Exon skipping due to a mutation in a donor splice site in the WT-1 gene is associated with Wilms' tumor and severe genital malformations.
A germline WT-1 point mutation is described in a patient with unilateral Wilms' tumor, nephritis and ambiguous external genitalia. The patient was diagnosed as a possible case of Denys Drash syndrome (DDS). Analysis of the WT-1 exons and intron borders revealed a G to C transversion in the +1 position of the splice donor consensus sequence in intron 6. Two transcripts of abnormal size were identified in tumor RNA. Sequencing of the altered WT-1 mRNA revealed that this point mutation leads to exon-skipping, resulting in transcripts either missing exon 6 or exons 5 and 6. The normally occurring alternative splicing of exon 5 in the WT-1 gene is not affected by this mutation. The reading frame is changed when either both exons 5 and 6 or exon 6 alone are missing and a stop codon follows immediately downstream in exon 7. Most mutations identified in DDS are missense mutations located in the zinc finger (ZF) region (exons 7, 8 and 9) but recently a patient with a germline mutation in exon 6 leading to premature chain termination was described. Therefore the site of the mutation in the WT-1 gene in this patient cannot exclude the possibility that he has DDS.
Institut für Humangenetik, Universität Heidelberg, Germany.
S
S
Schneider
G
G
Wildhardt
R
R
Ludwig
B
B
Royer-Pokora
D001483:Base Sequence; D002872:Chromosome Deletion; D002880:Chromosomes, Human, Pair 11; D016384:Consensus Sequence; D004268:DNA-Binding Proteins / Q000235:genetics*; D005091:Exons; D016147:Genes, Tumor Suppressor; D005835:Genitalia / Q000002:abnormalities*; D006579:Heterozygote; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D012326:RNA Splicing; D013577:Syndrome; D025721:WT1 Proteins; D009396:Wilms Tumor / Q000235:genetics*; D016335:Zinc Fingers
D004268:DNA-Binding Proteins; D025721:WT1 Proteins