Abstract
Development of male external genitalia is dependent on androgens, and karyotypic males lacking appropriate levels of androgens or functionally normal receptors may show abnormal virilization. Mutations in the androgen receptor gene cause abnormal receptor function and diverser mutations may be associated with heterogenous clinical signs of androgen insensitivity. In this study, we have searched for the existence of androgen receptor gene mutations carried by some patients with hypospadias. Genomic DNA samples from peripheral blood leucocytes from 21 patients with different degrees of hypospadias were studied. Analysis of the androgen receptor gene was performed by exon-specific amplification using polymerase chain reaction, single strand conformation polymorphism analysis, and direct genomic sequencing. Although a silent polymorphism was identified in exon 1 of the androgen receptor gene, the majority of patients studied (20/21) did not carry androgen receptor gene mutations. One patient with severe hypospadias and bilateral cryptorchidism was found to carry a point mutation in exon 8. We conclude that mutations in the androgen receptor gene may be carried by subset of patients with genital ambiguity presenting primarily with hypospadias, but this is not the underlying cause in the majority of cases. Characterization of this genetic defect may be important for classification and subsequent conservative therapeutic approaches for these patients.
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Abbreviations
- PCR :
-
polymerase chain reaction
- SSCP :
-
single strand conformation polymorphism
References
Allen TD, Griffin JE (1984) Endocrine studies in patients with advanced hypospadias. J Urol 131:310–314
Batch JA, Evans BA, Hughes IA, Patterson MN (1993) Mutations of the androgen receptor gene identified in perineal hypospadias. J Med Genet 30: 198–201
Edwards A, Hammond HA, Jin L, Caskey CT, Chakraborty R (1992) Genetic variation at five trimeric and tetrameric tandem repeat loci in four human population groups. Genomics 12:241–253
Gearhart JP, Linhard HR, Berkovitz GD, Jeffs RD, Brown TR (1984) Androgen receptor levels and 5α-reductase activities in preputial skin and chordee tissue of boys with isolated hypospadias. J Urol 140:1243–1246
Gonzales-Cadavid NF, Swerdloff RS, Lemmi CAE, Rajfer J (1991) Expression of the androgen receptor gene in rat penile tissue and cells during sexual maturation. Endocrinology 129: 1671–1678
Griffin JE, Wilson JD (1989) The androgen resistance syndromes: 5α-reductase deficiency, testicular feminization, and related syndromes. In: Scriver CR, Beauder AAL, Sly WS, Valle D (eds) The metabolic basis of inherited discase, 6th edn. McGraw-Hill, New York, pp 1919–1944
Hiort O, Huang Q, Sinnecker GHG, Sadeghi-Nejad A, Kruse K, Wolfe HJ, Yandell DW (1993) SSCP analysis of androgen receptor gene mutations in patients with androgen insensitivity syndromes: Application for diagnosis, genetic counseling, and therapy. J Clin Endocrinol Metab 77:262–266
Jenster G, Koput HAGM van der, Vroonhoven C van, Kwast TH van der, Trapman J, Brinkman AO (1991) Domains of the human androgen receptor involved in steroid binding, transcriptional activation, and subcellular localization. Mol Endocrinol 5:1396–1404
Keenan BS, McNeel RL, Gonzales ET (1984) Abnormality of intracellular 5α-dihydrotestosterone binding in simple hypospadias. Studies on equilibrium steroid binding in sonicates of genital skin fibroblasts. Pediatric Res 18: 216–220
La Spada AR, Wilson EM, Lubahn DB, Harding AE, Fischbeck KH (1991) Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature 352:77–79
Lubahn DB, Brown TR, Simental JA, Higgs HN, Migeon CJ, Wilson EM, French FS (1989) 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 USA 86:9534–9538
McPhaul MJ, Marcelli M, Tilley WD, Griffin JE, Isidro-Gutierrez RF, Wilson JD (1991) Molecular basis of androgen resistance in a patient with a qualitative abnormality of the androgen receptor and responsive to high-dose androgen therapy. J Clin Invest 87:1413–1421
McPhaul MJ, Marcelli M, Zoppi S, Griffin JE, Wilson JD (1993) The spectrum of mutations in the androgen receptor gene that causes androgen resistance. J Clin Endocrinol Metab 76: 17–23
Orita M, Suzuki Y, Sekiya T, Hayashi K (1989) Rapid and sensitive detection of point mutations and DNA polymorphisms using the polymerase chain reaction. Genomics 5:874–879
Pinsky L, Trifiro M, Kaufman M, Beitel LK, Mhatre A, Kazemi-Esfarjani, Sabbaghian N, Lumbroso R, Alvarado C, Vasiliou M, Gottlieb B (1992) Androgen resistance due to mutation of the androgen receptor. Clin Invest Med 15:456–472
Sambrook J, Fritsch EF, Maniatis T (1989) Molecular cloning — a laboratory manual, 2nd edn. Cold Spring Harbor Laboratory Press, Cold Spring Harbor
Schweikert HU, Knauf W, Romalo G, Höller W, Bidlingmaier F, Knorr D (1987) Androgen binding in cultured human fibroblasts from patients with idiopathic hypospadias. Horm Metabol Res 19:497–501
Schweikert HU, Schlüter M, Romalo G (1989) Intracellular and nuclear binding of (3H)dihydrotestosterone in cultured genital skin fibroblasts of patients with severe hypospadias. J Clin Invest 83:662–668
Sheldon CA, Duckett JW (1987) Hypospadias. Pediatr Clin North Am 34: 1259–1272
Sinnecker G, Köhler S (1989) Sex hormone-binding globulin response to the anabolic steroid stanozolol: evidence for its suitability as a biological androgen sensitivity test. J Clin Endocrinol Metab 68:1195–1200
Sinnecker GHG, Hiort O, Brack C, Nitsche E, Kruse K (1993) Partial androgen insensitivity due to Val-Leu substitution in codon 866 of the androgen receptor can be treated with high doses of testosterone (abstract). Pediatr Res 33 [Suppl]: S 17
Svensson J, Snochowski M (1979) Androgen receptor levels in preputial skin from boys with hypospadias. J Clin Endocrinol Metab 49:340–345
Terakawa T, Shima H, Yabumoto H, Koyama K, Ikoma F (1990) Androgen receptor levels in patients with isolated hypospadias. Acta Endocrinol (Copenh) 123:24–29
Winter JSD, Faiman C (1972) Pituitary gonadal relations in male children and adolescents. Pediatr Res 6:126–135
Yandell DW, Little J, Beauchamp R, Deneen V, Merritt V, Dryja T, Huang Q (1992) The spectrum of germ-line versus somatic mutations of the retinoblastoma and p53 genes: a comparison of 217 point mutations that occured in vivo (abstract). Am J Hum Genet 51 [Suppl]: A39
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Hiort, O., Klauber, G., Cendron, M. et al. Molecular characterization of the androgen receptor gene in boys with hypospadias. Eur J Pediatr 153, 317–321 (1994). https://doi.org/10.1007/BF01956409
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DOI: https://doi.org/10.1007/BF01956409