The imprinted domain in mouse distal Chromosome 7: reagents for mutagenesis and sequencing

Several lines of evidence suggest that human Chromosome (Chr) band 11p15.5 contains genes involved in tumor suppression and embryonic growth (reviewed in Reid et al. 1997 and Cooper et al. 1998). First, rare chromosomal breakpoints in Beckwith-Wiedemann syndrome (BWS) patients and pediatric tumors map to 11p15.5. Since BWS patients suffer from a variety of over-growth disorders and predisposition to embryonic tumors including Wilms' tumor (WT) and rhabdomyosarcoma, the breakpoints may disrupt developmental genes or their regulation. Second, loss of heterozygosity (LOH) in 11p15.5 has been detected in BWS and sporadic WT cases. LOH in the same region of 11p15.5 is also observed in a variety of adult tumors, suggesting the presence of a common tumor suppressor gene or a cluster of cancer-related genes. Third, 11p15.5 contains at least seven imprinted genes (IPL, ORCTL2/IMPT1, p57 super(KIP2), KvLQT1, ASCL2, IGF2, and H19) that are normally expressed primarily from one, parent-specific allele. Loss of imprinting (LOI) mutations have been detected at H19, IGF2, and to a lesser extent p57 super(KIP2) in WT and BWS patients. The resulting abnormal expression of these genes may contribute to BWS and sporadic tumor development. Finally, studies involving the transfer of regions of 11p15.5 into mammalian cells demonstrate tumor suppressor activity in the G401 WT cell line and growth arrest in the RD rhabdomyosarcoma cell line.