title: Distant cis-elements regulate imprinted expression of the mouse p57( Kip2) (Cdkn1c) gene: implications for the human disorder, Beckwith--Wiedemann syndrome.
abstract: 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 p57(Kip2) (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 p57(KIP2) (CDKN1C) gene through mutations that occur at a substantial distance from the gene.
authors.affiliation: Wellcome/CRC Institute of Cancer and Developmental Biology, Tennis Court Road, Cambridge CB2 1QR, UK. rmj22@cus.cam.ac.uk
authors.forename: R M
authors.initials: RM
authors.lastname: John
authors.forename: J F
authors.initials: JF
authors.lastname: Ainscough
authors.forename: S C
authors.initials: SC
authors.lastname: Barton
authors.forename: M A
authors.initials: MA
authors.lastname: Surani
mesh_terms: D000818:Animals; D001506:Beckwith-Wiedemann Syndrome / Q000235:genetics* / Q000378:metabolism*; D002356:Cartilage / Q000378:metabolism; D002874:Chromosome Mapping; D020451:Contig Mapping; D018899:CpG Islands; D050761:Cyclin-Dependent Kinase Inhibitor p57; D004742:Enhancer Elements, Genetic; D005260:Female; D018392:Genomic Imprinting; D005838:Genotype; D006801:Humans; D017403:In Situ Hybridization; D008297:Male; D008745:Methylation; D051379:Mice; D008822:Mice, Transgenic; D008957:Models, Genetic; D018482:Muscle, Skeletal / Q000378:metabolism; D009154:Mutation; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000235:genetics*; D010641:Phenotype; D011401:Promoter Regions, Genetic; D014018:Tissue Distribution; D019076:Transgenes; D014178:Translocation, Genetic
chemical_list: C493964:CDKN1C protein, human; C493965:Cdkn1c protein, mouse; D050761:Cyclin-Dependent Kinase Inhibitor p57; D009687:Nuclear Proteins