A SPLICING MUTATION IN RB1 IN LOW PENETRANCE RETINOBLASTOMA

The pediatric eye-tumor retinoblastoma is widely held as a paradigm of human cancer genetics and has been a model system for both the two-hi t hypothesis of dominantly inherited cancer as well as for the concept of tumor-specific loss of constitutional heterozygosity to achieve ex pression of the tumorigenic phenotype. Familial retinoblastoma is usua lly inherited as an autosomal dominant disease with high penetrance an d expressivity. In a small but significant number of families, however , retinoblastoma is inherited with greatly reduced penetrance and expr essivity. In these families, retinoblastoma tumors occur relatively la te, are often unilateral, and unaffected carriers may exist. We have i dentified a mutation in such a family that exhibited extremely low pen etrance and expressivity. This mutation appeared to affect splicing of the mutant allele such that both a normal length RB1 mRNA and a trunc ated RB1 mRNA were expressed from the same allele.