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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)
 
 
 

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

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.[1]

References

  1. Deletion of RB exons 24 and 25 causes low-penetrance retinoblastoma. Bremner, R., Du, D.C., Connolly-Wilson, M.J., Bridge, P., Ahmad, K.F., Mostachfi, H., Rushlow, D., Dunn, J.M., Gallie, B.L. Am. J. Hum. Genet. (1997) [Pubmed]
 
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