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American Journal of Human Genetics logoLink to American Journal of Human Genetics
. 1993 Feb;52(2):343–353.

Physical mapping of four serpin genes: alpha 1-antitrypsin, alpha 1-antichymotrypsin, corticosteroid-binding globulin, and protein C inhibitor, within a 280-kb region on chromosome I4q32.1.

G D Billingsley 1, M A Walter 1, G L Hammond 1, D W Cox 1
PMCID: PMC1682208  PMID: 8381582

Abstract

Alpha 1-antitrypsin (alpha 1AT; protease inhibitor [PI] locus), alpha 1-antichymotrypsin (alpha 1ACT; AACT locus), corticosteroid-binding globulin (CBG; CBG locus), and protein C inhibitor (PCI; PCI locus) are members of the serine protease inhibitor (serpin) superfamily. A noncoding PI-like (PIL) gene has been located 12 kb 3' of the PI gene. The PI, PIL, and AACT loci have been localized to 14q32.1, the CBG locus has been localized to 14q31-14q32.1, and PCI has been mapped to chromosome 14. Genetic linkage analysis suggests tight linkage between PI and AACT. We have used pulsed-field gel electrophoresis to generate a physical map linking these five serpin genes. The order of the genetic loci is AACT/PCI-PI-PIL-CBG, with a maximum distance of about 220 kb between the AACT/PCI and PI genes. These genes form a PI cluster at 14q32.1, similar to that of the homologous genes on murine chromosome l2. The close proximity of these genes has implications for disease-association studies.

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Selected References

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  1. Bao J. J., Reed-Fourquet L., Sifers R. N., Kidd V. J., Woo S. L. Molecular structure and sequence homology of a gene related to alpha 1-antitrypsin in the human genome. Genomics. 1988 Feb;2(2):165–173. doi: 10.1016/0888-7543(88)90099-7. [DOI] [PubMed] [Google Scholar]
  2. Borriello F., Krauter K. S. Multiple murine alpha 1-protease inhibitor genes show unusual evolutionary divergence. Proc Natl Acad Sci U S A. 1991 Nov 1;88(21):9417–9421. doi: 10.1073/pnas.88.21.9417. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Chandra T., Stackhouse R., Kidd V. J., Robson K. J., Woo S. L. Sequence homology between human alpha 1-antichymotrypsin, alpha 1-antitrypsin, and antithrombin III. Biochemistry. 1983 Oct 25;22(22):5055–5061. doi: 10.1021/bi00291a001. [DOI] [PubMed] [Google Scholar]
  4. Church G. M., Gilbert W. Genomic sequencing. Proc Natl Acad Sci U S A. 1984 Apr;81(7):1991–1995. doi: 10.1073/pnas.81.7.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Cox D. W., Billingsley G. D., Mansfield T. DNA restriction-site polymorphisms associated with the alpha 1-antitrypsin gene. Am J Hum Genet. 1987 Nov;41(5):891–906. [PMC free article] [PubMed] [Google Scholar]
  6. Cox D. W., Mansfield T. Prenatal diagnosis for alpha 1-antitrypsin deficiency. Lancet. 1985 Jan 26;1(8422):230–230. doi: 10.1016/s0140-6736(85)92078-1. [DOI] [PubMed] [Google Scholar]
  7. 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]
  8. Hammond G. L. Molecular properties of corticosteroid binding globulin and the sex-steroid binding proteins. Endocr Rev. 1990 Feb;11(1):65–79. doi: 10.1210/edrv-11-1-65. [DOI] [PubMed] [Google Scholar]
  9. Hammond G. L., Smith C. L., Goping I. S., Underhill D. A., Harley M. J., Reventos J., Musto N. A., Gunsalus G. L., Bardin C. W. Primary structure of human corticosteroid binding globulin, deduced from hepatic and pulmonary cDNAs, exhibits homology with serine protease inhibitors. Proc Natl Acad Sci U S A. 1987 Aug;84(15):5153–5157. doi: 10.1073/pnas.84.15.5153. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Hammond G. L., Smith C. L., Paterson N. A., Sibbald W. J. A role for corticosteroid-binding globulin in delivery of cortisol to activated neutrophils. J Clin Endocrinol Metab. 1990 Jul;71(1):34–39. doi: 10.1210/jcem-71-1-34. [DOI] [PubMed] [Google Scholar]
  11. Heeb M. J., España F., Geiger M., Collen D., Stump D. C., Griffin J. H. Immunological identity of heparin-dependent plasma and urinary protein C inhibitor and plasminogen activator inhibitor-3. J Biol Chem. 1987 Nov 25;262(33):15813–15816. [PubMed] [Google Scholar]
  12. Heeb M. J., Griffin J. H. Physiologic inhibition of human activated protein C by alpha 1-antitrypsin. J Biol Chem. 1988 Aug 25;263(24):11613–11616. [PubMed] [Google Scholar]
  13. Hill R. E., Shaw P. H., Barth R. K., Hastie N. D. A genetic locus closely linked to a protease inhibitor gene complex controls the level of multiple RNA transcripts. Mol Cell Biol. 1985 Aug;5(8):2114–2122. doi: 10.1128/mcb.5.8.2114. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Hill R. E., Shaw P. H., Boyd P. A., Baumann H., Hastie N. D. Plasma protease inhibitors in mouse and man: divergence within the reactive centre regions. Nature. 1984 Sep 13;311(5982):175–177. doi: 10.1038/311175a0. [DOI] [PubMed] [Google Scholar]
  15. Hodgson I., Kalsheker N. RFLP for a gene-related sequence of alpha 1-antitrypsin (AAT). Nucleic Acids Res. 1986 Aug 26;14(16):6779–6779. doi: 10.1093/nar/14.16.6779. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Hofker M. H., Nelen M., Klasen E. C., Nukiwa T., Curiel D., Crystal R. G., Frants R. R. Cloning and characterization of an alpha 1-antitrypsin like gene 12 KB downstream of the genuine alpha 1-antitrypsin gene. Biochem Biophys Res Commun. 1988 Sep 15;155(2):634–642. doi: 10.1016/s0006-291x(88)80542-4. [DOI] [PubMed] [Google Scholar]
  17. Hofker M. H., van Ommen G. J., Bakker E., Burmeister M., Pearson P. L. Development of additional RFLP probes near the locus for Duchenne muscular dystrophy by cosmid cloning of the DXS84 (754) locus. Hum Genet. 1986 Nov;74(3):270–274. doi: 10.1007/BF00282547. [DOI] [PubMed] [Google Scholar]
  18. Inglis J. D., Hill R. E. The murine Spi-2 proteinase inhibitor locus: a multigene family with a hypervariable reactive site domain. EMBO J. 1991 Feb;10(2):255–261. doi: 10.1002/j.1460-2075.1991.tb07945.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Inglis J. D., Lee M., Davidson D. R., Hill R. E. Isolation of two cDNAs encoding novel alpha 1-antichymotrypsin-like proteins in a murine chondrocytic cell line. Gene. 1991 Oct 15;106(2):213–220. doi: 10.1016/0378-1119(91)90201-l. [DOI] [PubMed] [Google Scholar]
  20. Kelsey G. D., Abeliovich D., McMahon C. J., Whitehouse D., Corney G., Povey S., Hopkinson D. A., Wolfe J., Mieli-Vergani G., Mowat A. P. Cloning of the human alpha 1 antichymotrypsin gene and genetic analysis of the gene in relation to alpha 1 antitrypsin deficiency. J Med Genet. 1988 Jun;25(6):361–368. doi: 10.1136/jmg.25.6.361. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Kelsey G. D., Parkar M., Povey S. The human alpha-1-antitrypsin-related sequence gene: isolation and investigation of its expression. Ann Hum Genet. 1988 May;52(Pt 2):151–160. doi: 10.1111/j.1469-1809.1988.tb01091.x. [DOI] [PubMed] [Google Scholar]
  22. Lai E. C., Kao F. T., Law M. L., Woo S. L. Assignment of the alpha 1-antitrypsin gene and a sequence-related gene to human chromosome 14 by molecular hybridization. Am J Hum Genet. 1983 May;35(3):385–392. [PMC free article] [PubMed] [Google Scholar]
  23. Leicht M., Long G. L., Chandra T., Kurachi K., Kidd V. J., Mace M., Jr, Davie E. W., Woo S. L. Sequence homology and structural comparison between the chromosomal human alpha 1-antitrypsin and chicken ovalbumin genes. Nature. 1982 Jun 24;297(5868):655–659. doi: 10.1038/297655a0. [DOI] [PubMed] [Google Scholar]
  24. Long G. L., Chandra T., Woo S. L., Davie E. W., Kurachi K. Complete sequence of the cDNA for human alpha 1-antitrypsin and the gene for the S variant. Biochemistry. 1984 Oct 9;23(21):4828–4837. doi: 10.1021/bi00316a003. [DOI] [PubMed] [Google Scholar]
  25. Meijers J. C., Chung D. W. Organization of the gene coding for human protein C inhibitor (plasminogen activator inhibitor-3). Assignment of the gene to chromosome 14. J Biol Chem. 1991 Aug 15;266(23):15028–15034. [PubMed] [Google Scholar]
  26. Patterson S. D., Bell K., Shaw D. C. The equine major plasma serpin multigene family: partial characterization including sequence of the reactive-site regions. Biochem Genet. 1991 Oct;29(9-10):477–499. doi: 10.1007/BF02399689. [DOI] [PubMed] [Google Scholar]
  27. Pemberton P. A., Stein P. E., Pepys M. B., Potter J. M., Carrell R. W. Hormone binding globulins undergo serpin conformational change in inflammation. Nature. 1988 Nov 17;336(6196):257–258. doi: 10.1038/336257a0. [DOI] [PubMed] [Google Scholar]
  28. Prochownik E. V., Bock S. C., Orkin S. H. Intron structure of the human antithrombin III gene differs from that of other members of the serine protease inhibitor superfamily. J Biol Chem. 1985 Aug 15;260(17):9608–9612. [PubMed] [Google Scholar]
  29. Purrello M., Alhadeff B., Whittington E., Buckton K. E., Daniel A., Arnaud P., Rocchi M., Archidiacono N., Filippi G., Siniscalco M. Comparison of cytologic and genetic distances between long arm subtelomeric markers of human autosome 14 suggests uneven distribution of crossing-over. Cytogenet Cell Genet. 1987;44(1):32–40. doi: 10.1159/000132337. [DOI] [PubMed] [Google Scholar]
  30. Rabin M., Watson M., Kidd V., Woo S. L., Breg W. R., Ruddle F. H. Regional location of alpha 1-antichymotrypsin and alpha 1-antitrypsin genes on human chromosome 14. Somat Cell Mol Genet. 1986 Mar;12(2):209–214. doi: 10.1007/BF01560668. [DOI] [PubMed] [Google Scholar]
  31. Sefton L., Kelsey G., Kearney P., Povey S., Wolfe J. A physical map of the human PI and AACT genes. Genomics. 1990 Jul;7(3):382–388. doi: 10.1016/0888-7543(90)90172-q. [DOI] [PubMed] [Google Scholar]
  32. Seralini G. E., Bérubé D., Gagné R., Hammond G. L. The human corticosteroid binding globulin gene is located on chromosome 14q31-q32.1 near two other serine protease inhibitor genes. Hum Genet. 1990 Nov;86(1):73–75. doi: 10.1007/BF00205177. [DOI] [PubMed] [Google Scholar]
  33. Siiteri P. K., Murai J. T., Hammond G. L., Nisker J. A., Raymoure W. J., Kuhn R. W. The serum transport of steroid hormones. Recent Prog Horm Res. 1982;38:457–510. doi: 10.1016/b978-0-12-571138-8.50016-0. [DOI] [PubMed] [Google Scholar]
  34. Stief T. W., Radtke K. P., Heimburger N. Inhibition of urokinase by protein C-inhibitor (PCI). Evidence for identity of PCI and plasminogen activator inhibitor 3. Biol Chem Hoppe Seyler. 1987 Oct;368(10):1427–1433. doi: 10.1515/bchm3.1987.368.2.1427. [DOI] [PubMed] [Google Scholar]
  35. Suzuki K., Deyashiki Y., Nishioka J., Kurachi K., Akira M., Yamamoto S., Hashimoto S. Characterization of a cDNA for human protein C inhibitor. A new member of the plasma serine protease inhibitor superfamily. J Biol Chem. 1987 Jan 15;262(2):611–616. [PubMed] [Google Scholar]
  36. Travis J., Salvesen G. S. Human plasma proteinase inhibitors. Annu Rev Biochem. 1983;52:655–709. doi: 10.1146/annurev.bi.52.070183.003255. [DOI] [PubMed] [Google Scholar]
  37. Underhill D. A., Hammond G. L. Organization of the human corticosteroid binding globulin gene and analysis of its 5'-flanking region. Mol Endocrinol. 1989 Sep;3(9):1448–1454. doi: 10.1210/mend-3-9-1448. [DOI] [PubMed] [Google Scholar]
  38. Walter M. A., Cox D. W. A method for two-dimensional DNA electrophoresis (2D-DE): application to the immunoglobulin heavy chain variable region. Genomics. 1989 Jul;5(1):157–159. doi: 10.1016/0888-7543(89)90102-x. [DOI] [PubMed] [Google Scholar]

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