© 1995 Oxford University Press
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Imprinting mutations in the Beckwith—Wiedemann syndrome suggested by an altered imprinting pattern in the IGF2–H19 domain
Laboratory of Developmental Genetics and Imprinting, The Babraham Institute Cambridge CB2 4AT 1Department of Pathology and Microbiology, School of Medical Sciences, University Walk Bristol BS8 1TD, UK 2Laboratoire d'explorations fonctionnelles endocriniennes, Hôpital D'Enfants Armand-Trousseau Paris, France 3Cell Genetics Section, MRC Human Genetics Unit Edinburgh 4Department of Clinical Genetics, Addenbrooke's NHS Trust and Cambridge University, Department of Pathology Tennis Court Road, Cambridge, UK
*To whom correspondence should be addressed
Received September 6, 1995; Revised October 13, 1995; Accepted October 13, 1995
Regional regulation of parental imprinting in the IGF2–H19 domain of imprinted genes was studied in the Beckwith—Wiedemann syndrome (BWS). We identified BWS patients who had inherited a normal biparental chromosome complement of the chromosome 11p15.5 region (where IGF2 and H19 reside), but had an altered pattern of allelic methylation of both genes, with the maternal chromosome carrying a paternal imprinting pattern. In fibroblasts, IGF2 was expressed from both parental alleles and H19 was not expressed, precisely as predicted from the altered pattern of allelic methylation. Interestingly, DNA replication patterns in the 11p15.5 region remained asynchronous as in controls. Our results therefore provide the first example of a dissociation of regional control of DNA replication from regional control of allelic methylation and expression in imprinting. We suggest that the altered pattern of allelic methylation and expression arises in the germline or in the early embryo from defects in resetting or setting of imprinting in the maternal germline. Potential candidate regions for mutations include the previously identified translocation breakpoint clusters and the H19 gene itself. The finding of possible ‘imprinting mutations’ in BWS raises the prospect of identifying genetic factors that control imprinting in this region.
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