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. 1992 Oct 11;20(19):4975–4979. doi: 10.1093/nar/20.19.4975

Insertion of the B2 sequence into intron 13 is the only defect of the H-2k C4 gene which causes low C4 production.

J H Zheng 1, S Natsuume-Sakai 1, M Takahashi 1, M Nonaka 1
PMCID: PMC334272  PMID: 1329034

Abstract

The serum level of the fourth component of complement (C4) in mice bearing H-2k haplotype is only 1/10 of that of non-H-2k mice. H-2k bearing mice, but not non-H-2k bearing mice, have an insertion of the B2 sequence into intron 13 of the C4 gene, and aberrant C4 mRNA in liver apparently generated by abnormal RNA splicing caused by the insertion of the B2 sequence. To test the possible causal relationship between the B2 insertion and low C4 production in H-2k mice directly, we constructed the H-2k C4 gene without the B2 insertion and the H-2w7 (non-H-2k) C4 gene with the B2 insertion by exchanging a part of intron 13 between these two genes. Transfection of the intact H-2w7 C4 gene or the chimeric H-2k gene without the B2 insertion into HepG2 cells resulted in the production of only normal C4 mRNA at the normal level. On the other hand, the intact H-2k C4 gene or the chimeric H-2w7 C4 gene with the B2 insertion directed production of both aberrant and a decreased amount of normal C4 mRNA. These results demonstrated that the insertion of B2 sequence into intron 13 of the C4 gene is the only determinant of low C4 production by H-2k mice through aberrant RNA processing.

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Selected References

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

  1. Berkvens T. M., van Ormondt H., Gerritsen E. J., Khan P. M., van der Eb A. J. Identical 3250-bp deletion between two AluI repeats in the ADA genes of unrelated ADA-SCID patients. Genomics. 1990 Aug;7(4):486–490. doi: 10.1016/0888-7543(90)90190-6. [DOI] [PubMed] [Google Scholar]
  2. Chaplin D. D., Woods D. E., Whitehead A. S., Goldberger G., Colten H. R., Seidman J. G. Molecular map of the murine S region. Proc Natl Acad Sci U S A. 1983 Nov;80(22):6947–6951. doi: 10.1073/pnas.80.22.6947. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. 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]
  4. 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]
  5. Green S., Issemann I., Sheer E. A versatile in vivo and in vitro eukaryotic expression vector for protein engineering. Nucleic Acids Res. 1988 Jan 11;16(1):369–369. doi: 10.1093/nar/16.1.369. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Huang Z. M., Takahashi M., Nonaka M. Differential expression of the five C4-related genes of H-2w7 mice. Immunogenetics. 1991;33(5-6):361–366. doi: 10.1007/BF00216695. [DOI] [PubMed] [Google Scholar]
  7. Lehrman M. A., Goldstein J. L., Russell D. W., Brown M. S. Duplication of seven exons in LDL receptor gene caused by Alu-Alu recombination in a subject with familial hypercholesterolemia. Cell. 1987 Mar 13;48(5):827–835. doi: 10.1016/0092-8674(87)90079-1. [DOI] [PubMed] [Google Scholar]
  8. Markert M. L., Hutton J. J., Wiginton D. A., States J. C., Kaufman R. E. Adenosine deaminase (ADA) deficiency due to deletion of the ADA gene promoter and first exon by homologous recombination between two Alu elements. J Clin Invest. 1988 May;81(5):1323–1327. doi: 10.1172/JCI113458. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Nakayama K., Nonaka M., Yokoyama S., Yeul Y. D., Pattanakitsakul S. N., Takahashi M. Recombination of two homologous MHC class III genes of the mouse (C4 and Slp) that accounts for the loss of testosterone dependence of sex-limited protein expression. J Immunol. 1987 Jan 15;138(2):620–627. [PubMed] [Google Scholar]
  10. Nakayama K., Pattanakitsakul S., Yokoyama S., Kimura H., Nonaka M., Takahashi M. Post-transcriptional regulation of complement C4 in low C4-producing strain of mouse. Immunogenetics. 1990;31(5-6):361–367. doi: 10.1007/BF02115011. [DOI] [PubMed] [Google Scholar]
  11. Nonaka M., Kimura H., Yeul Y. D., Yokoyama S., Nakayama K., Takahashi M. Identification of the 5'-flanking regulatory region responsible for the difference in transcriptional control between mouse complement C4 and Slp genes. Proc Natl Acad Sci U S A. 1986 Oct;83(20):7883–7887. doi: 10.1073/pnas.83.20.7883. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Nonaka M., Nakayama K., Yeul Y. D., Takahashi M. Complete nucleotide and derived amino acid sequences of sex-limited protein (Slp), nonfunctional isotype of the fourth component of mouse complement (C4). J Immunol. 1986 Apr 15;136(8):2989–2993. [PubMed] [Google Scholar]
  13. Nonaka M., Nakayama K., Yeul Y. D., Takahashi M. Complete nucleotide and derived amino acid sequences of the fourth component of mouse complement (C4). Evolutionary aspects. J Biol Chem. 1985 Sep 15;260(20):10936–10943. [PubMed] [Google Scholar]
  14. Ogata R. T., Sepich D. S. Genes for murine fourth complement component (C4) and sex-limited protein (Slp) identified by hybridization to C4- and Slp-specific cDNA. Proc Natl Acad Sci U S A. 1984 Aug;81(15):4908–4911. doi: 10.1073/pnas.81.15.4908. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Ogata R. T., Sepich D. S. Murine sex-limited protein: complete cDNA sequence and comparison with murine fourth complement component. J Immunol. 1985 Dec;135(6):4239–4244. [PubMed] [Google Scholar]
  16. Pattanakitsakul S., Zheng J. H., Natsuume-Sakai S., Takahashi M., Nonaka M. Aberrant splicing caused by the insertion of the B2 sequence into an intron of the complement C4 gene is the basis for low C4 production in H-2k mice. J Biol Chem. 1992 Apr 15;267(11):7814–7820. [PubMed] [Google Scholar]
  17. Rogers J. H. The origin and evolution of retroposons. Int Rev Cytol. 1985;93:187–279. doi: 10.1016/s0074-7696(08)61375-3. [DOI] [PubMed] [Google Scholar]
  18. Rosa P. A., Sepich D. S., Robins D. M., Ogata R. T. Constitutive expression of Slp genes in mouse strain B10.WR directed by C4 regulatory sequences. J Immunol. 1987 Sep 1;139(5):1568–1577. [PubMed] [Google Scholar]
  19. Rosa P. A., Shreffler D. C. Cultured hepatocytes from mouse strains expressing high and low levels of the fourth component of complement differ in rate of synthesis of the protein. Proc Natl Acad Sci U S A. 1983 Apr;80(8):2332–2336. doi: 10.1073/pnas.80.8.2332. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Sackstein R., Colten H. R. Molecular regulation of MHC class III (C4 and factor B) gene expression in mouse peritoneal macrophages. J Immunol. 1984 Sep;133(3):1618–1626. [PubMed] [Google Scholar]
  21. 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]
  22. Sepich D. S., Noonan D. J., Ogata R. T. Complete cDNA sequence of the fourth component of murine complement. Proc Natl Acad Sci U S A. 1985 Sep;82(17):5895–5899. doi: 10.1073/pnas.82.17.5895. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Stavenhagen J., Loreni F., Hemenway C., Kalff M., Robins D. M. Molecular genetics of androgen-dependent and -independent expression of mouse sex-limited protein. Mol Cell Biol. 1987 May;7(5):1716–1724. doi: 10.1128/mcb.7.5.1716. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Wallace M. R., Andersen L. B., Saulino A. M., Gregory P. E., Glover T. W., Collins F. S. A de novo Alu insertion results in neurofibromatosis type 1. Nature. 1991 Oct 31;353(6347):864–866. doi: 10.1038/353864a0. [DOI] [PubMed] [Google Scholar]
  25. Yu D. Y., Huang Z. M., Murakami S., Takahashi M., Nonaka M. Specific binding of a hepatoma nuclear factor to the NF.kappa B/H2TF1 recognition motif found in the C4 promoter, but not in the Slp promoter. J Immunol. 1989 Oct 1;143(7):2395–2400. [PubMed] [Google Scholar]
  26. Yu D. Y., Nonaka M., Takahashi M. Mapping of the transcriptional regulatory domains responsible for the difference in the promoter activity between mouse C4 and Slp (sex-limited protein) genes. J Immunol. 1988 Dec 15;141(12):4381–4387. [PubMed] [Google Scholar]

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