Imprinting mutation in the Beckwith-Wiedemann syndrome leads to biallelic IGF2 expression through an H19-independent pathway.

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 pathogenesis 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 IGF2 allele 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 centrometric 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.