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. 1992 Dec 1;89(23):11431–11435. doi: 10.1073/pnas.89.23.11431

Reading-frame restoration with an apolipoprotein B gene frameshift mutation.

M F Linton 1, V Pierotti 1, S G Young 1
PMCID: PMC50565  PMID: 1454832

Abstract

We examined a mutant human apolipoprotein B (apoB) allele that causes hypobetalipoproteinemia and has a single cytosine deletion in exon 26. This frameshift mutation was associated with the synthesis of a truncated apoB protein of the predicted size; however, studies in human subjects and minigene expression studies in cultured cells indicated that the mutant allele also yielded a full-length apoB protein. The 1-base-pair deletion in the mutant apoB allele created a stretch of eight consecutive adenines. To understand the mechanism whereby the mutant apoB allele yielded a full-length apoB protein, the cDNA from cells transfected with the mutant apoB minigene expression vector was examined. Splicing of the mRNA was normal; however, 11% of the cDNA clones had an additional adenine within the stretch of eight adenines, yielding nine consecutive adenines. The insertion of the extra adenine, presumably during apoB gene transcription, is predicted to restore the correct apoB reading frame, thereby permitting the synthesis of a full-length apoB protein.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Atkins J. F., Weiss R. B., Gesteland R. F. Ribosome gymnastics--degree of difficulty 9.5, style 10.0. Cell. 1990 Aug 10;62(3):413–423. doi: 10.1016/0092-8674(90)90007-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Chamorro M., Parkin N., Varmus H. E. An RNA pseudoknot and an optimal heptameric shift site are required for highly efficient ribosomal frameshifting on a retroviral messenger RNA. Proc Natl Acad Sci U S A. 1992 Jan 15;89(2):713–717. doi: 10.1073/pnas.89.2.713. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Curtiss L. K., Edgington T. S. Immunochemical heterogeneity of human plasma apolipoprotein B. I. Apolipoprotein B binding of mouse hybridoma antibodies. J Biol Chem. 1982 Dec 25;257(24):15213–15221. [PubMed] [Google Scholar]
  4. Farese R. V., Jr, Flynn L. M., Young S. G. Modification of the apolipoprotein B gene in HepG2 cells by gene targeting. J Clin Invest. 1992 Jul;90(1):256–261. doi: 10.1172/JCI115845. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Flower A. M., McHenry C. S. The gamma subunit of DNA polymerase III holoenzyme of Escherichia coli is produced by ribosomal frameshifting. Proc Natl Acad Sci U S A. 1990 May;87(10):3713–3717. doi: 10.1073/pnas.87.10.3713. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Groden J., Nakamura Y., German J. Molecular evidence that homologous recombination occurs in proliferating human somatic cells. Proc Natl Acad Sci U S A. 1990 Jun;87(11):4315–4319. doi: 10.1073/pnas.87.11.4315. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. HAVEL R. J., EDER H. A., BRAGDON J. H. The distribution and chemical composition of ultracentrifugally separated lipoproteins in human serum. J Clin Invest. 1955 Sep;34(9):1345–1353. doi: 10.1172/JCI103182. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Innerarity T. L., Young S. G., Poksay K. S., Mahley R. W., Smith R. S., Milne R. W., Marcel Y. L., Weisgraber K. H. Structural relationship of human apolipoprotein B48 to apolipoprotein B100. J Clin Invest. 1987 Dec;80(6):1794–1798. doi: 10.1172/JCI113273. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Ji J. P., Loeb L. A. Fidelity of HIV-1 reverse transcriptase copying RNA in vitro. Biochemistry. 1992 Feb 4;31(4):954–958. doi: 10.1021/bi00119a002. [DOI] [PubMed] [Google Scholar]
  10. Kazazian H. H., Jr The thalassemia syndromes: molecular basis and prenatal diagnosis in 1990. Semin Hematol. 1990 Jul;27(3):209–228. [PubMed] [Google Scholar]
  11. Kunkel T. A. Rapid and efficient site-specific mutagenesis without phenotypic selection. Proc Natl Acad Sci U S A. 1985 Jan;82(2):488–492. doi: 10.1073/pnas.82.2.488. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Lichter P., Tang C. J., Call K., Hermanson G., Evans G. A., Housman D., Ward D. C. High-resolution mapping of human chromosome 11 by in situ hybridization with cosmid clones. Science. 1990 Jan 5;247(4938):64–69. doi: 10.1126/science.2294592. [DOI] [PubMed] [Google Scholar]
  13. Mount S. M. A catalogue of splice junction sequences. Nucleic Acids Res. 1982 Jan 22;10(2):459–472. doi: 10.1093/nar/10.2.459. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Nelson F. K., Frankel W., Rajan T. V. Mitotic recombination is responsible for the loss of heterozygosity in cultured murine cell lines. Mol Cell Biol. 1989 Mar;9(3):1284–1288. doi: 10.1128/mcb.9.3.1284. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Ohshima Y., Gotoh Y. Signals for the selection of a splice site in pre-mRNA. Computer analysis of splice junction sequences and like sequences. J Mol Biol. 1987 May 20;195(2):247–259. doi: 10.1016/0022-2836(87)90647-4. [DOI] [PubMed] [Google Scholar]
  16. Pease R. J., Milne R. W., Jessup W. K., Law A., Provost P., Fruchart J. C., Dean R. T., Marcel Y. L., Scott J. Use of bacterial expression cloning to localize the epitopes for a series of monoclonal antibodies against apolipoprotein B100. J Biol Chem. 1990 Jan 5;265(1):553–568. [PubMed] [Google Scholar]
  17. Powell L. M., Wallis S. C., Pease R. J., Edwards Y. H., Knott T. J., Scott J. A novel form of tissue-specific RNA processing produces apolipoprotein-B48 in intestine. Cell. 1987 Sep 11;50(6):831–840. doi: 10.1016/0092-8674(87)90510-1. [DOI] [PubMed] [Google Scholar]
  18. Saiki R. K., Gelfand D. H., Stoffel S., Scharf S. J., Higuchi R., Horn G. T., Mullis K. B., Erlich H. A. Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. Science. 1988 Jan 29;239(4839):487–491. doi: 10.1126/science.2448875. [DOI] [PubMed] [Google Scholar]
  19. Sanger F., Nicklen S., Coulson A. R. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5463–5467. doi: 10.1073/pnas.74.12.5463. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Sekine Y., Ohtsubo E. Frameshifting is required for production of the transposase encoded by insertion sequence 1. Proc Natl Acad Sci U S A. 1989 Jun;86(12):4609–4613. doi: 10.1073/pnas.86.12.4609. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Steinberg D., Grundy S. M., Mok H. Y., Turner J. D., Weinstein D. B., Brown W. V., Albers J. J. Metabolic studies in an unusual case of asymptomatic familial hypobetalipoproteinemia with hypolphalipoproteinemia and fasting chylomicronemia. J Clin Invest. 1979 Jul;64(1):292–301. doi: 10.1172/JCI109451. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Takeuchi Y., Nagumo T., Hoshino H. Low fidelity of cell-free DNA synthesis by reverse transcriptase of human immunodeficiency virus. J Virol. 1988 Oct;62(10):3900–3902. doi: 10.1128/jvi.62.10.3900-3902.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Taylor S. A., Deugau K. V., Lillicrap D. P. Somatic mosaicism and female-to-female transmission in a kindred with hemophilia B (factor IX deficiency). Proc Natl Acad Sci U S A. 1991 Jan 1;88(1):39–42. doi: 10.1073/pnas.88.1.39. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Tsuchihashi Z., Kornberg A. Translational frameshifting generates the gamma subunit of DNA polymerase III holoenzyme. Proc Natl Acad Sci U S A. 1990 Apr;87(7):2516–2520. doi: 10.1073/pnas.87.7.2516. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Tsuchihashi Z. Translational frameshifting in the Escherichia coli dnaX gene in vitro. Nucleic Acids Res. 1991 May 11;19(9):2457–2462. doi: 10.1093/nar/19.9.2457. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Wagner L. A., Weiss R. B., Driscoll R., Dunn D. S., Gesteland R. F. Transcriptional slippage occurs during elongation at runs of adenine or thymine in Escherichia coli. Nucleic Acids Res. 1990 Jun 25;18(12):3529–3535. doi: 10.1093/nar/18.12.3529. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Wallis G. A., Starman B. J., Zinn A. B., Byers P. H. Variable expression of osteogenesis imperfecta in a nuclear family is explained by somatic mosaicism for a lethal point mutation in the alpha 1(I) gene (COL1A1) of type I collagen in a parent. Am J Hum Genet. 1990 Jun;46(6):1034–1040. [PMC free article] [PubMed] [Google Scholar]
  28. Yao Z. M., Blackhart B. D., Linton M. F., Taylor S. M., Young S. G., McCarthy B. J. Expression of carboxyl-terminally truncated forms of human apolipoprotein B in rat hepatoma cells. Evidence that the length of apolipoprotein B has a major effect on the buoyant density of the secreted lipoproteins. J Biol Chem. 1991 Feb 15;266(5):3300–3308. [PubMed] [Google Scholar]
  29. Young S. G., Bertics S. J., Curtiss L. K., Dubois B. W., Witztum J. L. Genetic analysis of a kindred with familial hypobetalipoproteinemia. Evidence for two separate gene defects: one associated with an abnormal apolipoprotein B species, apolipoprotein B-37; and a second associated with low plasma concentrations of apolipoprotein B-100. J Clin Invest. 1987 Jun;79(6):1842–1851. doi: 10.1172/JCI113026. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Young S. G., Bertics S. J., Curtiss L. K., Witztum J. L. Characterization of an abnormal species of apolipoprotein B, apolipoprotein B-37, associated with familial hypobetalipoproteinemia. J Clin Invest. 1987 Jun;79(6):1831–1841. doi: 10.1172/JCI113025. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Young S. G., Bertics S. J., Scott T. M., Dubois B. W., Curtiss L. K., Witztum J. L. Parallel expression of the MB19 genetic polymorphism in apoprotein B-100 and apoprotein B-48. Evidence that both apoproteins are products of the same gene. J Biol Chem. 1986 Mar 5;261(7):2995–2998. [PubMed] [Google Scholar]
  32. Young S. G., Hubl S. T. An ApaLI restriction site polymorphism is associated with the MB19 polymorphism in apolipoprotein B. J Lipid Res. 1989 Mar;30(3):443–449. [PubMed] [Google Scholar]
  33. Young S. G., Northey S. T., McCarthy B. J. Low plasma cholesterol levels caused by a short deletion in the apolipoprotein B gene. Science. 1988 Jul 29;241(4865):591–593. doi: 10.1126/science.3399894. [DOI] [PubMed] [Google Scholar]
  34. Young S. G., Peralta F. P., Dubois B. W., Curtiss L. K., Boyles J. K., Witztum J. L. Lipoprotein B37, a naturally occurring lipoprotein containing the amino-terminal portion of apolipoprotein B100, does not bind to the apolipoprotein B,E (low density lipoprotein) receptor. J Biol Chem. 1987 Dec 5;262(34):16604–16611. [PubMed] [Google Scholar]

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