Human Molecular Genetics, 2003, Vol. 12, Review Issue 1 R61-R68
DOI: 10.1093/hmg/ddg067
© 2003 Oxford University Press
Beckwith–Wiedemann syndrome demonstrates a role for epigenetic control of normal development
1Institute of Medical Sciences, 2Department of Laboratory Medicine and Pathobiology, 3Department of Medical Genetics and Microbiology and 4Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada, 5Division of Clinical and Metabolic Genetics and 6The Research Institute Programme in Genetics and Genomic Biology, The Hospital for Sick Children, Toronto, Ontario, Canada and 7Ontario Cancer Institute, Toronto, Ontario, Canada
Received January 3, 2003; Revised January 10, 2003; Accepted January 15, 2003
The Beckwith–Wiedemann syndrome (BWS) is characterized by somatic overgrowth and a predisposition to pediatric embryonal tumors. It is associated with genetic or epigenetic abnormalities in a cluster of imprinted genes found within a genomic region of approximately one megabase on human chromosome 11p15. Imprinted genes are expressed preferentially or exclusively from either the paternal or maternal allele. The 11p15 region is organized into two imprinted domains in which genomic imprinting is controlled by separate ‘imprinting control regions’. Twenty-five to 50% of BWS patients have biallelic rather than monoallelic expression of the insulin-like growth factor 2 (IGF2) gene. Another 50% of patients have an epigenetic mutation resulting in loss of imprinting of a transcript called KCNQ1OT1. Each of these genes resides in one of the two imprinted domains that appear to be subject to developmental dysregulation in BWS. In this review, we discuss the insights that the study of BWS have contributed to our understanding of the mechanisms of growth control, oncogenesis and genomic imprinting. Specifically, methylation and chromatin modification may coordinate the expression of closely linked imprinted genes. Finally, we discuss how knowledge of epigenetic mechanisms associated with the early stages of embryogenesis suggest caution in the current debate surrounding assisted reproductive and cloning technologies.
* To whom correspondence should be addressed at: Clinical and Metabolic Genetics, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8. Tel: +1 4168136386; Email: rweksb{at}sickkids.ca
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