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Family studies of the steroid 21-hydroxylase and coplement C4 genes define 11 haplotypes in classical congenital adrenal hyperplasia in The Netherlands

  • Medical Genetics
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Abstract

Two steroid 21-hydroxylase genes are normally present within the human major histocompatibility complex near the genes encoding the fourth component of complement (C4A and C4B). Steroid 21-hydroxylase is encoded by the CYP21 gene, while the highly homologous CYP21P gene is a pseudogene. We studied steroid 21-hydroxylase and complement C4 haplotypes in 33 Dutch patients (29 families) suffering form classical congenital adrenal hyperplasia (CAH) and in their 80 family members, and also in 55 unrelated healthy controls, using 21-hydroxylase and complement C4 cDNA probes. Eleven different haplotypes, defined in terms of gene deletions, gene duplications, conversions of CYP21 to CYP21P, and “long” and “short” C4 genes, were found. In 23% of the patients' haplotypes, the CYP21 gene was deleted; in 12%, it was converted into a CYP21P pseudogene. In the remaining 65%, the defect was apparently caused by a mutation not detectable by this method. The most common haplotype (with one CYP21 and one CYP21P gene) was significantly more often observed in patients with simple virilizing CAH than in those with salt-losing CAH. Comparison of the 21-hydroxylase haplotypes found in CAH patients from several countries shows evidence for considerable genetic variation between the groups studied.

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Abbreviations

AGS:

adrenogenital syndrome

CAH:

congenital adrenal hyperplasia

C4, C4A, C4B:

fourth component of complement

CV:

coefficient of variation

CYP21:

steroid 21-hydroxylase gene

CYP21P:

steroid 21-hydroxylase pseudogene

HLA:

human leucocyte antigen

MHC:

major histocompatibility complex

SEM:

standard error of the mean

SL:

salt losing/salt loser(s)

SV:

simple virilizer(s)

References

  1. Belt KT, Carroll MC, Porter RR (1984) The structural basis of the multiple forms of human complement component C4. Cell 36:907–914

    Article  PubMed  Google Scholar 

  2. Carroll MC, Palsdottir A, Belt KT, Porter RR (1985) Deletion of complement C4 and steroid 21-hydroxylase genes in the HLA class III region. EMBO J 4:2547–2552

    PubMed  Google Scholar 

  3. Collier S, Sinnott PJ, Dyer PA, Price DA, Harris R, Strachan T (1989) 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 8:1393–1402

    PubMed  Google Scholar 

  4. Cooper DN, Smith BA, Cooke HJ, Niemann S, Schmidtke J (1985) An estimate of unique DNA sequence heterozygosity in the human genome. Hum Genet 69:201–205

    Article  PubMed  Google Scholar 

  5. Degenhart HJ (1979) Normal and abnormal adrenal steroidogenesis in man. In: Shire JGM (ed) Genetic variation in hormone systems, vol I. CRC Press, Boca Raton, pp 11–42

    Google Scholar 

  6. Donohoue PA, Van Dop C, Jospe N, Migeon CJ (1986) Congenital adrenal hyperplasia: molecular mechanisms resulting in 21-hydroxylase deficiency. Acta Endocrinol 113 [Suppl 279]: 315–320

    Google Scholar 

  7. Donohoue PA, Jospe N, Migeon CJ, Van Dop C (1989) Two distinct areas of unequal crossingover within the steroid 21-hydroxylase genes produce absence of CYP21B. Genomics 5: 397–406

    Article  PubMed  Google Scholar 

  8. Garlepp MJ, Wilton AN, Dawkins RL, White PC (1986) Rearrangement of 21-hydroxylase genes in disease-associated MHC supratypes. Immunogenetics 23:100–105

    Article  PubMed  Google Scholar 

  9. Harada F, Kimura A, Iwanaga T, Shimozawa K, Yata J, Sasazuki T (1987) Gene conversion-like events cause steroid 21-hydroxylase deficiency in congenital adrenal hyperplasia. Proc Natl Acad Sci USA 84:8091:8094

    PubMed  Google Scholar 

  10. Higashi Y, Yoshioka H, Yamane M, Gotoh O, 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

    PubMed  Google Scholar 

  11. Matteson KJ, Phillips JA, Miller WL, Chung BC, Orlando PJ, Frisch H, Ferrandez A, Burr IM (1987) P450XXI (steroid 21-hydroxylase) gene deletions are not found in family studies of congenital adrenal hyperplasia. Proc Natl Acad Sci USA 84:5858–5862

    PubMed  Google Scholar 

  12. Miller WL, Levine LS (1987) Molecular and clinical advances in congenital adrenal hyperplasia. J Pediatr 111:1–17

    PubMed  Google Scholar 

  13. Miller WL, Morel Y (1989) The molecular genetics of 21-hydroxylase deficiency. Annu Rev Genet 27:371–393

    Article  Google Scholar 

  14. Morel Y, André J, Uring-Lambert B, Hauptmann G, Bétuel H, Tossi M, Forest MG, David M, Bertrand J, Miller WL (1989) 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 83:527–536

    PubMed  Google Scholar 

  15. Mornet E, Crété P, Kuttenn F, Raux-Demay MC, Boué J, White PC, Boué A (1991) Distribution of deletions and seven point mutations on CYP21B genes in three clinical forms of steroid 21-hydroxylase deficiency. Am J Hum Genet 48:79–88

    PubMed  Google Scholar 

  16. Palsdottir A, Fossdal R, Arnason A, Edwards JH, Jensson O (1987) Heterogeneity of human C4 gene size. A large intron (6.5 kb) is present in all C4A genes and some C4B genes. Immunogenetics 25:299–304

    Article  PubMed  Google Scholar 

  17. Partanen J, Koskimies S, Sipilä I, Lipsanen V (1989) Majorhistocompatibility-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

    PubMed  Google Scholar 

  18. Rice DA, Kronenberg MS, Mouw AR, Aitken LD, Franklin A, Schimmer BP, Parker KL (1990) Multiple regulatory elements determine adrenocortical expression of steroid 21-hydroxylase. J Biol Chem 265:8052–8058

    PubMed  Google Scholar 

  19. Rumsby G, Fielder AHL, Hague WM, Honour JW (1988) Heterogeneity in the gene locus for steroid 21-hydroxylase deficiency. J Med Genet 25:596–599

    PubMed  Google Scholar 

  20. Schneider PM (1990) C4 DNA RFLP reference typing report. Complement Inflamm 7:218–224

    PubMed  Google Scholar 

  21. Schneider PM, Carroll MC, Alper CA, Rittner C, Whitehead AS, Yunis EJ, Colten HR (1986) Polymorphism of the human complement component C4 and steroid 21-hydroxylase genes. Restriction fragment length polymorphisms revealing structural deletions, homoduplications, and size variants. J Clin Invest 78:650–657

    PubMed  Google Scholar 

  22. Sinnott P, Collier S, Costigan C, Dyer PA, Harris R, Strachan T (1990) Genesis by unequal crossover of a de novo deletion that contributes to steroid 21-hydroxylase deficiency. Proc Natl Acad Sci USA 87:2107–2111

    PubMed  Google Scholar 

  23. Sokal RR, Rohlf FJ (1981) Biometry. The principles and practice of statistics in biological research, 2nd edn. Freeman, San Francisco

    Google Scholar 

  24. Speiser PW, Laforgia N, Kato K, Pareira J, Khan R, Yang SY, Whorwood C, White PC, Elias S, Schriock E, Schriock E, Simpson JL, Taslimi M, Najjar J, May S, Mills G, Crawford C, New MI (1990) First trimester prenatal treatment and molecular genetic diagnosis of congenital adrenal hyperplasia (21-hydroxylase deficiency). J Clin Endocrinol Metab 70:838–848

    PubMed  Google Scholar 

  25. Strachan T, Sinnott PJ, Smeaton I, Dyer PA, Harris R (1987) Prenatal diagnosis of congenital adrenal hyperplasia. Lancet II:1272–1273

    Article  Google Scholar 

  26. White PC (1989) Analysis of mutations causing steroid 21-hydroxylase deficiency. Endocr Res 15:239–256

    PubMed  Google Scholar 

  27. White PC, Grossberger D, Onufer BJ, Chaplin DD, New MI, Dupont B, Strominger JL (1985) Two genes encoding steroid 21-hydroxylase are located near the genes encoding the fourth component of complement in man. Proc Natl Acad Sci USA 82:1089–1093

    PubMed  Google Scholar 

  28. White PC, New MI, Dupont B (1986) Structure of human steroid 21-hydroxylase genes. Proc Natl Acad Sci USA 83:5111–5115

    PubMed  Google Scholar 

  29. White PC, New MI, Dupont B (1987) Congenital adrenal hyperplasia (first of two parts). N Engl J Med 316:1519–1524

    PubMed  Google Scholar 

  30. White PC, New MI, Dupont B (1987) Congenital adrenal hyperplasia (second of two parts). N Engl J Med 316:1580–1586

    PubMed  Google Scholar 

  31. White PC, Vitek A, Dupont B, New MI (1988) Characterization of frequent deletions causing steroid 21-hydroxylase deficiency. Proc Natl Acad Sci USA 85:4436–4440

    PubMed  Google Scholar 

  32. Wyman AR, White R (1980) A highly polymorphic locus in human DNA. Proc Natl Acad Sci USA 77:6754–6758

    PubMed  Google Scholar 

  33. Yu CY, Campbell RD (1987) Definitive RFLPs to distinguish between the human complement C4A/C4B isotypes and the major Rodgers/Chido determinants: application to the study of C4 null alleles. Immunogenetics 25:383–390

    Article  PubMed  Google Scholar 

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Koppens, P.F.J., Hoogenboezem, T., Halley, D.J.J. et al. Family studies of the steroid 21-hydroxylase and coplement C4 genes define 11 haplotypes in classical congenital adrenal hyperplasia in The Netherlands. Eur J Pediatr 151, 885–892 (1992). https://doi.org/10.1007/BF01954123

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  • DOI: https://doi.org/10.1007/BF01954123

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