Search tips
Search criteria 


Logo of jmedgeneJournal of Medical GeneticsVisit this articleSubmit a manuscriptReceive email alertsContact usBMJ
J Med Genet. 1993 March; 30(3): 198–201.
PMCID: PMC1016298

Mutations of the androgen receptor gene identified in perineal hypospadias.


Hypospadias is a common urological abnormality and may occur in simple (glandular or penile) or severe forms (perineal). Perineal hypospadias often occurs in association with other genital abnormalities, such as bilateral cryptorchidism and micropenis, and may be the result of partial androgen insensitivity. We have investigated the androgen binding status and androgen receptor gene of boys from two unrelated families. The first pair of brothers had partial androgen insensitivity with perineal hypospadias, bilateral cryptorchidism, and micropenis, while the other boys had isolated perineal hypospadias. Qualitative androgen binding defects were shown in both sets of brothers and different point mutations of the androgen receptor gene were found in the two families. These findings suggest that the genital abnormalities in the affected brothers result from defects in the androgen receptor. Furthermore, severe familial hypospadias may be a previously unrecognised part of the phenotypic spectrum of the partial androgen insensitivity syndrome. This study provides valuable information for the genetic counselling of families affected by this X linked genital abnormality.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (943K), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Images in this article

Click on the image to see a larger version.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Roberts CJ, Lloyd S. Observations on the epidemiology of simple hypospadias. Br Med J. 1973 Mar 31;1(5856):768–770. [PMC free article] [PubMed]
  • Harris EL. Genetic epidemiology of hypospadias. Epidemiol Rev. 1990;12:29–40. [PubMed]
  • Evans BA, Williams DM, Hughes IA. Normal postnatal androgen production and action in isolated micropenis and isolated hypospadias. Arch Dis Child. 1991 Sep;66(9):1033–1036. [PMC free article] [PubMed]
  • Gearhart JP, Linhard HR, Berkovitz GD, Jeffs RD, Brown TR. Androgen receptor levels and 5 alpha-reductase activities in preputial skin and chordee tissue of boys with isolated hypospadias. J Urol. 1988 Nov;140(5 Pt 2):1243–1246. [PubMed]
  • Schweikert HU, Schlüter M, Romalo G. Intracellular and nuclear binding of [3H]dihydrotestosterone in cultured genital skin fibroblasts of patients with severe hypospadias. J Clin Invest. 1989 Feb;83(2):662–668. [PMC free article] [PubMed]
  • Hughes IA, Evans BA. Androgen insensitivity in forty-nine patients: classification based on clinical and androgen receptor phenotypes. Horm Res. 1987;28(1):25–29. [PubMed]
  • Lubahn DB, Joseph DR, Sullivan PM, Willard HF, French FS, Wilson EM. Cloning of human androgen receptor complementary DNA and localization to the X chromosome. Science. 1988 Apr 15;240(4850):327–330. [PubMed]
  • Chang CS, Kokontis J, Liao ST. Molecular cloning of human and rat complementary DNA encoding androgen receptors. Science. 1988 Apr 15;240(4850):324–326. [PubMed]
  • Simental JA, Sar M, Lane MV, French FS, Wilson EM. Transcriptional activation and nuclear targeting signals of the human androgen receptor. J Biol Chem. 1991 Jan 5;266(1):510–518. [PubMed]
  • Jenster G, van der Korput HA, van Vroonhoven C, van der Kwast TH, Trapman J, Brinkmann AO. Domains of the human androgen receptor involved in steroid binding, transcriptional activation, and subcellular localization. Mol Endocrinol. 1991 Oct;5(10):1396–1404. [PubMed]
  • Batch JA, Williams DM, Davies HR, Brown BD, Evans BA, Hughes IA, Patterson MN. Androgen receptor gene mutations identified by SSCP in fourteen subjects with androgen insensitivity syndrome. Hum Mol Genet. 1992 Oct;1(7):497–503. [PubMed]
  • Evans BA, Jones TR, Hughes IA. Studies of the androgen receptor in dispersed fibroblasts: investigation of patients with androgen insensitivity. Clin Endocrinol (Oxf) 1984 Jan;20(1):93–105. [PubMed]
  • Orita M, Suzuki Y, Sekiya T, Hayashi K. Rapid and sensitive detection of point mutations and DNA polymorphisms using the polymerase chain reaction. Genomics. 1989 Nov;5(4):874–879. [PubMed]
  • Edwards A, Hammond HA, Jin L, Caskey CT, Chakraborty R. Genetic variation at five trimeric and tetrameric tandem repeat loci in four human population groups. Genomics. 1992 Feb;12(2):241–253. [PubMed]
  • Sleddens HF, Oostra BA, Brinkmann AO, Trapman J. Trinucleotide repeat polymorphism in the androgen receptor gene (AR). Nucleic Acids Res. 1992 Mar 25;20(6):1427–1427. [PMC free article] [PubMed]
  • Marcelli M, Tilley WD, Wilson CM, Griffin JE, Wilson JD, McPhaul MJ. Definition of the human androgen receptor gene structure permits the identification of mutations that cause androgen resistance: premature termination of the receptor protein at amino acid residue 588 causes complete androgen resistance. Mol Endocrinol. 1990 Aug;4(8):1105–1116. [PubMed]
  • Lubahn DB, Brown TR, Simental JA, Higgs HN, Migeon CJ, Wilson EM, French FS. 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. [PubMed]

Articles from Journal of Medical Genetics are provided here courtesy of BMJ Publishing Group