Deletion of RB exons 24 and 25 causes low-penetrance retinoblastoma

Am J Hum Genet. 1997 Sep;61(3):556-70. doi: 10.1086/515499.


A deletion in the tumor-suppressor gene, RB, discovered by quantitative multiplex PCR, shows low penetrance (LP), since only 39% of eyes at risk in this family develop retinoblastoma. The 4-kb deletion spanning exons 24 and 25 (delta24-25) is the largest ever observed in an LP retinoblastoma family. Unlike the usual RB mutations, which cause retinoblastoma in 95% of at-risk eyes and yield no detectable protein, the delta24-25 allele transcribed a message splicing exon 23 to exon 26, resulting in a detectable protein (pRBdelta24-25) that lacks 58 amino acids from the C-terminal domain, proving that this domain is essential for suppression of retinoblastoma. Two functions were partially impaired by delta24-25-nuclear localization and repression of E2F-consistent with the idea that LP mutations generate "weak alleles" by reducing but not eliminating essential activities. However, delta24-25 ablated interaction of pRB with MDM2. Since a homozygous LP allele is considered nontumorigenic, the pRB/MDM2 interaction may be semi- or nonessential for suppressing retinoblastoma. Alternatively, some homozygous LP alleles may not cause tumorigenesis because an additional event is required (the "three-hit hypothesis"), or the resulting imbalance in pRB function may cause apoptosis (the "death allele hypothesis"). pRBdelta24-25 was also completely defective in suppressing growth of Saos-2 osteosarcoma cells. Targeting pRBdelta24-25 to the nucleus did not improve Saos-2 growth suppression, suggesting that C-terminal domain functions other than nuclear localization are essential for blocking proliferation in these cells. Since delta24-25 behaves like a null allele in these cells but like an LP allele in the retina, pRB may use different mechanisms to control growth in different cell types.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Canada
  • Carrier Proteins*
  • Cell Cycle Proteins*
  • Cell Division
  • Cell Nucleus / chemistry
  • DNA-Binding Proteins*
  • E2F Transcription Factors
  • Exons / genetics*
  • Female
  • Gene Expression Regulation / genetics
  • Gene Expression Regulation, Neoplastic / genetics
  • Genes, Retinoblastoma / genetics*
  • Humans
  • Male
  • Melanoma / genetics
  • Nuclear Proteins*
  • Osteosarcoma
  • Pedigree
  • Prenatal Diagnosis
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-mdm2
  • Recombinant Fusion Proteins
  • Retinoblastoma / diagnosis
  • Retinoblastoma / genetics*
  • Retinoblastoma Protein / analysis
  • Retinoblastoma Protein / metabolism
  • Retinoblastoma-Binding Protein 1
  • Sequence Deletion / genetics*
  • Transcription Factor DP1
  • Transcription Factors / metabolism
  • Tumor Cells, Cultured


  • Carrier Proteins
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • E2F Transcription Factors
  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • Recombinant Fusion Proteins
  • Retinoblastoma Protein
  • Retinoblastoma-Binding Protein 1
  • Transcription Factor DP1
  • Transcription Factors
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2