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Imprinting mutations in the Beckwith—Wiedemann syndrome suggested by an altered imprinting pattern in the IGF2–H19 domain
Ist Teil von
Human molecular genetics, 1995-12, Vol.4 (12), p.2379-2385
Ort / Verlag
Oxford: Oxford University Press
Erscheinungsjahr
1995
Link zum Volltext
Quelle
MEDLINE
Beschreibungen/Notizen
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.