Beckwith-Wiedemann syndrome (BWS) is a clinically variable disorder characterized by somatic overgrowth, macroglossia, abdominal wall defects, visceromegaly, and an increased susceptibility to childhood tumors. The disease has been linked to a large cluster of imprinted genes at human chromosome 11p15.5. A subset of BWS patients has been identified with loss- of-function mutations in p57(KIP2), a maternally expressed gene encoding a G1 cyclin-dependent kinase inhibitor. Some patients display loss of imprinting of IGF2, a fetal-specific growth factor that is paternally expressed. To understand how the same disease can result from misregulation of two linked, but unrelated, genes, we generated a mouse model for BWS that both harbors a null mutation in p57(Kip2) and displays loss of Igf2 imprinting. These mice display many of the characteristics of BWS, including placentomegaly and dysplasia, kidney dysplasia, macroglossia, cleft palate, omphalocele, and polydactyly. Some, but not all, of the phenotypes are shown to be Igf2 dependent. In two affected tissues, the two imprinted genes appear to act in an antagonistic manner, a finding that may help explain how BWS can arise from mutations in either gene.
All Science Journal Classification (ASJC) codes
- Developmental Biology
- Beckwith-Wiedemann syndrome
- Genomic imprinting