Parental allele specific methylation of the human insulin-like growth factor II gene and Beckwith-Wiedemann syndrome.

Abstract

In an attempt to elucidate the role of methylation in parental imprinting at the IGF-II gene locus, for which imprinting has already been described in the mouse; we undertook an allele specific methylation study of the human IGF-II gene (mapped to 1lpl5.5) in a control population and in patients with Beckwith-Wiedemann syndrome.In control leucocyte DNA (16 unrelated adults and eight families), the maternal allele of the IGF-II gene was specifically hypomethylated, whereas no such allele specific methylation was found for either the insulin or the calcitonin genes which are located in llpl5.5 and lpl5

Relaxation of IGF2 imprinting in Wilms tumours associated with specific changes in IGF2 methylation

“…(Leighton et al, 1995a,b). The presence of paternal allele-speci®c methylation on both the mouse and human IGF2 genes, has lent support to this model (Schneid, 1993), but we show here that the only site of allele-speci®c methylation of the human IGF2 gene was present on the maternal allele not the paternal allele.…”

“…In contrast to the maternal allele-speci®c methylation shown in exons 2 and 3, two previous reports identi®ed paternal allele-speci®c methylation at exon 9 in peripheral blood lymphocyte DNA of normal individuals, and in patients with the Beckwith-Wiedemann syndrome (Schneid, 1993;Reik et al, 1995). This region is homologous to mouse Igf2 dmr 2, a site of paternal allele-speci®c methylation.…”

“…In previous methylation studies of the human IGF2 gene by Schneid et al (1993) and Reik et al (1994), di erential methylation was identi®ed on the active paternal allele at exon 9 in peripheral blood lymphocytes from normal individuals and patients with the Beckwith-Wiedemann syndrome. In a similar analysis of this region, we have shown the exon 9 region to be biallelically unmethylated in the normal kidney and in Wilms tumours regardless of the expression state of IGF2 imprinting.…”

“…This region is homologous to mouse Igf2 dmr 2, a site of paternal allele-speci®c methylation. To investigate methylation of exons 7, 8 and 9 in normal kidney and Wilms tumour, a DNA methylation analysis was done using the method previously reported by Schneid et al, (1993). The relevant restriction map of exons 6 ± 9 is shown in Figure 4.…”

“…Firstly, the human IGF2 promoter complex was found to be unmethylated in cell lines (Eversole-Cire et al, 1993) and in another study the IGF2 promoter region acquired de novo methylation in the colonic epithelium of ageing individuals (Issa et al, 1996). Secondly, a region of allele-speci®c methylation similar to the mouse dmr 2 was identi®ed within exon 9 on the active paternal allele in peripheral blood DNA (Schneid, 1993;Reik et al, 1995). In an earlier report of Wilms tumours we found evidence for allele-speci®c methylation of IGF2 in Wilms tumours with normal IGF2 imprinting.…”