PARTIAL INACTIVATION OF THE RB PRODUCT IN A FAMILY WITH INCOMPLETE PENETRANCE OF FAMILIAL RETINOBLASTOMA AND BENIGN RETINAL TUMORS

While familial retinoblastoma has served as the paradigm for the two-h it theory of tumorigenesis and for the concept of the tumor suppressor gene, the etiology of incomplete penetrance of familial retinoblastom a is poorly understood. To address the molecular basis for this phenot ype we have studied the functional properties of a mutant Rb gene iden tified in a kindred with incomplete penetrance of familial retinoblast oma and evidence for regressed retinal lesions (retinomas). In contras t to all previously isolated RB mutant proteins, we demonstrated that the mutant product from this kindred retained the wildtype properties of nuclear localization, the ability to undergo hyperphosphorylation i n vivo, and the capacity to suppress growth of RB((-)) cells. Protein binding ('pocket') activity, however, was defective defining a new cla ss of RB mutant with partial inactivation. The presence of this unique RB mutant in the germline of obligate carriers with incomplete penetr ance and regressed retinal lesions suggests a molecular basis for this phenotype and supports the hypothesis that a minimum 'RB threshold' l evel of protein binding activity is required to suppress tumorigenesis .