Human Molecular Genetics Advance Access published online on December 17, 2003
Human Molecular Genetics, doi:10.1093/hmg/ddh038
© 2003 by Oxford University Press
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1 Cancer & Leukaemia in Childhood (CLIC) Research Unit, and Cancer Research UK Colorectal Tumour Biology Research Group [A.C.W.], Department of Pathology and Microbiology, School of Medical Sciences, University of Bristol, University Walk, Bristol BS8 1TD, UK
* To whom correspondence should be addressed. E-mail: k.t.a.malik{at}bristol.ac.uk.
The Wilms' tumour suppressor gene, WT1, is mutated in 10-15% of Wilms' tumours and encodes zing-finger proteins with diverse cellular functions critical for nephrogenesis, genitourinary development, haematopoiesis, and sex-determination. Here we report that a novel alternative WT1 transcript, AWT1, is co-expressed with WT1 in renal and haematopoietic cells. AWT1 maintains WT1 exonic structure between exons 2 and 10, but deploys a new 5'-exon located in intron 1 of WT1. The AWT1 gene predicts proteins of approximately 33 kDa, comprising all exon 5 and exon 9 splicing variants previously characterised for WT1. Although WT1 is not genomically imprinted in kidney, we have previously shown monoallelic expression of a WT1 antisense transcript (WT1-AS) that is consistent with genomic imprinting. Here we demonstrate that both WT1-AS and the novel AWT1 transcript are imprinted in normal kidney with expression confined to the paternal allele. Wilms' tumours display biallelic AWT1 expression, indicating relaxation of imprinting of AWT1 in a subset of WTs. Our findings define human chromosome 11p13 as a new imprinted locus, and also suggest a possible molecular basis for the strong bias of paternal allele mutations and variable penetrance observed in syndromes with inherited WT1 mutations.
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Genomic Imprinting at the WT1 gene involves a novel coding transcript (AWT1) that shows deregulation in Wilms' tumours
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