Transactivation of Igf2 in a mouse model of Beckwith-Wiedemann syndrome.

The gene IGF2, which encodes a fetal insulin-like growth factor, is imprinted, so only one of two parental copies of the gene is expressed. The altered expression of IGF2 has been implicated in Beckwith-Wiedemann syndrome, a human fetal overgrowth syndrome, which is characterized by overgrowth of several organs and an increased risk of developing childhood tumours. We have introduced Igf2 transgenes into the mouse genome by using embryonic stem cells, which leads to transactivation of the endogenous Igf2 gene. The consequent overexpression of Igf2 results in most of the symptoms of Beckwith-Wiedemann syndrome, including prenatal overgrowth, polyhydramnios, fetal and neonatal lethality, disproportionate organ overgrowth including tongue enlargement, and skeletal abnormalities. These phenotypes establish Igf2 overexpression as a key determinant of Beckwith-Wiedemann syndrome.