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. 1989 May;44(5):660–670.

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.

J Partanen 1, S Koskimies 1, I Sipilä 1, V Lipsanen 1
PMCID: PMC1715632  PMID: 2565078

Abstract

The gene CYP21B, encoding the steroid 21-hydroxylase enzyme of adrenal steroid biosynthesis, has been mapped to the human major histocompatibility complex (MHC). Deficiency of this enzyme leads to congenital adrenal hyperplasia (CAH). We report the phenotypes of the HLA and complement C4 and Bf genes, which are closely linked to the CYP21B gene, together with a detailed analysis of the CYP21 and C4 RFLP, in 17 Finnish families with CAH. The RFLP analysis with six restriction enzymes suggested that, altogether, 35% of the affected chromosomes had a CYP21B + C4B gene deletion, 9% an obvious gene conversion of the CYP21B gene to a CYP21A-like gene, and 3% a CYP21A + C4B duplication. The remaining 53% gave the RFLP patterns also found in nonaffected chromosomes. We also found that a 14.0-kb EcoRI RFLP marker of the CYP21 genes was strongly associated with the presence of a short C4B gene, suggesting that some of the RFLP markers found with the CYP21 probe may actually derive from C4B gene polymorphism. Three particular MHC haplotypes, each with a characteristic RFLP pattern, were found in many unrelated families. These three haplotypes accounted for 59% of the affected chromosomes in our study group, the rest (41%) of the affected chromosomes being distributed among various subtypes. The results suggest that, within a single, well-defined population such as in Finland, only a few CYP21B gene defects may constitute a substantial part of the affected chromosomes. This finding will help in genetic studies of CAH in such populations.

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Selected References

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  1. Belt K. T., Carroll M. C., Porter R. R. The structural basis of the multiple forms of human complement component C4. Cell. 1984 Apr;36(4):907–914. doi: 10.1016/0092-8674(84)90040-0. [DOI] [PubMed] [Google Scholar]
  2. Carlsson B., Wallin J., Böhme J., Möller E. HLA-DR-DQ haplotypes defined by restriction fragment analysis. Correlation to serology. Hum Immunol. 1987 Oct;20(2):95–113. doi: 10.1016/0198-8859(87)90025-5. [DOI] [PubMed] [Google Scholar]
  3. 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]
  4. 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]
  5. Couillin P., Rappaport R., Kuttenn F., Canlorbe P., Hors J., Marcelli-Barge A., Feingold J., Grisard M. C., Boué J., Boué A. HLA and 21 hydroxylase deficiency (congenital and late onset adrenal hyperplasia) in the French population. Tissue Antigens. 1982 Feb;19(2):100–107. doi: 10.1111/j.1399-0039.1982.tb01424.x. [DOI] [PubMed] [Google Scholar]
  6. 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]
  7. 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]
  8. Fleischnick E., Awdeh Z. L., Raum D., Granados J., Alosco S. M., Crigler J. F., Jr, Gerald P. S., Giles C. M., Yunis E. J., Alper C. A. Extended MHC haplotypes in 21-hydroxylase-deficiency congenital adrenal hyperplasia: shared genotypes in unrelated patients. Lancet. 1983 Jan 22;1(8317):152–156. doi: 10.1016/s0140-6736(83)92757-5. [DOI] [PubMed] [Google Scholar]
  9. 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]
  10. 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]
  11. 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]
  12. Keller E., Andreas-Zietz A., Knorr D., Scholz S., Albert E. D. Identification of a new HLA-B7-associated C21-hydroxylase deficiency gene by restriction enzyme length polymorphism. Immunogenetics. 1987;25(2):123–125. doi: 10.1007/BF00364278. [DOI] [PubMed] [Google Scholar]
  13. Layrisse Z., White C., Gunczler P., Gafaro Valera L., Arias S., Yunis E. J., Alper C. A., Awdeh Z. L. Sharing of MHC haplotypes among apparently unrelated patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Immunogenetics. 1987;25(2):99–103. doi: 10.1007/BF00364274. [DOI] [PubMed] [Google Scholar]
  14. Lokki M. L., Julin M. HLA-A,B,C and haplotype frequencies in the Finnish population. Tissue Antigens. 1982 Oct;20(4):239–250. doi: 10.1111/j.1399-0039.1982.tb00352.x. [DOI] [PubMed] [Google Scholar]
  15. Long E. O., Wake C. T., Gorski J., Mach B. Complete sequence of an HLA-dR beta chain deduced from a cDNA clone and identification of multiple non-allelic DR beta chain genes. EMBO J. 1983;2(3):389–394. doi: 10.1002/j.1460-2075.1983.tb01435.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. 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]
  17. Miller W. L., Levine L. S. Molecular and clinical advances in congenital adrenal hyperplasia. J Pediatr. 1987 Jul;111(1):1–17. doi: 10.1016/s0022-3476(87)80334-7. [DOI] [PubMed] [Google Scholar]
  18. Mornet E., Couillin P., Kutten F., Raux M. C., White P. C., Cohen D., Boué A., Dausset J. Associations between restriction fragment length polymorphisms detected with a probe for human 21-hydroxylase (21-OH) and two clinical forms of 21-OH deficiency. Hum Genet. 1986 Dec;74(4):402–408. doi: 10.1007/BF00280494. [DOI] [PubMed] [Google Scholar]
  19. New M. I., Speiser P. W. Genetics of adrenal steroid 21-hydroxylase deficiency. Endocr Rev. 1986 Aug;7(3):331–349. doi: 10.1210/edrv-7-3-331. [DOI] [PubMed] [Google Scholar]
  20. Partanen J., Koskimies S. Human MHC class III genes, Bf and C4. Polymorphism, complotypes and association with MHC class I genes in the Finnish population. Hum Hered. 1986;36(5):269–275. doi: 10.1159/000153642. [DOI] [PubMed] [Google Scholar]
  21. Partanen J., Koskimies S., Sipilä I. DNA polymorphism unique for a complotype with deletion of HLA-linked C4B and 21-hydroxylase B genes causing congenital adrenal hyperplasia. Hum Genet. 1988 Apr;78(4):372–373. doi: 10.1007/BF00291739. [DOI] [PubMed] [Google Scholar]
  22. Pollack M. S., New M. I., O'Neill G. J., Levine L. S., Callaway C., Pang S., Cacciari E., Mantero F., Cassio A., Scaroni C. HLA genotypes and HLA-linked genetic markers in Italian patients with classical 21-hydroxylase deficiency. Hum Genet. 1981;58(3):331–337. doi: 10.1007/BF00294933. [DOI] [PubMed] [Google Scholar]
  23. Prentice H. L., Schneider P. M., Strominger J. L. C4B gene polymorphism detected in a human cosmid clone. Immunogenetics. 1986;23(4):274–276. doi: 10.1007/BF00373024. [DOI] [PubMed] [Google Scholar]
  24. 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]
  25. Schneider P. M., Carroll M. C., Alper C. A., Rittner C., Whitehead A. S., Yunis E. J., Colten H. R. Polymorphism of the human complement C4 and steroid 21-hydroxylase genes. Restriction fragment length polymorphisms revealing structural deletions, homoduplications, and size variants. J Clin Invest. 1986 Sep;78(3):650–657. doi: 10.1172/JCI112623. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Schneider P. M., Rittner C. Bgl II restriction fragment length polymorphism of human complement C4A gene coincides with BF*F allele of factor B. Immunogenetics. 1988;27(3):225–228. doi: 10.1007/BF00346591. [DOI] [PubMed] [Google Scholar]
  27. Sim E., Cross S. J. Phenotyping of human complement component C4, a class-III HLA antigen. Biochem J. 1986 Nov 1;239(3):763–767. doi: 10.1042/bj2390763. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. 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]
  29. 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]
  30. 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]
  31. Yu C. Y., Belt K. T., Giles C. M., Campbell R. D., Porter R. R. Structural basis of the polymorphism of human complement components C4A and C4B: gene size, reactivity and antigenicity. EMBO J. 1986 Nov;5(11):2873–2881. doi: 10.1002/j.1460-2075.1986.tb04582.x. [DOI] [PMC free article] [PubMed] [Google Scholar]

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