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Proc Natl Acad Sci U S A. Jul 1, 1992; 89(13): 6177–6181.
PMCID: PMC402145

Oncogenic point mutations in exon 20 of the RB1 gene in families showing incomplete penetrance and mild expression of the retinoblastoma phenotype.

Abstract

The retinoblastoma-predisposition gene, RB1, segregates as an autosomal dominant trait with high (90%) penetrance. Certain families, however, show an unusual low-penetrance phenotype with many individuals being unaffected, unilaterally affected, or with evidence of spontaneously regressed tumors. We have used single-strand conformation polymorphism analysis and PCR sequencing to study two such families. Mutations were found in exon 20 of RB1 in both cases. In one family a C----T transition in codon 661 converts an arginine (CGG) to a tryptophan (TGG) codon. In this family, incomplete penetrance and mild phenotypic expression were observed in virtually all patients, possibly indicating that single amino acid changes may modify protein structure/function such that tumorigenesis is not inevitable. In the second family the mutation in codon 675 is a G----T transversion that converts a glutamine (GAA) to a stop (TAA) codon. However, this mutation also occurs near a potential cryptic splice acceptor site, raising the possibility of alternative splicing resulting in a less severely disrupted protein.

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  • Vogel F. Genetics of retinoblastoma. Hum Genet. 1979 Nov 1;52(1):1–54. [PubMed]
  • Knudson AG., Jr Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci U S A. 1971 Apr;68(4):820–823. [PMC free article] [PubMed]
  • MACKLIN MT. A study of retinoblastoma in Ohio. Am J Hum Genet. 1960 Mar;12:1–43. [PMC free article] [PubMed]
  • Connolly MJ, Payne RH, Johnson G, Gallie BL, Allderdice PW, Marshall WH, Lawton RD. Familial, EsD-linked, retinoblastoma with reduced penetrance and variable expressivity. Hum Genet. 1983;65(2):122–124. [PubMed]
  • Onadim Z, Hykin PG, Hungerford JL, Cowell JK. Genetic counselling in retinoblastoma: importance of ocular fundus examination of first degree relatives and linkage analysis. Br J Ophthalmol. 1991 Mar;75(3):147–150. [PMC free article] [PubMed]
  • Onadim ZO, Mitchell CD, Rutland PC, Buckle BG, Jay M, Hungerford JL, Harper K, Cowell JK. Application of intragenic DNA probes in prenatal screening for retinoblastoma gene carriers in the United Kingdom. Arch Dis Child. 1990 Jul;65(7 Spec No):651–656. [PMC free article] [PubMed]
  • Gallie BL, Ellsworth RM, Abramson DH, Phillips RA. Retinoma: spontaneous regression of retinoblastoma or benign manifestation of the mutation? Br J Cancer. 1982 Apr;45(4):513–521. [PMC free article] [PubMed]
  • Wiggs J, Nordenskjöld M, Yandell D, Rapaport J, Grondin V, Janson M, Werelius B, Petersen R, Craft A, Riedel K, et al. Prediction of the risk of hereditary retinoblastoma, using DNA polymorphisms within the retinoblastoma gene. N Engl J Med. 1988 Jan 21;318(3):151–157. [PubMed]
  • Yandell DW, Dryja TP. Detection of DNA sequence polymorphisms by enzymatic amplification and direct genomic sequencing. Am J Hum Genet. 1989 Oct;45(4):547–555. [PMC free article] [PubMed]
  • Friend SH, Bernards R, Rogelj S, Weinberg RA, Rapaport JM, Albert DM, Dryja TP. A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma. Nature. 1986 Oct 16;323(6089):643–646. [PubMed]
  • McGee TL, Yandell DW, Dryja TP. Structure and partial genomic sequence of the human retinoblastoma susceptibility gene. Gene. 1989 Aug 1;80(1):119–128. [PubMed]
  • Yandell DW, Campbell TA, Dayton SH, Petersen R, Walton D, Little JB, McConkie-Rosell A, Buckley EG, Dryja TP. Oncogenic point mutations in the human retinoblastoma gene: their application to genetic counseling. N Engl J Med. 1989 Dec 21;321(25):1689–1695. [PubMed]
  • Orita M, Suzuki Y, Sekiya T, Hayashi K. Rapid and sensitive detection of point mutations and DNA polymorphisms using the polymerase chain reaction. Genomics. 1989 Nov;5(4):874–879. [PubMed]
  • Hogg A, Onadim Z, Baird PN, Cowell JK. Detection of heterozygous mutations in the RB1 gene in retinoblastoma patients using single-strand conformation polymorphism analysis and polymerase chain reaction sequencing. Oncogene. 1992 Jul;7(7):1445–1451. [PubMed]
  • Onadim Z, Hungerford J, Cowell JK. Follow-up of retinoblastoma patients having prenatal and perinatal predictions for mutant gene carrier status using intragenic polymorphic probes from the RB1 gene. Br J Cancer. 1992 May;65(5):711–716. [PMC free article] [PubMed]
  • Mount SM. A catalogue of splice junction sequences. Nucleic Acids Res. 1982 Jan 22;10(2):459–472. [PMC free article] [PubMed]
  • Hoshijima K, Inoue K, Higuchi I, Sakamoto H, Shimura Y. Control of doublesex alternative splicing by transformer and transformer-2 in Drosophila. Science. 1991 May 10;252(5007):833–836. [PubMed]
  • Dunn JM, Phillips RA, Zhu X, Becker A, Gallie BL. Mutations in the RB1 gene and their effects on transcription. Mol Cell Biol. 1989 Nov;9(11):4596–4604. [PMC free article] [PubMed]
  • Horowitz JM, Park SH, Bogenmann E, Cheng JC, Yandell DW, Kaye FJ, Minna JD, Dryja TP, Weinberg RA. Frequent inactivation of the retinoblastoma anti-oncogene is restricted to a subset of human tumor cells. Proc Natl Acad Sci U S A. 1990 Apr;87(7):2775–2779. [PMC free article] [PubMed]
  • Weinberg RA. Tumor suppressor genes. Science. 1991 Nov 22;254(5035):1138–1146. [PubMed]
  • Whyte P, Buchkovich KJ, Horowitz JM, Friend SH, Raybuck M, Weinberg RA, Harlow E. Association between an oncogene and an anti-oncogene: the adenovirus E1A proteins bind to the retinoblastoma gene product. Nature. 1988 Jul 14;334(6178):124–129. [PubMed]
  • DeCaprio JA, Ludlow JW, Lynch D, Furukawa Y, Griffin J, Piwnica-Worms H, Huang CM, Livingston DM. The product of the retinoblastoma susceptibility gene has properties of a cell cycle regulatory element. Cell. 1989 Sep 22;58(6):1085–1095. [PubMed]
  • Dyson N, Howley PM, Münger K, Harlow E. The human papilloma virus-16 E7 oncoprotein is able to bind to the retinoblastoma gene product. Science. 1989 Feb 17;243(4893):934–937. [PubMed]
  • Hu QJ, Dyson N, Harlow E. The regions of the retinoblastoma protein needed for binding to adenovirus E1A or SV40 large T antigen are common sites for mutations. EMBO J. 1990 Apr;9(4):1147–1155. [PMC free article] [PubMed]
  • Huang HJ, Yee JK, Shew JY, Chen PL, Bookstein R, Friedmann T, Lee EY, Lee WH. Suppression of the neoplastic phenotype by replacement of the RB gene in human cancer cells. Science. 1988 Dec 16;242(4885):1563–1566. [PubMed]
  • Kaelin WG, Jr, Pallas DC, DeCaprio JA, Kaye FJ, Livingston DM. Identification of cellular proteins that can interact specifically with the T/E1A-binding region of the retinoblastoma gene product. Cell. 1991 Feb 8;64(3):521–532. [PubMed]
  • Chittenden T, Livingston DM, Kaelin WG., Jr The T/E1A-binding domain of the retinoblastoma product can interact selectively with a sequence-specific DNA-binding protein. Cell. 1991 Jun 14;65(6):1073–1082. [PubMed]
  • Horowitz JM, Yandell DW, Park SH, Canning S, Whyte P, Buchkovich K, Harlow E, Weinberg RA, Dryja TP. Point mutational inactivation of the retinoblastoma antioncogene. Science. 1989 Feb 17;243(4893):937–940. [PubMed]
  • Shew JY, Lin BT, Chen PL, Tseng BY, Yang-Feng TL, Lee WH. C-terminal truncation of the retinoblastoma gene product leads to functional inactivation. Proc Natl Acad Sci U S A. 1990 Jan;87(1):6–10. [PMC free article] [PubMed]
  • Sakai T, Ohtani N, McGee TL, Robbins PD, Dryja TP. Oncogenic germ-line mutations in Sp1 and ATF sites in the human retinoblastoma gene. Nature. 1991 Sep 5;353(6339):83–86. [PubMed]
  • Zhu XP, Dunn JM, Phillips RA, Goddard AD, Paton KE, Becker A, Gallie BL. Preferential germline mutation of the paternal allele in retinoblastoma. Nature. 1989 Jul 27;340(6231):312–313. [PubMed]
  • Cavenee WK, Dryja TP, Phillips RA, Benedict WF, Godbout R, Gallie BL, Murphree AL, Strong LC, White RL. Expression of recessive alleles by chromosomal mechanisms in retinoblastoma. Nature. 305(5937):779–784. [PubMed]
  • Reed R, Maniatis T. A role for exon sequences and splice-site proximity in splice-site selection. Cell. 1986 Aug 29;46(5):681–690. [PubMed]
  • Bookstein R, Rio P, Madreperla SA, Hong F, Allred C, Grizzle WE, Lee WH. Promoter deletion and loss of retinoblastoma gene expression in human prostate carcinoma. Proc Natl Acad Sci U S A. 1990 Oct;87(19):7762–7766. [PMC free article] [PubMed]
  • Mittnacht S, Weinberg RA. G1/S phosphorylation of the retinoblastoma protein is associated with an altered affinity for the nuclear compartment. Cell. 1991 May 3;65(3):381–393. [PubMed]
  • Scheffner M, Münger K, Byrne JC, Howley PM. The state of the p53 and retinoblastoma genes in human cervical carcinoma cell lines. Proc Natl Acad Sci U S A. 1991 Jul 1;88(13):5523–5527. [PMC free article] [PubMed]

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