Imprinting in clusters: lessons from Beckwith-Wiedemann syndrome

Imprinted genes in mammals can be clustered in the genome. This raises important questions about mechanistic and functional relationships between imprinted genes in a cluster. The insulin-like growth factor II (IGF2) gene is paternally expressed and is surrounded by maternally expressed genes. Loss of imprinting of IGF2 is the most common molecular defect found in the human foetal overgrowth syndrome, Beckwith-Wiedemann syndrome (BWS). Transgenic experiments in the mouse establish that overexpression of IGF2 can result in most of the symptoms of BWS. However, mutations, translocations, or methylation defects in BWS have so far been found in three of the linked maternally expressed genes. We present a model where the paternal growth enhancer IGF2 is surrounded by multiple maternal suppressors, and mutations, or epigenetic alterations, in any of these suppressors could cause BWS. In addition, the precise phenotypic spectrum of BWS might depend on which maternally expressed gene is mutated.