Distant cis-elements regulate imprinted expression of the mouse p57KiP2 (Cdkn1C) gene:: implications for the human disorder, Beckwith-Wiedemann syndrome

Complex phenotypes and genotypes characterize the human disease, Beckwith-Wiedemann syndrome (BWS). Genetic and epigenetic mutations are found in five different genes which all lie within a 1 Mb imprinted domain on human chromosome 11p15. Only two of these genes, p57(KIP2) (CDKN1C) and IGF2, are likely to be functionally involved in this disease. The presence of the additional mutations therefore suggests a role for the regulation of these two genes by distant cis-elements. The mouse Igf2 gene is regulated by enhancers and imprinting elements which lie > 120 kb downstream of its promoter. Here we show that key elements for expression of the mouse p57(KiP2) (Cdkn1c) gene also lie at a distance. Enhancers for expression within skeletal muscle and cartilage lie > 25 kb downstream of the gene. In addition, we find no evidence for allele-specific expression of p57KiP2 (Cdkn1c) from our bacterial artificial chromosome transgenes that span 315 kb around the locus. This suggests that a key imprinting element for p57(Kip2) (Cdkn1c) also lies at a distance. Therefore, BWS in humans may result from disruption of appropriate expression of the p57KIP2 (CDKN1C) gene through mutations that occur at a substantial distance from the gene.