Homozygous deletion in Wilms tumours of a zinc-finger gene identified by chromosome jumping.
Cytogenetic analysis has identified chromosome 11p13 as the smallest overlap region for deletions found in individuals with WAGR syndrome, which includes Wilms tumour (a recessive childhood nephroblastoma), aniridia, genito-urinary abnormalities and mental retardation. The underlying loci have since been resolved into an aniridia (AN2) locus at a telomeric position, and a locus of closely spaced genes or a single pleiotropic gene involved in genito-urinary tract abnormalities and Wilms tumour at a more centromeric position. Pulsed-field gel analysis of the 11p13 region has revealed the presence of several putative CpG islands, structures which are frequently associated with the 5' ends of expressed sequences, mainly housekeeping genes and some tissue-specific genes. Starting from a CpG island, we have now isolated four neighbouring CpG islands, all within 650 kilobases (kb), by means of two consecutive bidirectional jumps in rare-cutting restriction-enzyme jumping libraries. In two instances, flanking sequences were conserved in other species and RNA transcripts were identified. A complementary DNA clone isolated for one of them derives from an RNA highly expressed in fetal kidney, and is predicted to encode a Krüppel-like zinc-finger protein that is probably a transcription factor. The entire cDNA region is included in two partially overlapping homozygous deletions found in Wilms tumour DNA samples. Cloning of the breakpoints in one tumour revealed a deletion size of 170 kb, one-third of which is covered by the cDNA. The expression pattern and sequence of this cDNA could point to an important role for its corresponding gene in the normal development of the renal system as well as in Wilms tumour.
Gessler
M
M
Genetics Division, Children's Hospital, Boston, Massachusetts.
Poustka
A
A
Cavenee
W
W
Neve
R L
RL
Orkin
S H
SH
Bruns
G A
GA
D000595:Amino Acid Sequence; D001483:Base Sequence; D002872:Chromosome Deletion; D002880:Chromosomes, Human, Pair 11; D003001:Cloning, Molecular; D004247:DNA / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics*; D008667:Metalloproteins / Q000235:genetics*; D008969:Molecular Sequence Data; D009693:Nucleic Acid Hybridization; D012091:Repetitive Sequences, Nucleic Acid; D015183:Restriction Mapping; D009396:Wilms Tumor / Q000235:genetics*
D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D008667:Metalloproteins; D004247:DNA