive to think that mutations may interfere with some aspect of H19 imprinting, thus leading to an inactive maternal allele, and indirectly to activation of the maternal IGF2allele as reported in mice with an H19 gene deletion. However, no mutations have been identified so far in these patients. The only known mutations associated with BWS are maternally transmitted translocations, which are clustered in two locations centromeric to IGF2. The first cluster is 200-400 kb from IGF2 and the second is several megabases away. Hence, genes located far from the translocation breakpoints are potentially deregulated by them. Here we provide the first evidence of alteration of imprinting in a translocation family, with biallelic expression of IGF2 and altered DNA replication patterns in the IGF2 region. Interestingly, H19 imprinting was normal, suggesting an H19-independent pathway to biallelic IGF2 transcription. DNA methylation in IGF2 remained monoallelic, suggesting that the mutation in this family had uncoupled allele-specific methylation from expression. © 1993 Oxford University Press Brown Keith W. Department of Pathology and Microbiology, School of Medical Sciences, University Walk, Bristol BS8 1TD, UK aut Villar Angela J. Laboratory of Developmental Genetics and Imprinting, The Babraham Institute, Cambridge CB2 4AT, UK aut Bickmore Wendy Cell Genetics Section, MRC Human Genetics Unit, Edinburgh, UK aut Clayton-Smith Jill Regional Genetics Service, St Mary's Hospital, Manchester M13 OJH, UK aut Catchpoole Daniel Department of Clinical Genetics, Addenbrooke's NHS Trust and Cambridge University, Department of Pathology, Tennis Court Road, Cambridge, UK aut Maher Eamonn R. Department of Clinical Genetics, Addenbrooke's NHS Trust and Cambridge University, Department of Pathology, Tennis Court Road, Cambridge, UK aut Reik Wolf Laboratory of Developmental Genetics and Imprinting, The Babraham Institute, Cambridge CB2 4AT, UK aut Human Molecular Genetics Oxford University Press 5/12(1996-12), 2027-2032 0964-6906 5:12<2027 1996 5 hmg https://doi.org/10.1093/hmg/5.12.2027 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1093/hmg/5.12.2027 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Brown Keith W. Department of Pathology and Microbiology, School of Medical Sciences, University Walk, Bristol BS8 1TD, UK aut NATIONALLICENCE 700 1- Villar Angela J. Laboratory of Developmental Genetics and Imprinting, The Babraham Institute, Cambridge CB2 4AT, UK aut NATIONALLICENCE 700 1- Bickmore Wendy Cell Genetics Section, MRC Human Genetics Unit, Edinburgh, UK aut NATIONALLICENCE 700 1- Clayton-Smith Jill Regional Genetics Service, St Mary's Hospital, Manchester M13 OJH, UK aut NATIONALLICENCE 700 1- Catchpoole Daniel Department of Clinical Genetics, Addenbrooke's NHS Trust and Cambridge University, Department of Pathology, Tennis Court Road, Cambridge, UK aut NATIONALLICENCE 700 1- Maher Eamonn R. Department of Clinical Genetics, Addenbrooke's NHS Trust and Cambridge University, Department of Pathology, Tennis Court Road, Cambridge, UK aut NATIONALLICENCE 700 1- Reik Wolf Laboratory of Developmental Genetics and Imprinting, The Babraham Institute, Cambridge CB2 4AT, UK aut NATIONALLICENCE 773 0- Human Molecular Genetics Oxford University Press 5/12(1996-12), 2027-2032 0964-6906 5:12<2027 1996 5 hmg Metadata rights reserved CC BY-NC-4.0 http://creativecommons.org/licenses/by-nc/4.0 nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-oxford