A possible hot spot in exon 21 of the retinoblastoma gene predisposing to a low penetrant retinoblastoma phenotype?

• Published in: Ophthalmic genetics Vol. 20; no. 4; pp. 225 - 231
• Main Authors: Ahmad, N. Nina, Barbosa de Melo, Mônica, Singh, Arun D., Donoso, Larry A., Shields, Jerry A.
• Format: Journal Article
• Language: English
• Published: England Informa UK Ltd 1999; Taylor & Francis
• Subjects: Adult; Amino Acid Substitution; Child; DNA - chemistry; DNA - genetics; DNA Mutational Analysis; Exons - genetics; Family Health; Female; Genes, Retinoblastoma - genetics; Genetic Predisposition to Disease; Humans; Infant; Male; Middle Aged; Mutation; Pedigree; Phenotype; Point Mutation; Retinal Neoplasms - genetics; Retinal Neoplasms - pathology; Retinoblastoma - genetics; Retinoblastoma - pathology
• ISSN: 1381-6810; 1744-5094
• DOI: 10.1076/opge.20.4.225.2269

Purpose: To identify the mutation in the RB1 gene in a Syrian family showing incomplete penetrance of retinoblastoma (RB). Methods: Genomic DNA was used as a template for the PCR reaction to amplify all exons as well as the promoter region of RB1 gene. These PCR products were screened by conformational sensitive gel electrophoresis and the 331-bp product containing exon 21 showing anomalous migration was sequenced directly to identify the mutation. Results: We identified the missense point mutation in exon 21 of the RB1 gene converting a Cys?Arg (codon 712) in one family with a low penetrant phenotype. The proband was unilaterally affected, whereas the paternal uncle was bilaterally affected and the mutation carrier father was unaffected. The T?C substitution abolished a cleavage site for the Nde I restriction enzyme, enabling rapid detection of the mutant allele. Conclusion: Phenotypically, this family is different from the previously described low penetrant phenotype pedigree with the same mutation whose affected members all had unilateral tumors. These results suggest that codon 712 may represent a mutational `hot spot' for the low penetrant phenotypes and that the mutation codes for retinoblastoma protein with an apparently residual tumor-suppressive function give rise to low penetrance. These results also raise the interesting question: what other factors influence the phenotype of mutation carriers in addition to the predisposing missense mutation.