Imprint establishment in Prader-Willi and Angelman syndromes is controlled by two major transcription factors acting at alternative promoters of Snurf-Snrpn during gametogenesis and preimplantation development.  

Tohru Ohta¹, Jyoti R. Khadake³, Christine Mione³, Petr Svoboda², Wolfgang W. Quitschke⁴, Sara Rodriguez-Jato³, John R. McCarrey⁵, Richard M. Schultz², Thomas P. Yang³, and Robert D. Nicholls¹. ¹Center for Neurobiology and Behavior, Department of Psychiatry, and ²Department of Biology, University of Pennsylvania, Philadelphia, PA; ³Department of Biochemistry and Molecular Biology, University of Florida College of Medicine, Gainesville, FL; ⁴Department of Psychiatry and Behavioral Science, State University of New York, Stony Brook, NY; ⁵Department of Genetics, Southwest Foundation for Biomedical Research, PO Box 760549, San Antonio, TX 

Prader-Willi and Angelman syndromes (PWS and AS) are neurobehavioral and developmental syndromes that are associated with genetic defects of imprinted expression in chromosome 15q11-q13. Among other clinical features, PWS infants have hypotonia and failure-to-thrive, with onset of hyperphagia and severe obesity after ~2 years of age. PWS results from the loss of function of more than one paternally expressed imprinted genes. Candidates include several intronless genes and a novel polycistronic locus, encoding two proteins (SNURF, SmN/SNRPN) and at least 5 subfamilies of snoRNAs. The 7 functions encoded by the polycistronic locus are each nuclear in function and may represent a mammalian operon. AS patients have a severe neurological disease, associated with loss of function of maternal-only expression of UBE3A in specific parts of the brain, while an adjacent maternally expressed gene, ATP10C, may be associated with obesity. Imprinted expression in 15q11-q13 is bidirectionally controlled in cis by an imprinting center (IC) located at the 5’ end of the SNURF-SNRPN locus. The IC is a genetic element functional in germline and/or early postzygotic development that establishes parental specific allelic differences in DNA methylation and chromatin structure across the entire 2 Mb imprinted domain. To gain insight into the molecular basis of imprinting in PWS and AS, we have examined the structure and function of the IC in human 15q11-q13 and the homologous mouse locus. An unusually complex set of at least eleven alternative promoters for Snurf-Snrpn is differentially expressed and methylated in germ cell and preimplantation stages, correlating with the establishment of the genomic imprints. Transcription factors that are involved in the gene expression and putatively in imprint establishment patterns have been identified by phylogenetic as well as in vitro and in vivo techniques. Interestingly, within the IC, it is the NRF-1 and CTCF binding sites that are most highly conserved in evolution. A new model for genomic imprinting in the PWS/AS domain that explains the effects of mutations in the imprinting process in PWS and AS families will be presented.

 July 2002