Naturally Occurring Mutations in the WTI Gene

Abstract

Dominant oncogenes, like myc or ras, confer a gain of func-tion to transformed cells.^1,2 Gain-of-function mutations result in abnormal, positive signals for cell proliferation. In general, however, genetic alterations such as point mutations and deletions most often result in a loss of function and contribute to tumorigenesis by interference with mechanisms restraining cell proliferation. Such is the case for the Wilms tumor suppressor gene, WT1. Theoretically, mutations can occur at any site within the gene. However, it is important to consider whether the mutation results in the production of a modified protein (missense mutation) or in the production of a truncated WT1 protein (nonsense or frameshift mutation). Depending upon the biochemical function of the protein and the nature of its interaction with other proteins, missense or nonsense mutations could be expected to produce different phenotypes. And, indeed, constitutional missense mutations of the WT1 gene appear to disrupt several organ systems and result in a far more severe phenotype (Denys-Drash syndrome — DDS, see chapter 1) than constitutional deletions (WAGR syndrome) or nonsense mutations (Wilms tumor only).