Characterization of Gene Rearrangements and Gene Conversion Events in the 21-Hydroxylase Gene

  • Simon C. Ramsden
  • Paul J. Sinnott
Part of the Methods in Molecular Medicine™ book series (MIMM, volume 5)


Congenital adrenal hyperplasia (CAH) is an inherited disorder of steroidogenesis with a wide spectrum of expression. In about 95% of cases, the disease is the result of 21-hydroxylase deficiency, an autosomal recessive condition that maps to the major histocompatibility complex (MHC) on 6p21.3 (1). Classical CAH results in excessive androgen production. Females with this disorder are frequently diagnosed at birth because of ambiguous development of external genitalia, whereas males may not present until age 4–7 when they begin to manifest inappropriate virilization. Approximately 30% of individuals with classical CAH have this simple virilizing form of the disease. The remaining 70% in addition manifest the potentially life-threatening salt-wasting form of classical CAH characterized by an inability to retain dietary sodium.


Congenital Adrenal Hyperplasia Human Leucocyte Antigen Gene Conversion Event Amplification Refractory Mutation System Gene Tracking 
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  1. 1.
    Aston, C. E., Sherman, S. L., Morton, N. E., Spieser, P. W., and New, M. I. (1988) Genetic mapping of the 21-hydroxylase locus: estimation of small recombination frequencies. Am. J. Hum. Genet. 43, 304–310.PubMedGoogle Scholar
  2. 2.
    Pang, S., Wallace, M. A., Hofman, L., Thuline, H. C., Dorche, C., Lyon, I. C. T., et al. (1988) Worldwide experience in newborn screening for classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Paediatrics 81, 866–874.Google Scholar
  3. 3.
    Spiezer, P. W., Dupont, B., Rubenstein, P., Piazza, A., Kastelan, A., and New, M. I. (1985) High frequency of non-classical steroid 21-hydroxylase deficiency Am. J. Hum. Genet. 37, 650–667.Google Scholar
  4. 4.
    Carroll, M. C., Campbell, R. D., and Porter, R. R. (1985) Mapping of steroid 21-hydroxylase genes to complement component C4 genes in HLA, the major histoincompatability locus in man. Proc Natl. Acad Sci. USA 83, 521–525.CrossRefGoogle Scholar
  5. 5.
    White, P. C., New, M. I., and Dupont, B. (1986) Structure of the human 21-hydroxylase genes. Proc. Natl. Acad. Sci. USA 83, 5111–5115.PubMedCrossRefGoogle Scholar
  6. 6.
    Higashi, Y., Yoshioka, H., Yamane, M., Gotoh, O., and Fujii-Kuriyama, Y. (1986) Complete nucleotide sequence of two steroid 21-hydroxylase genes tandemly arranged in human chromosome: a pseudogene and a genuine gene. Proc. Natl Acad. Sci. USA 83, 2841–2845.PubMedCrossRefGoogle Scholar
  7. 7.
    Morel, Y., Andre, J., Uring-Lambert, B., Hauptman, G., Bétuel, H., Tosi, M., et al. (1989) Rearrangements and point mutations of the 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 83, 527–536.PubMedCrossRefGoogle Scholar
  8. 8.
    Holliday, R. (1964) A mechanism for gene conversion in fungi. Genetic Res. 5, 282–304.CrossRefGoogle Scholar
  9. 9.
    Udalova, I. A., Nedospasov, S. A., Webb, G. C., Chaplin, D. D., and Turetskaya, R. L. (1993) Highly informative typing of the human TNF locus using six adjacent polymorphic markers. Genomics 16, 180–186.PubMedCrossRefGoogle Scholar
  10. 10.
    Wedell, A. and Luthman, H. (1993) Steroid 21-hydroxylase deficiency: two additional mutations in salt wasting disease and rapid screening of disease causing mutations. Hum. Mol. Genet. 2, 4499–4504.CrossRefGoogle Scholar
  11. 11.
    Sinnott, P. J., Dyer, P. A., Price, D. A., and Strachan, T. (1989) 21-Hydroxylase deficiency patients with HLA identical affected and unaffected siblings. J. Med. Genet 26, 10–17.PubMedCrossRefGoogle Scholar
  12. 12.
    Schneideer, P. M., Carroll, M. C., Alper, C. A., Rittner, C., Whitehead, A. S., Yunis, E. J., and Colten, H. R. (1986) Polymorphism of the human complement C4 and steroid 21-hydroxylase genes. J. Clin. Invest. 78, 650–657.CrossRefGoogle Scholar
  13. 13.
    Partenan, J, Koskimies, S., Sipilia, I., and Lipsanen, V. (1989) Major histocompatibility—complex gene markers and restriction fragment analysis of steroid 21-hydroxylase (CYP21) and complement C4 genes in classical congenital adrenal hyperplasia patients in a single population Am J Hum Genet 44, 660–670.Google Scholar
  14. 14.
    Fleischnick, E, Awdeh, Z. L, Raum, D., Granados, J., Alosco, S. M., Crigler, J. R., Jr., et al. (1983) Extended MHC haplotypes in 21-hydroxylase deficiency congenital adrenal hyperplasia: shared genotypes in unrelated patients. Lancet 1, 152–156.PubMedCrossRefGoogle Scholar
  15. 15.
    Holler, W., Scholtz, S., Knorr, D., Bidlingmaier, F, Keller, E., and Ekkehard, D. A (1985) Genetic differences between the salt-wasting simple virilising and nonclassical types of congenital adrenal hyperplasia. J Clin. Endocrinol Metab. 60, 757–763.PubMedCrossRefGoogle Scholar
  16. 16.
    Pollack, M. S., Levine, L. S., and O’Neill, G. L. (1981) HLA linkage and B14, DR1, BfS haplotype association with the genes for late onset and cryptic 21-hydroxylase deficiency. Am. J. Hum. Genet 33, 540–550.PubMedGoogle Scholar
  17. 17.
    Bidwell, J. L. and Jarrold, E. A. (1986) HLA-DR allogenotyping using exon specific cDNA probes and application of minigel methods. Mol. Immunol 23, 1111–1115.PubMedCrossRefGoogle Scholar
  18. 18.
    Dyer, P. A., Jawaheer, D., Ollier, B., Poulton, K., Sinnott, P. J., and Thomson, W. (1993) HLA allele detection using molecular techniques. Disease Markers 1, 145–160.Google Scholar
  19. 19.
    Browning, M. J., Krausa, P., Rowan, A., Bicknell, D. C., Bodmer, J. G., and Bodmer, W. F. (1993) Tissue typing the HLA-A locus from genomic DNA by sequence specific PCR: comparison of HLA genotype and surface expression on colorectal tumour lines. Proc Natl Acad Sci. USA 90, 2842–2845.PubMedCrossRefGoogle Scholar
  20. 20.
    Olerup, O. and Zetterquist, H. (1992) HLA-DR typing by PCR amplification with sequence specific primers (PCR-SSP) in 2 hours: an alternative to serological DR typing in clinical practice including donor recipient matching in cadaveric transplantation. Tissue Antigens 39, 225–235.PubMedCrossRefGoogle Scholar
  21. 21.
    Bunce, M. and Welsh, K I. (1994) Rapid DNA typing for HLA-C using sequencespecific primers (PCR-SSP): identification of serological and non-serologically defined HLA-C alleles including several new alleles. Tissue Antigens 43, 7–17.PubMedCrossRefGoogle Scholar
  22. 22.
    Morel, Y. and Miller, W. L. (1991) Clinical and molecular genetics of congenital adrenal hyperplasia due to 21-hydroxylase deficiency, in Advances in Human Genetics, vol. 20 (Harris, H. and Hirschorn, K., eds.), Plenum, New York, pp. 1–88.Google Scholar
  23. 23.
    Yu, Y. C., Belt, K. T., Giles, C. M., Campbell, R. D., and Porter, R. R. (1986) Structural basis of the polymorphism of the human complement components C4A and C4B: gene size, reactivity and antigenicity EMBO J. 5, 2873–2881.PubMedGoogle Scholar
  24. 24.
    Collier, S., Sinnott, P. J., Dyer, P. A., Price, D A., Harris, R., and Strachan, T. (1989) Pulsed field gel electrophoresis identifies a high degree of variability in the number of tandem 21-hydroxylase and complement C4 repeats in 21-hydroxylase deficiency haplotypes. EMBO J. 8, 1393–1402.PubMedGoogle Scholar

Copyright information

© Humana Press Inc, Totowa, NJ 1996

Authors and Affiliations

  • Simon C. Ramsden
    • 1
  • Paul J. Sinnott
    • 2
  1. 1.Regional Molecular Genetics LaboratorySt. Mary’s HospitalManchesterUK
  2. 2.Regional Tissue Typing LaboratorySt. Mary’s HospitalManchesterUK

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