Genomic imprinting at the WT1 gene involves a novel coding transcript (AWT1) that shows deregulation in Wilms' tumours.
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.
Dallosso
Anthony R
AR
Department of Pathology and Microbiology, School of Medical Sciences, University of Bristol, Bristol, UK.
Hancock
Anne L
AL
Brown
Keith W
KW
Williams
Ann C
AC
Jackson
Sally
S
Malik
Karim
K
D017398:Alternative Splicing / Q000235:genetics*; D001483:Base Sequence; D002478:Cells, Cultured; D005091:Exons / Q000235:genetics; D018392:Genomic Imprinting; D006801:Humans; D007438:Introns / Q000235:genetics; D007668:Kidney / Q000378:metabolism; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism; D019656:Loss of Heterozygosity / Q000235:genetics*; D008745:Methylation; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D025721:WT1 Proteins / Q000235:genetics* / Q000378:metabolism; D009396:Wilms Tumor / Q000235:genetics* / Q000378:metabolism
D025721:WT1 Proteins