| The human insulin-like growth factor-II is an important fetal mitogen with demonstrated effects on growth, proliferation and survival of a wide spectrum of cells and tissues in mice and humans. The transcriptional regulation of the gene (IGF2) is under developmental control and is subject to epigenetic and genetic effects. At the epigenetic level, the mouse gene is parentally imprinted with exclusive expression of the paternally-inherited gene copy in most of the tissues examined. In this work, we demonstrate that the human gene is also subject to genomic imprinting and that the trait is tissue-specific and polymorphic whose basis may be genotype-dependent. Additionally, we show that in culture, primary placental fibroblasts lose the ability to functionally imprint IGF2. In instances of biallelic IGF2 gene expression, both in human tissue as well as in culture, we observe that the adjacent, reciprocally-imprinted H19 gene, which is normally expressed from the maternally-transmitted allele, is undetectable.;The imprinted IGF2 gene is located in close physical proximity to a variable number of tandem repeats (VNTR) sequence polymorphism that is found upstream of the insulin gene promoter, in humans. Alleles of the VNTR have demonstrated transcriptional effects on insulin gene expression in human fetal and adult pancreas in vivo and in pancreatic beta cells in vitro. In this work, we show that the VNTR also has allelic effects on IGF2 expression in human placenta in vivo and on INS-IGF2 reporter gene activity in human lymphoblasts, in vitro.;Alleles of the 5' INS (VNTR) are associated with susceptibility to type I diabetes mellitus. The preferential transmission of paternal susceptibility haplotypes at this locus suggests the functional involvement of a nearby imprinted gene in the susceptibility to type I diabetes. The demonstration of allelic effects of the VNTR on IGF2 mRNA levels, in vivo and in vitro, makes IGF2 an attractive functional candidate. |
