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. 1987 Oct;84(20):7198–7202. doi: 10.1073/pnas.84.20.7198

DNA inversion within the apolipoproteins AI/CIII/AIV-encoding gene cluster of certain patients with premature atherosclerosis.

S K Karathanasis 1, E Ferris 1, I A Haddad 1
PMCID: PMC299257  PMID: 3118360

Abstract

The genes coding for apolipoproteins (apo) AI, CIII, and AIV, designated APOA1, APOC3, and APOA4, respectively, are closely linked and tandemly organized in the long arm of the human chromosome 11. A DNA rearrangement involving the genes encoding apoAI and apoCIII in certain patients with premature atherosclerosis has been associated with deficiency of both apoAI and apoCIII in the plasma of these patients. Structural characterization of the genes for apoAI and apoCIII in one of these patients indicates that this rearrangement consists of a DNA inversion containing portions of the 3' ends of the apoAI and apoCIII genes, including the DNA region between these genes. The breakpoints of this DNA inversion are located within the fourth exon of the apoAI gene and the first intron of the apoCIII gene. Thus, this DNA inversion results in reciprocal fusion of the apoAI and apoCIII gene transcriptional units. Expression of these gene fusions in cultured mammalian cells results in stable mRNA transcripts with sequences representing fusions of the apoAI and apoCIII mRNAs. These results indicate that absence of transcripts with correct apoAI and apoCIII mRNA sequences causes apoAI and apoCIII deficiency in the plasma of these patients and suggest that these apolipoproteins are involved in cholesterol homeostasis and protection against premature atherosclerosis.

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Selected References

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

  1. Bender W., Spierer P., Hogness D. S. Chromosomal walking and jumping to isolate DNA from the Ace and rosy loci and the bithorax complex in Drosophila melanogaster. J Mol Biol. 1983 Jul 25;168(1):17–33. doi: 10.1016/s0022-2836(83)80320-9. [DOI] [PubMed] [Google Scholar]
  2. Berk A. J., Sharp P. A. Spliced early mRNAs of simian virus 40. Proc Natl Acad Sci U S A. 1978 Mar;75(3):1274–1278. doi: 10.1073/pnas.75.3.1274. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Birnboim H. C., Doly J. A rapid alkaline extraction procedure for screening recombinant plasmid DNA. Nucleic Acids Res. 1979 Nov 24;7(6):1513–1523. doi: 10.1093/nar/7.6.1513. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Chirgwin J. M., Przybyla A. E., MacDonald R. J., Rutter W. J. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry. 1979 Nov 27;18(24):5294–5299. doi: 10.1021/bi00591a005. [DOI] [PubMed] [Google Scholar]
  5. Feinberg A. P., Vogelstein B. A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity. Anal Biochem. 1983 Jul 1;132(1):6–13. doi: 10.1016/0003-2697(83)90418-9. [DOI] [PubMed] [Google Scholar]
  6. Frischauf A. M., Lehrach H., Poustka A., Murray N. Lambda replacement vectors carrying polylinker sequences. J Mol Biol. 1983 Nov 15;170(4):827–842. doi: 10.1016/s0022-2836(83)80190-9. [DOI] [PubMed] [Google Scholar]
  7. Gluzman Y. SV40-transformed simian cells support the replication of early SV40 mutants. Cell. 1981 Jan;23(1):175–182. doi: 10.1016/0092-8674(81)90282-8. [DOI] [PubMed] [Google Scholar]
  8. Gotto A. M., Jr, Pownall H. J., Havel R. J. Introduction to the plasma lipoproteins. Methods Enzymol. 1986;128:3–41. doi: 10.1016/0076-6879(86)28061-1. [DOI] [PubMed] [Google Scholar]
  9. Graham F. L., van der Eb A. J. A new technique for the assay of infectivity of human adenovirus 5 DNA. Virology. 1973 Apr;52(2):456–467. doi: 10.1016/0042-6822(73)90341-3. [DOI] [PubMed] [Google Scholar]
  10. Haddad I. A., Ordovas J. M., Fitzpatrick T., Karathanasis S. K. Linkage, evolution, and expression of the rat apolipoprotein A-I, C-III, and A-IV genes. J Biol Chem. 1986 Oct 5;261(28):13268–13277. [PubMed] [Google Scholar]
  11. Jennings M. W., Jones R. W., Wood W. G., Weatherall D. J. Analysis of an inversion within the human beta globin gene cluster. Nucleic Acids Res. 1985 Apr 25;13(8):2897–2906. doi: 10.1093/nar/13.8.2897. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Karathanasis S. K. Apolipoprotein multigene family: tandem organization of human apolipoprotein AI, CIII, and AIV genes. Proc Natl Acad Sci U S A. 1985 Oct;82(19):6374–6378. doi: 10.1073/pnas.82.19.6374. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Karathanasis S. K., Norum R. A., Zannis V. I., Breslow J. L. An inherited polymorphism in the human apolipoprotein A-I gene locus related to the development of atherosclerosis. Nature. 1983 Feb 24;301(5902):718–720. doi: 10.1038/301718a0. [DOI] [PubMed] [Google Scholar]
  14. Karathanasis S. K., Oettgen P., Haddad I. A., Antonarakis S. E. Structure, evolution, and polymorphisms of the human apolipoprotein A4 gene (APOA4). Proc Natl Acad Sci U S A. 1986 Nov;83(22):8457–8461. doi: 10.1073/pnas.83.22.8457. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Karathanasis S. K., Zannis V. I., Breslow J. L. A DNA insertion in the apolipoprotein A-I gene of patients with premature atherosclerosis. 1983 Oct 27-Nov 2Nature. 305(5937):823–825. doi: 10.1038/305823a0. [DOI] [PubMed] [Google Scholar]
  16. Karathanasis S. K., Zannis V. I., Breslow J. L. Isolation and characterization of the human apolipoprotein A-I gene. Proc Natl Acad Sci U S A. 1983 Oct;80(20):6147–6151. doi: 10.1073/pnas.80.20.6147. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Kozak M. Point mutations define a sequence flanking the AUG initiator codon that modulates translation by eukaryotic ribosomes. Cell. 1986 Jan 31;44(2):283–292. doi: 10.1016/0092-8674(86)90762-2. [DOI] [PubMed] [Google Scholar]
  18. Lehrman M. A., Russell D. W., Goldstein J. L., Brown M. S. Exon-Alu recombination deletes 5 kilobases from the low density lipoprotein receptor gene, producing a null phenotype in familial hypercholesterolemia. Proc Natl Acad Sci U S A. 1986 Jun;83(11):3679–3683. doi: 10.1073/pnas.83.11.3679. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Lewis S., Gifford A., Baltimore D. DNA elements are asymmetrically joined during the site-specific recombination of kappa immunoglobulin genes. Science. 1985 May 10;228(4700):677–685. doi: 10.1126/science.3158075. [DOI] [PubMed] [Google Scholar]
  20. Malissen M., McCoy C., Blanc D., Trucy J., Devaux C., Schmitt-Verhulst A. M., Fitch F., Hood L., Malissen B. Direct evidence for chromosomal inversion during T-cell receptor beta-gene rearrangements. Nature. 1986 Jan 2;319(6048):28–33. doi: 10.1038/319028a0. [DOI] [PubMed] [Google Scholar]
  21. Messing J., Crea R., Seeburg P. H. A system for shotgun DNA sequencing. Nucleic Acids Res. 1981 Jan 24;9(2):309–321. doi: 10.1093/nar/9.2.309. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Miller G. J. High density lipoproteins and atherosclerosis. Annu Rev Med. 1980;31:97–108. doi: 10.1146/annurev.me.31.020180.000525. [DOI] [PubMed] [Google Scholar]
  23. Oram J. F., Albers J. J., Cheung M. C., Bierman E. L. The effects of subfractions of high density lipoprotein on cholesterol efflux from cultured fibroblasts. Regulation of low density lipoprotein receptor activity. J Biol Chem. 1981 Aug 25;256(16):8348–8356. [PubMed] [Google Scholar]
  24. Protter A. A., Levy-Wilson B., Miller J., Bencen G., White T., Seilhamer J. J. Isolation and sequence analysis of the human apolipoprotein CIII gene and the intergenic region between the apo AI and apo CIII genes. DNA. 1984 Dec;3(6):449–456. doi: 10.1089/dna.1.1984.3.449. [DOI] [PubMed] [Google Scholar]
  25. 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]
  26. Southern E. M. Detection of specific sequences among DNA fragments separated by gel electrophoresis. J Mol Biol. 1975 Nov 5;98(3):503–517. doi: 10.1016/s0022-2836(75)80083-0. [DOI] [PubMed] [Google Scholar]
  27. Subbaiah P. V., Albers J. J., Chen C. H., Bagdade J. D. Low density lipoprotein-activated lysolecithin acylation by human plasma lecithin-cholesterol acyltransferase. Identity of lysolecithin acyltransferase and lecithin-cholesterol acyltransferase. J Biol Chem. 1980 Oct 10;255(19):9275–9280. [PubMed] [Google Scholar]
  28. Thomas P. S. Hybridization of denatured RNA and small DNA fragments transferred to nitrocellulose. Proc Natl Acad Sci U S A. 1980 Sep;77(9):5201–5205. doi: 10.1073/pnas.77.9.5201. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Treisman R., Orkin S. H., Maniatis T. Specific transcription and RNA splicing defects in five cloned beta-thalassaemia genes. Nature. 1983 Apr 14;302(5909):591–596. doi: 10.1038/302591a0. [DOI] [PubMed] [Google Scholar]
  30. Vieira J., Messing J. The pUC plasmids, an M13mp7-derived system for insertion mutagenesis and sequencing with synthetic universal primers. Gene. 1982 Oct;19(3):259–268. doi: 10.1016/0378-1119(82)90015-4. [DOI] [PubMed] [Google Scholar]
  31. Walker M. D., Edlund T., Boulet A. M., Rutter W. J. Cell-specific expression controlled by the 5'-flanking region of insulin and chymotrypsin genes. Nature. 1983 Dec 8;306(5943):557–561. doi: 10.1038/306557a0. [DOI] [PubMed] [Google Scholar]
  32. Wieringa B., Hofer E., Weissmann C. A minimal intron length but no specific internal sequence is required for splicing the large rabbit beta-globin intron. Cell. 1984 Jul;37(3):915–925. doi: 10.1016/0092-8674(84)90426-4. [DOI] [PubMed] [Google Scholar]

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