Skip to main content
PMC home page
American Journal of Human Genetics logoLink to American Journal of Human Genetics
. 1990 Jun;46(6):1095–1100.

An exonic point mutation of the androgen receptor gene in a family with complete androgen insensitivity

Tetsujun Sai, Susumu Seino, Chawnshang Chang, Mark Trifiro, Leonard Pinsky, Anand Mhatre, Morris Kaufman, Bernard Lambert, Jan Trapman, Albert O Brinkmann, Robert L Rosenfield, Shutsung Liao
PMCID: PMC1683844  PMID: 2339702

Abstract

We have discovered in the X-linked androgen receptor gene a single exonic nucleotide substitution that causes complete androgen insensitivity (resistance) in a sibship with three affected individuals. The mutation, a guanine-to-adenine transition, occurs at nucleotide number 2682 and changes the sense of codon 717 from tryptophan to a translation stop signal. Codon 717 is in exon 4, so the mutation predicts the synthesis of a truncated receptor that lacks most of its androgen-binding domain. The substitution abolishes a recognition sequence for the restriction endonuclease HaeIII. Amplification of exon 4 by the polymerase chain reaction followed by double digestion with HinfI and HaeIII permits facile recognition of hemizygotes and heterozygous carriers of the mutation.

Full text

PDF
1100

Images in this article

1097Figure 1
on p.1097
1097Figure 2
on p.1097
1098Figure 4
on p.1098

Selected References

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

  1. Brown C. J., Goss S. J., Lubahn D. B., Joseph D. R., Wilson E. M., French F. S., Willard H. F. Androgen receptor locus on the human X chromosome: regional localization to Xq11-12 and description of a DNA polymorphism. Am J Hum Genet. 1989 Feb;44(2):264–269. [PMC free article] [PubMed] [Google Scholar]
  2. Brown T. R., Lubahn D. B., Wilson E. M., Joseph D. R., French F. S., Migeon C. J. Deletion of the steroid-binding domain of the human androgen receptor gene in one family with complete androgen insensitivity syndrome: evidence for further genetic heterogeneity in this syndrome. Proc Natl Acad Sci U S A. 1988 Nov;85(21):8151–8155. doi: 10.1073/pnas.85.21.8151. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Brown T. R., Maes M., Rothwell S. W., Migeon C. J. Human complete androgen insensitivity with normal dihydrotestosterone receptor binding capacity in cultured genital skin fibroblasts: evidence for a qualitative abnormality of the receptor. J Clin Endocrinol Metab. 1982 Jul;55(1):61–69. doi: 10.1210/jcem-55-1-61. [DOI] [PubMed] [Google Scholar]
  4. Chang C. S., Kokontis J., Liao S. T. Structural analysis of complementary DNA and amino acid sequences of human and rat androgen receptors. Proc Natl Acad Sci U S A. 1988 Oct;85(19):7211–7215. doi: 10.1073/pnas.85.19.7211. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Elawady M. K., Allman D. R., Griffin J. E., Wilson J. D. Expression of a mutant androgen receptor in cloned fibroblasts derived from a heterozygous carrier for the syndrome of testicular feminization. Am J Hum Genet. 1983 May;35(3):376–384. [PMC free article] [PubMed] [Google Scholar]
  6. Faber P. W., Kuiper G. G., van Rooij H. C., van der Korput J. A., Brinkmann A. O., Trapman J. The N-terminal domain of the human androgen receptor is encoded by one, large exon. Mol Cell Endocrinol. 1989 Feb;61(2):257–262. doi: 10.1016/0303-7207(89)90137-8. [DOI] [PubMed] [Google Scholar]
  7. Godowski P. J., Rusconi S., Miesfeld R., Yamamoto K. R. Glucocorticoid receptor mutants that are constitutive activators of transcriptional enhancement. Nature. 1987 Jan 22;325(6102):365–368. doi: 10.1038/325365a0. [DOI] [PubMed] [Google Scholar]
  8. Greenberg C. R., Hamerton J. L., Nigli M., Wrogemann K. DNA studies in a family with Duchenne muscular dystrophy and a deletion at Xp21. Am J Hum Genet. 1987 Aug;41(2):128–137. [PMC free article] [PubMed] [Google Scholar]
  9. Hollenberg S. M., Giguere V., Segui P., Evans R. M. Colocalization of DNA-binding and transcriptional activation functions in the human glucocorticoid receptor. Cell. 1987 Apr 10;49(1):39–46. doi: 10.1016/0092-8674(87)90753-7. [DOI] [PubMed] [Google Scholar]
  10. Kaufman M., Straisfeld C., Pinsky L. Male pseudohermaphroditism presumably due to target organ unresponsiveness to androgens. Deficient 5alpha-dihydrotestosterone binding in cultured skin fibroblasts. J Clin Invest. 1976 Aug;58(2):345–350. doi: 10.1172/JCI108478. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Lubahn D. B., Brown T. R., Simental J. A., Higgs H. N., Migeon C. J., Wilson E. M., French F. S. Sequence of the intron/exon junctions of the coding region of the human androgen receptor gene and identification of a point mutation in a family with complete androgen insensitivity. Proc Natl Acad Sci U S A. 1989 Dec;86(23):9534–9538. doi: 10.1073/pnas.86.23.9534. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Lubahn D. B., Joseph D. R., Sar M., Tan J., Higgs H. N., Larson R. E., French F. S., Wilson E. M. The human androgen receptor: complementary deoxyribonucleic acid cloning, sequence analysis and gene expression in prostate. Mol Endocrinol. 1988 Dec;2(12):1265–1275. doi: 10.1210/mend-2-12-1265. [DOI] [PubMed] [Google Scholar]
  13. Meyer W. J., 3rd, Migeon B. R., Migeon C. J. Locus on human X chromosome for dihydrotestosterone receptor and androgen insensitivity. Proc Natl Acad Sci U S A. 1975 Apr;72(4):1469–1472. doi: 10.1073/pnas.72.4.1469. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Migeon B. R., Brown T. R., Axelman J., Migeon C. J. Studies of the locus for androgen receptor: localization on the human X chromosome and evidence for homology with the Tfm locus in the mouse. Proc Natl Acad Sci U S A. 1981 Oct;78(10):6339–6343. doi: 10.1073/pnas.78.10.6339. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Pinsky L., Kaufman M. Genetics of steroid receptors and their disorders. Adv Hum Genet. 1987;16:299–472. doi: 10.1007/978-1-4757-0620-8_5. [DOI] [PubMed] [Google Scholar]
  16. Pinsky L., Kaufman M., Lambert B., Faucher G., Rosenfeld R. Male pseudohermaphroditism: diagnosis in cell culture. Can Med Assoc J. 1977 Jun 4;116(11):1274-5, 1277. [PMC free article] [PubMed] [Google Scholar]
  17. Saiki R. K., Gelfand D. H., Stoffel S., Scharf S. J., Higuchi R., Horn G. T., Mullis K. B., Erlich H. A. Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. Science. 1988 Jan 29;239(4839):487–491. doi: 10.1126/science.2448875. [DOI] [PubMed] [Google Scholar]
  18. Sanger F., Coulson A. R., Barrell B. G., Smith A. J., Roe B. A. Cloning in single-stranded bacteriophage as an aid to rapid DNA sequencing. J Mol Biol. 1980 Oct 25;143(2):161–178. doi: 10.1016/0022-2836(80)90196-5. [DOI] [PubMed] [Google Scholar]
  19. Tilley W. D., Marcelli M., Wilson J. D., McPhaul M. J. Characterization and expression of a cDNA encoding the human androgen receptor. Proc Natl Acad Sci U S A. 1989 Jan;86(1):327–331. doi: 10.1073/pnas.86.1.327. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Trapman J., Klaassen P., Kuiper G. G., van der Korput J. A., Faber P. W., van Rooij H. C., Geurts van Kessel A., Voorhorst M. M., Mulder E., Brinkmann A. O. Cloning, structure and expression of a cDNA encoding the human androgen receptor. Biochem Biophys Res Commun. 1988 May 31;153(1):241–248. doi: 10.1016/s0006-291x(88)81214-2. [DOI] [PubMed] [Google Scholar]
  21. Wieacker P., Griffin J. E., Wienker T., Lopez J. M., Wilson J. D., Breckwoldt M. Linkage analysis with RFLPs in families with androgen resistance syndromes: evidence for close linkage between the androgen receptor locus and the DXS1 segment. Hum Genet. 1987 Jul;76(3):248–252. doi: 10.1007/BF00283617. [DOI] [PubMed] [Google Scholar]

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

RESOURCES