Genomic imprinting at the WT1 gene involves a novel coding transcript (AWT1) that shows deregulation in Wilms' tumours

Hum Mol Genet. 2004 Feb 15;13(4):405-15. doi: 10.1093/hmg/ddh038. Epub 2003 Dec 17.

Abstract

The Wilms' tumour suppressor gene, WT1, is mutated in 10-15% of Wilms' tumours and encodes zinc-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 characterized 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing / genetics*
  • Base Sequence
  • Cells, Cultured
  • Exons / genetics
  • Genomic Imprinting*
  • Humans
  • Introns / genetics
  • Kidney / metabolism
  • Kidney Neoplasms / genetics
  • Kidney Neoplasms / metabolism
  • Loss of Heterozygosity / genetics*
  • Methylation
  • Molecular Sequence Data
  • Mutation / genetics
  • WT1 Proteins / genetics*
  • WT1 Proteins / metabolism
  • Wilms Tumor / genetics*
  • Wilms Tumor / metabolism

Substances

  • WT1 Proteins