Skip to main content
PMC home page
American Journal of Human Genetics logoLink to American Journal of Human Genetics
. 1992 Apr;50(4):766–780.

Evolutionary origin of mutations in the primate cytochrome P450c21 gene.

H Kawaguchi 1, C O'hUigin 1, J Klein 1
PMCID: PMC1682642  PMID: 1550121

Abstract

The CYP21 gene codes for the enzyme cytochrome P450c21 (21-hydroxylase), which is critically involved in the synthesis of glucocorticoids and mineralocorticoids. Standard human haplotypes contain two copies of CYP21--a functional gene and a pseudogene. Inactivation of the functional gene leads to congenital adrenal hyperplasia (CAH). The pseudogene has three main defects: an 8-bp deletion in exon 3, a T insertion in exon 7, and a stop codon in exon 8. To determine the origin of these defects and to shed light on the evolution of the CYP21 gene, we sequenced relevant segments of 10 primate CYP21 genes--three from a chimpanzee, another three from a gorilla, and four from an orangutan. We could show that the 8-bp deletion is present in the chimpanzee and humans, while the other two defects are restricted to humans only. In the gorilla and the orangutan, however, extra CYP21 copies are inactivated by other defects so that the number of functional copies is reduced in each species. Comparison of the sequences has revealed evidence for intraspecific homogenization (concerted evolution) of the CYP21 genes, presumably through an expansion-contraction process effected by relatively frequent unequal but homologous crossing-over.

Full text

PDF
767

Selected References

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

  1. Amor M., Parker K. L., Globerman H., New M. I., White P. C. Mutation in the CYP21B gene (Ile-172----Asn) causes steroid 21-hydroxylase deficiency. Proc Natl Acad Sci U S A. 1988 Mar;85(5):1600–1604. doi: 10.1073/pnas.85.5.1600. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Carroll M. C., Campbell R. D., Porter R. R. Mapping of steroid 21-hydroxylase genes adjacent to complement component C4 genes in HLA, the major histocompatibility complex in man. Proc Natl Acad Sci U S A. 1985 Jan;82(2):521–525. doi: 10.1073/pnas.82.2.521. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Carroll M. C., Palsdottir A., Belt K. T., Porter R. R. Deletion of complement C4 and steroid 21-hydroxylase genes in the HLA class III region. EMBO J. 1985 Oct;4(10):2547–2552. doi: 10.1002/j.1460-2075.1985.tb03969.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Chaplin D. D., Galbraith L. J., Seidman J. G., White P. C., Parker K. L. Nucleotide sequence analysis of murine 21-hydroxylase genes: mutations affecting gene expression. Proc Natl Acad Sci U S A. 1986 Dec;83(24):9601–9605. doi: 10.1073/pnas.83.24.9601. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Chiou S. H., Hu M. C., Chung B. C. A missense mutation at Ile172----Asn or Arg356----Trp causes steroid 21-hydroxylase deficiency. J Biol Chem. 1990 Feb 25;265(6):3549–3552. [PubMed] [Google Scholar]
  6. Collier S., Sinnott P. J., Dyer P. A., Price D. A., Harris R., Strachan T. Pulsed field gel electrophoresis identifies a high degree of variability in the number of tandem 21-hydroxylase and complement C4 gene repeats in 21-hydroxylase deficiency haplotypes. EMBO J. 1989 May;8(5):1393–1402. doi: 10.1002/j.1460-2075.1989.tb03520.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Conner B. J., Reyes A. A., Morin C., Itakura K., Teplitz R. L., Wallace R. B. Detection of sickle cell beta S-globin allele by hybridization with synthetic oligonucleotides. Proc Natl Acad Sci U S A. 1983 Jan;80(1):278–282. doi: 10.1073/pnas.80.1.278. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Donohoue P. A., Jospe N., Migeon C. J., Van Dop C. Two distinct areas of unequal crossingover within the steroid 21-hydroxylase genes produce absence of CYP21B. Genomics. 1989 Oct;5(3):397–406. doi: 10.1016/0888-7543(89)90002-5. [DOI] [PubMed] [Google Scholar]
  9. Donohoue P. A., van Dop C., McLean R. H., White P. C., Jospe N., Migeon C. J. Gene conversion in salt-losing congenital adrenal hyperplasia with absent complement C4B protein. J Clin Endocrinol Metab. 1986 May;62(5):995–1002. doi: 10.1210/jcem-62-5-995. [DOI] [PubMed] [Google Scholar]
  10. Dunham I., Sargent C. A., Trowsdale J., Campbell R. D. Molecular mapping of the human major histocompatibility complex by pulsed-field gel electrophoresis. Proc Natl Acad Sci U S A. 1987 Oct;84(20):7237–7241. doi: 10.1073/pnas.84.20.7237. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Dupont B., Oberfield S. E., Smithwick E. M., Lee T. D., Levine L. S. Close genetic linkage between HLA and congenital adrenal hyperplasia (21-hydroxylase deficiency). Lancet. 1977 Dec 24;2(8052-8053):1309–1312. doi: 10.1016/s0140-6736(77)90362-2. [DOI] [PubMed] [Google Scholar]
  12. Felsenstein J. Phylogenies from molecular sequences: inference and reliability. Annu Rev Genet. 1988;22:521–565. doi: 10.1146/annurev.ge.22.120188.002513. [DOI] [PubMed] [Google Scholar]
  13. Globerman H., Amor M., Parker K. L., New M. I., White P. C. Nonsense mutation causing steroid 21-hydroxylase deficiency. J Clin Invest. 1988 Jul;82(1):139–144. doi: 10.1172/JCI113562. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Harada F., Kimura A., Iwanaga T., Shimozawa K., Yata J., Sasazuki T. Gene conversion-like events cause steroid 21-hydroxylase deficiency in congenital adrenal hyperplasia. Proc Natl Acad Sci U S A. 1987 Nov;84(22):8091–8094. doi: 10.1073/pnas.84.22.8091. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Higashi Y., Hiromasa T., Tanae A., Miki T., Nakura J., Kondo T., Ohura T., Ogawa E., Nakayama K., Fujii-Kuriyama Y. Effects of individual mutations in the P-450(C21) pseudogene on the P-450(C21) activity and their distribution in the patient genomes of congenital steroid 21-hydroxylase deficiency. J Biochem. 1991 Apr;109(4):638–644. doi: 10.1093/oxfordjournals.jbchem.a123433. [DOI] [PubMed] [Google Scholar]
  16. Higashi Y., Tanae A., Inoue H., Fujii-Kuriyama Y. Evidence for frequent gene conversion in the steroid 21-hydroxylase P-450(C21) gene: implications for steroid 21-hydroxylase deficiency. Am J Hum Genet. 1988 Jan;42(1):17–25. [PMC free article] [PubMed] [Google Scholar]
  17. Higashi Y., Tanae A., Inoue H., Hiromasa T., Fujii-Kuriyama Y. Aberrant splicing and missense mutations cause steroid 21-hydroxylase [P-450(C21)] deficiency in humans: possible gene conversion products. Proc Natl Acad Sci U S A. 1988 Oct;85(20):7486–7490. doi: 10.1073/pnas.85.20.7486. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Higashi Y., Yoshioka H., Yamane M., Gotoh O., Fujii-Kuriyama Y. Complete nucleotide sequence of two steroid 21-hydroxylase genes tandemly arranged in human chromosome: a pseudogene and a genuine gene. Proc Natl Acad Sci U S A. 1986 May;83(9):2841–2845. doi: 10.1073/pnas.83.9.2841. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Jospe N., Donohoue P. A., Van Dop C., McLean R. H., Bias W. B., Migeon C. J. Prevalence of polymorphic 21-hydroxylase gene (CA21HB) mutations in salt-losing congenital adrenal hyperplasia. Biochem Biophys Res Commun. 1987 Feb 13;142(3):798–804. doi: 10.1016/0006-291x(87)91484-7. [DOI] [PubMed] [Google Scholar]
  20. Kawaguchi H., Golubic M., Figueroa F., Klein J. Organization of the chimpanzee C4-CYP21 region: implications for the evolution of human genes. Eur J Immunol. 1990 Apr;20(4):739–745. doi: 10.1002/eji.1830200405. [DOI] [PubMed] [Google Scholar]
  21. Kimura M. A simple method for estimating evolutionary rates of base substitutions through comparative studies of nucleotide sequences. J Mol Evol. 1980 Dec;16(2):111–120. doi: 10.1007/BF01731581. [DOI] [PubMed] [Google Scholar]
  22. Klein J., Bontrop R. E., Dawkins R. L., Erlich H. A., Gyllensten U. B., Heise E. R., Jones P. P., Parham P., Wakeland E. K., Watkins D. I. Nomenclature for the major histocompatibility complexes of different species: a proposal. Immunogenetics. 1990;31(4):217–219. doi: 10.1007/BF00204890. [DOI] [PubMed] [Google Scholar]
  23. Levine L. S., Zachmann M., New M. I., Prader A., Pollack M. S., O'Neill G. J., Yang S. Y., Oberfield S. E., Dupont B. Genetic mapping of the 21-hydroxylase-deficiency gene within the HLA linkage group. N Engl J Med. 1978 Oct 26;299(17):911–915. doi: 10.1056/NEJM197810262991702. [DOI] [PubMed] [Google Scholar]
  24. Li W. H., Wu C. I., Luo C. C. A new method for estimating synonymous and nonsynonymous rates of nucleotide substitution considering the relative likelihood of nucleotide and codon changes. Mol Biol Evol. 1985 Mar;2(2):150–174. doi: 10.1093/oxfordjournals.molbev.a040343. [DOI] [PubMed] [Google Scholar]
  25. Matteson K. J., Phillips J. A., 3rd, Miller W. L., Chung B. C., Orlando P. J., Frisch H., Ferrandez A., Burr I. M. P450XXI (steroid 21-hydroxylase) gene deletions are not found in family studies of congenital adrenal hyperplasia. Proc Natl Acad Sci U S A. 1987 Aug;84(16):5858–5862. doi: 10.1073/pnas.84.16.5858. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Mayer W. E., Jonker M., Klein D., Ivanyi P., van Seventer G., Klein J. Nucleotide sequences of chimpanzee MHC class I alleles: evidence for trans-species mode of evolution. EMBO J. 1988 Sep;7(9):2765–2774. doi: 10.1002/j.1460-2075.1988.tb03131.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. McAlpine P. J., Stranc L. C., Boucheix C., Shows T. B. The 1990 catalog of mapped genes and report of the nomenclature committee. Cytogenet Cell Genet. 1990;55(1-4):5–76. doi: 10.1159/000132995. [DOI] [PubMed] [Google Scholar]
  28. Miller W. L. Molecular biology of steroid hormone synthesis. Endocr Rev. 1988 Aug;9(3):295–318. doi: 10.1210/edrv-9-3-295. [DOI] [PubMed] [Google Scholar]
  29. Morel Y., André J., Uring-Lambert B., Hauptmann G., Bétuel H., Tossi M., Forest M. G., David M., Bertrand J., Miller W. L. Rearrangements and point mutations of P450c21 genes are distinguished by five restriction endonuclease haplotypes identified by a new probing strategy in 57 families with congenital adrenal hyperplasia. J Clin Invest. 1989 Feb;83(2):527–536. doi: 10.1172/JCI113914. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Mornet E., Crété P., Kuttenn F., Raux-Demay M. C., Boué J., White P. C., Boué A. Distribution of deletions and seven point mutations on CYP21B genes in three clinical forms of steroid 21-hydroxylase deficiency. Am J Hum Genet. 1991 Jan;48(1):79–88. [PMC free article] [PubMed] [Google Scholar]
  31. New M. I., Levine L. S. Recent advances in 21-hydroxylase deficiency. Annu Rev Med. 1984;35:649–663. doi: 10.1146/annurev.me.35.020184.003245. [DOI] [PubMed] [Google Scholar]
  32. Rasheed S., Rongey R. W., Bruszweski J., Nelson-Rees W. A., Rabin H., Neubauer R. H., Esra G., Gardner M. B. Establishment of a cell line with associated Epstein-Barr-like virus from a leukemic orangutan. Science. 1977 Oct 28;198(4315):407–409. doi: 10.1126/science.198878. [DOI] [PubMed] [Google Scholar]
  33. Raum D., Awdeh Z., Anderson J., Strong L., Granados J., Teran L., Giblett E., Yunis E. J., Alper C. A. Human C4 haplotypes with duplicated C4A or C4B. Am J Hum Genet. 1984 Jan;36(1):72–79. [PMC free article] [PubMed] [Google Scholar]
  34. Rodrigues N. R., Dunham I., Yu C. Y., Carroll M. C., Porter R. R., Campbell R. D. Molecular characterization of the HLA-linked steroid 21-hydroxylase B gene from an individual with congenital adrenal hyperplasia. EMBO J. 1987 Jun;6(6):1653–1661. doi: 10.1002/j.1460-2075.1987.tb02414.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Saitou N., Nei M. The neighbor-joining method: a new method for reconstructing phylogenetic trees. Mol Biol Evol. 1987 Jul;4(4):406–425. doi: 10.1093/oxfordjournals.molbev.a040454. [DOI] [PubMed] [Google Scholar]
  36. 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]
  37. Sinnott P., Collier S., Costigan C., Dyer P. A., Harris R., Strachan T. Genesis by meiotic unequal crossover of a de novo deletion that contributes to steroid 21-hydroxylase deficiency. Proc Natl Acad Sci U S A. 1990 Mar;87(6):2107–2111. doi: 10.1073/pnas.87.6.2107. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Speiser P. W., Dupont B., Rubinstein P., Piazza A., Kastelan A., New M. I. High frequency of nonclassical steroid 21-hydroxylase deficiency. Am J Hum Genet. 1985 Jul;37(4):650–667. [PMC free article] [PubMed] [Google Scholar]
  39. Speiser P. W., New M. I., White P. C. Molecular genetic analysis of nonclassic steroid 21-hydroxylase deficiency associated with HLA-B14,DR1. N Engl J Med. 1988 Jul 7;319(1):19–23. doi: 10.1056/NEJM198807073190104. [DOI] [PubMed] [Google Scholar]
  40. Tusie-Luna M. T., Speiser P. W., Dumic M., New M. I., White P. C. A mutation (Pro-30 to Leu) in CYP21 represents a potential nonclassic steroid 21-hydroxylase deficiency allele. Mol Endocrinol. 1991 May;5(5):685–692. doi: 10.1210/mend-5-5-685. [DOI] [PubMed] [Google Scholar]
  41. Tusie-Luna M. T., Traktman P., White P. C. Determination of functional effects of mutations in the steroid 21-hydroxylase gene (CYP21) using recombinant vaccinia virus. J Biol Chem. 1990 Dec 5;265(34):20916–20922. [PubMed] [Google Scholar]
  42. Urabe K., Kimura A., Harada F., Iwanaga T., Sasazuki T. Gene conversion in steroid 21-hydroxylase genes. Am J Hum Genet. 1990 Jun;46(6):1178–1186. [PMC free article] [PubMed] [Google Scholar]
  43. Wallace A. M., Beastall G. H., Cook B., Currie A. J., Ross A. M., Kennedy R., Girdwood R. W. Neonatal screening for congenital adrenal hyperplasia: a programme based on a novel direct radioimmunoassay for 17-hydroxyprogesterone in blood spots. J Endocrinol. 1986 Feb;108(2):299–308. doi: 10.1677/joe.0.1080299. [DOI] [PubMed] [Google Scholar]
  44. White P. C., Grossberger D., Onufer B. J., Chaplin D. D., New M. I., Dupont B., Strominger J. L. Two genes encoding steroid 21-hydroxylase are located near the genes encoding the fourth component of complement in man. Proc Natl Acad Sci U S A. 1985 Feb;82(4):1089–1093. doi: 10.1073/pnas.82.4.1089. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. White P. C., New M. I., Dupont B. Structure of human steroid 21-hydroxylase genes. Proc Natl Acad Sci U S A. 1986 Jul;83(14):5111–5115. doi: 10.1073/pnas.83.14.5111. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. White P. C., Vitek A., Dupont B., New M. I. Characterization of frequent deletions causing steroid 21-hydroxylase deficiency. Proc Natl Acad Sci U S A. 1988 Jun;85(12):4436–4440. doi: 10.1073/pnas.85.12.4436. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from American Journal of Human Genetics are provided here courtesy of American Society of Human Genetics

RESOURCES