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. 1989 Jan;26(1):10–17. doi: 10.1136/jmg.26.1.10

21-hydroxylase deficiency families with HLA identical affected and unaffected sibs.

P J Sinnott 1, P A Dyer 1, D A Price 1, R Harris 1, T Strachan 1
PMCID: PMC1015530  PMID: 2783976

Abstract

During our investigations of polymorphisms at, and in the immediate chromosomal vicinity of, the 21-hydroxylase locus in families with 21-hydroxylase deficiency, three families were found to show marked discordance in clinical features of HLA identical subjects. In one family, there is discordance between a boy with the simple virilising form of 21-hydroxylase deficiency and his two younger sisters, who are both HLA identical to their brother, but who have additional salt wasting features. In the other two families, one subject is severely affected and has very high 17-hydroxyprogesterone levels, but has an HLA identical sib who is asymptomatic and shows only slightly raised 17-hydroxyprogesterone levels. In all cases, HLA identity, as indicated by protein polymorphism studies (HLA-A, B, DR, C4A, C4B, and Bf typing), has been verified at the gene organisation level using 21-hydroxylase and complement C4 DNA probes. An HLA-Bw47 bearing haplotype in one of the latter families has not been transmitted to the affected child and appears to carry a normal 21-OHB allele and two genes which specify C4A allotypes.

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Selected References

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

  1. Alper C. A., Boenisch T., Watson L. Genetic polymorphism in human glycine-rich beta-glycoprotein. J Exp Med. 1972 Jan;135(1):68–80. doi: 10.1084/jem.135.1.68. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. 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]
  3. Boehm B. O., Rosak C., Boehm T. L., Kuehnl P., White P. C., Schöffling K. Classical and late-onset forms of congenital adrenal hyperplasia caused by 21-OH deficiency reveal different alterations in the C4/21-OH gene region. Mol Biol Med. 1986 Oct;3(5):437–448. [PubMed] [Google Scholar]
  4. 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]
  5. Donohoue P. A., Van Dop C., Migeon C. J., McLean R. H., Bias W. B. Coupling of HLA-A3,Cw6,Bw47,DR7 and a normal CA21HB steroid 21-hydroxylase gene in the Old Order Amish. J Clin Endocrinol Metab. 1987 Nov;65(5):980–986. doi: 10.1210/jcem-65-5-980. [DOI] [PubMed] [Google Scholar]
  6. 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]
  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. Feinberg A. P., Vogelstein B. "A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity". Addendum. Anal Biochem. 1984 Feb;137(1):266–267. doi: 10.1016/0003-2697(84)90381-6. [DOI] [PubMed] [Google Scholar]
  9. Garlepp M. J., Wilton A. N., Dawkins R. L., White P. C. Rearrangement of 21-hydroxylase genes in disease-associated MHC supratypes. Immunogenetics. 1986;23(2):100–105. doi: 10.1007/BF00377968. [DOI] [PubMed] [Google Scholar]
  10. Giles C. M., Uring-Lambert B., Boksch W., Braun M., Goetz J., Neumann R., Mauff G., Hauptmann G. The study of a French family with two duplicated C4A haplotypes. Hum Genet. 1987 Dec;77(4):359–365. doi: 10.1007/BF00291427. [DOI] [PubMed] [Google Scholar]
  11. HLA and congenital adrenal hyperplasia linkage confirmed. Lancet. 1978 Apr 29;1(8070):930–932. [PubMed] [Google Scholar]
  12. 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]
  13. Jeffreys A. J., Wilson V., Thein S. L. Hypervariable 'minisatellite' regions in human DNA. Nature. 1985 Mar 7;314(6006):67–73. doi: 10.1038/314067a0. [DOI] [PubMed] [Google Scholar]
  14. 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]
  15. Klouda P. T., Harris R., Price D. A. Linkage and association between HLA and 21-hydroxylase deficiency. J Med Genet. 1980 Oct;17(5):337–341. doi: 10.1136/jmg.17.5.337. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Kuhnle U., Chow D., Rapaport R., Pang S., Levine L. S., New M. I. The 21-hydroxylase activity in the glomerulosa and fasciculata of the adrenal cortex in congenital adrenal hyperplasia. J Clin Endocrinol Metab. 1981 Mar;52(3):534–544. doi: 10.1210/jcem-52-3-534. [DOI] [PubMed] [Google Scholar]
  17. Kunkel L. M., Smith K. D., Boyer S. H., Borgaonkar D. S., Wachtel S. S., Miller O. J., Breg W. R., Jones H. W., Jr, Rary J. M. Analysis of human Y-chromosome-specific reiterated DNA in chromosome variants. Proc Natl Acad Sci U S A. 1977 Mar;74(3):1245–1249. doi: 10.1073/pnas.74.3.1245. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. 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]
  19. 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]
  20. 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]
  21. 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]
  22. Rosenbloom A. L., Smith D. W. Varying expression for salt losing in related patients with congenital adrenal hyperplasia. Pediatrics. 1966 Aug;38(2):215–219. [PubMed] [Google Scholar]
  23. Rumsby G., Carroll M. C., Porter R. R., Grant D. B., Hjelm M. Deletion of the steroid 21-hydroxylase and complement C4 genes in congenital adrenal hyperplasia. J Med Genet. 1986 Jun;23(3):204–209. doi: 10.1136/jmg.23.3.204. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. 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]
  25. 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]
  26. Southern E. M. Detection of specific sequences among DNA fragments separated by gel electrophoresis. J Mol Biol. 1975 Nov 5;98(3):503–517. doi: 10.1016/s0022-2836(75)80083-0. [DOI] [PubMed] [Google Scholar]
  27. Stoner E., Dimartino-Nardi J., Kuhnle U., Levine L. S., Oberfield S. E., New M. I. Is salt-wasting in congenital adrenal hyperplasia due to the same gene as the fasciculata defect? Clin Endocrinol (Oxf) 1986 Jan;24(1):9–20. doi: 10.1111/j.1365-2265.1986.tb03249.x. [DOI] [PubMed] [Google Scholar]
  28. Strachan T., Sinnott P. J., Smeaton I., Dyer P. A., Harris R. Prenatal diagnosis of congenital adrenal hyperplasia. Lancet. 1987 Nov 28;2(8570):1272–1273. doi: 10.1016/s0140-6736(87)91880-0. [DOI] [PubMed] [Google Scholar]
  29. 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]
  30. White P. C., New M. I., Dupont B. Congenital adrenal hyperplasia (2). N Engl J Med. 1987 Jun 18;316(25):1580–1586. doi: 10.1056/NEJM198706183162506. [DOI] [PubMed] [Google Scholar]
  31. 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]

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