Beckwith-Wiedemann syndrome demonstrates a role for epigenetic control of normal development.
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.
Weksberg
Rosanna
R
Institute of Medical Sciences, Department of Medical Genetics and Microbiology, University of Toronto, Ontario, Canada. rweksb@sickkids.ca
Smith
Adam C
AC
Squire
Jeremy
J
Sadowski
Paul
P
D000483:Alleles; D000818:Animals; D001506:Beckwith-Wiedemann Syndrome / Q000235:genetics*; D002843:Chromatin / Q000378:metabolism; D002874:Chromosome Mapping; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D003001:Cloning, Molecular; D019175:DNA Methylation; D018507:Gene Expression Regulation, Developmental; D018392:Genomic Imprinting; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000235:genetics; D008957:Models, Genetic; D017434:Protein Structure, Tertiary
D002843:Chromatin; D007335:Insulin-Like Growth Factor II