MUTATIONS IN THE RETINOBLASTOMA GENE AND THEIR EXPRESSION IN SOMATIC AND TUMOR CULLS OF PATIENTS WITH HEREDITARY RETINOBLASTOMA

Two intragenic deletions (exon 18-19 and exon 24) and two point mutati ons (one missense mutation in exon 21 and one mutation at splice donor site for exon 13) were detected in the retinoblastoma gene in somatic and tumor cells of patients with hereditary retinoblastoma. Three mut ations were located in a domain essential for binding to oncoproteins encoded by DNA tumor viruses (Hu et al., 1990; Huang et al., 1990), On e mutation (deletion of exon 24) was outside this domain but it is in the region essential for binding to transcriptional factor E2F, and fo r suppression of malignant phenotypes (Qian et at, 1992; Qin et al., 1 992). A minisatellite-like sequence and short repeated sequences were located at the breakpoint of the deletion of exon 24, suggesting that two deletions on both sides of the minisatellite-like sequence may be generated by a ''DNA slippage and misalignment'' mechanism. Upon ampli fication of cDNA by the polymerase chain reaction, no transcript of ge ne with frameshift mutation (deletion of exon 24) was detected in skin fibroblasts, while transcripts of genes with missense mutations were detected. The results, in combination with previous reports (Dunn et a l., 1989; Hashimoto et al., 1991), suggest the instability of transcri pts with a premature stop codon or the suppressed expression of allele s with a premature stop codon in the retinoblastoma gene in somatic ce lls of hereditary patients. (C) 1994 Wiley-Liss, Inc.