WT1 exon deletion/insertion mutations in Wilms tumor patients associated with di- and trinucleotide repeats and deletion hotspot consensus sequences
- Univ. of Texas, Houston, TX (United States); and others
The genetic etiology of Wilms tumor (WT), a childhood kidney tumor, is known to be heterogeneous. One WT gene, WT1 located on chromosomal band 11p13, has been isolated, and mutations specific to the WT1 locus have been identified in some WT patients, demonstrating its importance in the etiology of at least some WT cases. Because of the patient populations selected for study and a focus on specific regions of the gene in identifying WT1 mutations, most mutations described to date are single base substitutions and have occurred in the 3{prime} portion of the gene in exons 7-10 which encode the zinc finger domains of the protein. DNA mutations at the WT1 locus have been reported to be infrequent in WT patients, implying that post-transcriptional modification of the WT1 gene product or alterations at other distinct loci perhaps more commonly play a role in tumorigenesis than do WT1 DNA mutations. We report here the occurrence in four WT patients of inactivating frameshift mutations, three somatic deletions and one germline insertion, in exon 1. This exon is GC-rich (>70%) and contains regions of both di- and trinucleotide direct repeats and ten copies of the sequence, CCTG (CAGG), which has been described as a deletion hotspot in mammalian DNA. The four WT1 exon 1 deletion/insertions range in size from four to 34 bases, are flanked by bi- and/or trinucleotide repeats, and occur in a general context of repetitive sequences. Furthermore, all breakpoints occur at or within five nucleotides of the tetranucleotide sequence, CCTG (CAGG). These data suggest that a mutational mechanism previously unrecognized in WT patients is operating in this repetitive portion of the WT1 gene. The frequency with which mutations of this type are observed in WT patients awaits the complete evaluation of a series of patients. Nevertheless these data indicate that WT1 mutations are more frequent in WT patients than previously thought.
- OSTI ID:
- 133399
- Report Number(s):
- CONF-941009-; ISSN 0002-9297; TRN: 95:005313-0127
- Journal Information:
- American Journal of Human Genetics, Vol. 55, Issue Suppl.3; Conference: 44. annual meeting of the American Society of Human Genetics, Montreal (Canada), 18-22 Oct 1994; Other Information: PBD: Sep 1994
- Country of Publication:
- United States
- Language:
- English
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