SYNTENIC ORGANIZATION OF THE MOUSE DISTAL CHROMOSOME-7 IMPRINTING CLUSTER AND THE BECKWITH-WIEDEMANN-SYNDROME REGION IN CHROMOSOME 11P15.5

In human and mouse, most imprinted genes are arranged in chromosomal c lusters. Their linked organization suggests co-ordinated mechanisms co ntrolling imprinting and gene expression. The identification of local and regional elements responsible for the epigenetic control of imprin ted gene expression will be important in understanding the molecular b asis of diseases associated with imprinting such as Beckwith-Wiedemann syndrome. We have established a complete contig of clones along the m urine imprinting cluster on distal chromosome 7 syntenic with the huma n imprinting region at 11p15.5 associated with Beckwith-Wiedemann synd rome. The cluster comprises similar to 1 Mb of DNA, contains at least eight imprinted genes and is demarcated by the two maternally expresse d genes Tssc3 (Ipl) and H19 which are directly flanked by the non-impr inted genes Nap 1/4(Nap2) and Rpl23l(L23mrp), respectively. We also lo calized Kcnq1 (Kviqt1) and Cd81 (Tapa-1) between Cdkn1c(p57(Kip2)) and Mash2. The mouse Kcnq1 gene is maternally expressed in most fetal but biallelically transcribed in most neonatal tissues, suggesting relaxa tion of imprinting during development. Our findings indicate conserved control mechanisms between mouse and human, but also reveal some stru ctural and functional differences. Our study opens the way for a syste matic analysis of the cluster by genetic manipulation in the mouse whi ch will lead to animal models of Beckwith-Wiedemann syndrome and child hood tumours.