DO INTRONIC MUTATIONS AFFECTING SPLICING OF WT1 EXON-9 CAUSE FRASIER-SYNDROME

The WT1 gene, one of the genes responsible for Wilms tumour, is though t to play a crucial role in the development of the kidneys and gonads. This gene encodes four protein isoforms resulting from two alternativ e splicing sites, one of which involves inclusion or exclusion of lysi ne, threonine, and serine (KTS) between the third and fourth zinc fing er domains. WT1 is virtually always mutationally inactivated in patien ts with Denys-Drash syndrome. We analysed WT1 in eight patients who ha d been diagnosed as having this syndrome, and identified five previous ly unknown mutations affecting splicing donor sites of intron 9. These mutations affect alternative splicing. The isoforms retaining KTS are not produced. The clinical features of the patients with these intron ic mutations were consistent with those of Frasier syndrome, character ised by a more slowly progressive nephropathy than Denys-Drash syndrom e, associated streak gonads, and no Wilms tumour development. Our resu lts indicate that WT1 isoforms, including/excluding KTS, have differen t functions in tumorigenesis and organogenesis of the kidneys and gona ds.