Imprinting of IGF2 and H19 : Lack of Reciprocity in Sporadic Beckwith-Wiedemann Syndrome

ISSN： 1460-2083

Source： Human Molecular Genetics, Vol.6, Iss.9, 1997-01, pp. : 1543-1548

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Abstract

Genomic imprinting is a novel form of control of gene expression in which the transcription of each allele of an imprinted gene is dependent on the sex of the gamete from which it was derived; to date >15 genes have been demonstrated to show imprinting. The maintenance of a normal imprinting pattern in many loci has been shown to be essential for normal development and adult life. Many tumours, and some developmental disorders, exhibit loss of imprinting (LOI) in key genes such as insulin-like growth factor 2 (IGF2) which often results in hyperplasia and is associated with cancer. The mechanism by which the genomic imprint is first established, then maintained, is not understood. However, in the case of IGF2, the expression of a neighbouring gene, H19, has been suggested to influence its transcription by competition for a common enhancer, thereby generating a mutually exclusive and allele-specific pattern of gene expression. Associated changes in CpG methylation in discrete areas of both genes have been implicated in maintenance of the imprint. We have examined the allele-specific expression of IGF2 and H19 in fibroblasts derived from patients with sporadic Beckwith-Wiedemann syndrome (BWS), a fetal overgrowth syndrome associated with an imprinted locus on 11p15.5. We report that the majority of karyotypically normal patients show LOI of IGF2 with biallelic expression. In a proportion of these patients, loss of IGF2 imprinting was associated with complete suppression of H19 expression, as predicted by the enhancer competition model. However, in a significant number of cases, IGF2 showed biallelic expression even though H19 expression and methylation status were normal. This indicates that there must be an alternative H19-independent pathway by which allele-spe-cific IGF2 expression is established or maintained.