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144 Pages

H Human Clinical Genetics

The Wilms' Tumour 1 gene (WT1) was isolated f r o m l l p l 3 , a chromosomal region disrupted or deleted i n a large number of W i l m s ' tumours . The gene is expressed dur ing the development of the urogenital system and loss of both copies of WT1 leads to W i l m s ' tumour format ion . In addi t ion to sporadic W i l m s ' tumours , different mutations (alleles) of WT1 give rise to three different h u m a n congenital syndromes - W i l m s ' tumour, anir idia (absence of the iris), genital abnormalities and mental retardation ( W A G R ) syndrome, D e n y s - D r a s h syndrome (DDS) and Frasier syndrome. Individuals w i t h these syndromes show genital abnormalities and, in the case of D D S and Frasier syndrome, also nephropathy. Analysis of the phenotype of the different WT1 -associated syndromes, and that of mice in w h i c h the Wtl gene has been deleted, identifies WT1 functions at several different stages of gonad and kidney development. The finding that WT1 is an important player i n kidney organogenesis supports the premise that W i l m s ' tumours arise as a result of n o r m a l kidney developmental processes gone awry. It further al lows a more detailed investigation of this method of tumorigenesis.