Human Molecular Genetics, Vol 5, 2027-2032, Copyright © 1996 by Oxford University Press
KW Brown, AJ Villar, W Bickmore, J Clayton-Smith, D Catchpoole, ER Maher and W Reik
The Beckwith-Wiedemann syndrome (BWS) is genetically linked to chromosome
11p15.5, and a variety of observations suggest that deregulation of
imprinted genes in this region is causally involved in the pathogenesis of
the disease. It has been shown that in some patients without cytogenetic
abnormalities the otherwise repressed maternal copy of the insulin-like
growth factor 2 (IGF2) gene is expressed, leading to biallelic expression
of IGF2. In some of these cases, this is accompanied by repression and DNA
methylation of the maternal (otherwise active) copy of the neighbouring H19
gene. Hence, it is attractive to think that mutations may interfere with
some aspect of H19 imprinting, thus leading to an inactive maternal allele,
and indirectly to activation of the maternal IGF2 allele as reported in
mice with an H19 gene deletion. However, no mutations have been identified
so far in these patients. The only known mutations associated with BWS are
maternally transmitted translocations, which are clustered in two locations
centrometric to IGF2. The first cluster is 200-400 kb from IGF2 and the
second is several megabases away. Hence, genes located far from the
translocation breakpoints are potentially deregulated by them. Here we
provide the first evidence of alteration of imprinting in a translocation
family, with biallelic expression of IGF2 and altered DNA replication
patterns in the IGF2 region. Interestingly, H19 imprinting was normal,
suggesting an H19- independent pathway to biallelic IGF2 transcription. DNA
methylation in IGF2 remained monoallelic, suggesting that the mutation in
this family had uncoupled allele-specific methylation from expression.
ARTICLES
Imprinting mutation in the Beckwith-Wiedemann syndrome leads to biallelic IGF2 expression through an H19-independent pathway
Department of Pathology and Microbiology, School of Medical Sciences, Bristol, UK.
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