CONSTITUTIONAL NONSENSE GERMLINE MUTATIONS IN THE RB1 GENE DETECTED IN PATIENTS WITH EARLY-ONSET UNILATERAL RETINOBLASTOMA

The 'two-hit' hypothesis for the development of the childhood eye canc er, retinoblastoma (Rb), predicts that bilaterally affected individual s will carry germline mutations. The second suggestion is that patient s with early presentation of unilateral tumours also carry predisposin g mutations. We have used SSCP analysis to study the 27 individual exo ns of the RBI gene in constitutional DNA from 3 patients whose tumours were treated under the age of 12 months. Bandshifts on SSCP gels were detected in 2 of these patients which, on sequencing, were shown to b e a C --> T transition converting a CGA(arg) to a TGA(stop) codon in e xon 17 and an 8 bp deletion in exon 20 resulting in a downstream stop codon. The mutations seen in these patients are reminiscent of those s een in patients with hereditary Rb and confirms that at least some ear ly onset unilateral cases carry constitutional mutations, which has im portant implications for genetic screening and counselling of these in dividuals. Copyright (C) 1996 Elsevier Science Ltd