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The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 11 3777-3782
Copyright © 1997 by The Endocrine Society

Original Studies

Long Polyglutamine Tracts in the Androgen Receptor Are Associated with Reduced Trans-Activation, Impaired Sperm Production, and Male Infertility1

Thein G. Tut, Farid J. Ghadessy, M. A. Trifiro, L. Pinsky and E. L. Yong

Department of Obstetrics and Gynecology, National University of Singapore, Republic of Singapore 119074; and Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, Departments of Human Genetics and Medicine, McGill University (M.A.T., L.P.), Montreal, Canada H3T 1E2

Address all correspondence and requests for reprints to: Dr. E. L. Yong, Department of Obstetrics and Gynecology, National University Hospital, Lower Kent Ridge Road, Republic of Singapore 119074.

The X-linked androgen receptor (AR) gene contains two polymorphic trinucleotide repeat segments that code for polyglutamine and polyglycine tracts in the N-terminal trans-activation domain of the AR protein. Changes in the lengths of these polymorphic repeat segments have been associated with increased risk of prostate cancer, an androgen-dependent tumor. Expansion of the polyglutamine tract causes a rare neuromuscular disease, spinal bulbar muscular atrophy, that is associated with low virilization, reduced sperm production, testicular atrophy, and infertility. As spermatogenesis is exquisitely androgen dependent, it is plausible that changes in these two repeat segments could have a role in some cases of male infertility associated with impaired spermatogenesis. To test this hypothesis, we examined the lengths of the polyglutamine and polyglycine repeats in 153 patients with defective sperm production and compared them to 72 normal controls of proven fertility. There was no significant association between the polyglycine tract and infertility. However, patients with 28 or more glutamines (Gln) in their AR had more than 4-fold (95% confidence interval, 4.9–3.2) increased risk of impaired spermatogenesis, and the more severe the spermatogenic defect, the higher the proportion of patients with a longer Gln repeat. Concordantly, the risk of defective spermatogenesis was halved when the polyglutamine tract was short (<=23 Gln). Whole cell transfection experiments using AR constructs harboring 15, 20, and 31 Gln repeats and a luciferase reporter gene with an androgen response element promoter confirmed an inverse relationship between Gln number and trans-regulatory activity. Immunoblot analyses indicated that the reduced androgenicity of the AR was unlikely to be due to a change in AR protein content. The data indicate a direct relation between length of the AR polyglutamine tract and the risk of defective spermatogenesis that is attributable to the decreased functional competence of AR with longer glutamine tracts.




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Mol. Hum. Reprod., May 1, 2001; 7(5): 409 - 413.
[Abstract] [Full Text] [PDF]

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 Mol Hum ReprodHome page
I. Sasagawa, Y. Suzuki, T. Tateno, T. Nakada, K. Muroya, and T. Ogata
CAG repeat length of the androgen receptor gene in Japanese males with cryptorchidism
Mol. Hum. Reprod., November 1, 2000; 6(11): 973 - 975.
[Abstract] [Full Text] [PDF]

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 J. Clin. Endocrinol. Metab.Home page
A. Mifsud, S. Ramirez, and E. L. Yong
Androgen Receptor Gene CAG Trinucleotide Repeats in Anovulatory Infertility and Polycystic Ovaries
J. Clin. Endocrinol. Metab., September 1, 2000; 85(9): 3484 - 3488.
[Abstract] [Full Text]

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 Mol Hum ReprodHome page
D.S. Cram, B. Song, R.I. McLachlan, and A.O. Trounson
CAG trinucleotide repeats in the androgen receptor gene of infertile men exhibit stable inheritance in female offspring conceived after ICSI
Mol. Hum. Reprod., September 1, 2000; 6(9): 861 - 866.
[Abstract] [Full Text] [PDF]

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 Cancer Res.Home page
A. W. Hsing, Y.-T. Gao, G. Wu, X. Wang, J. Deng, Y.-L. Chen, I. A. Sesterhenn, F. K. Mostofi, J. Benichou, and C. Chang
Polymorphic CAG and GGN Repeat Lengths in the Androgen Receptor Gene and Prostate Cancer Risk: A Population-based Case-Control Study in China
Cancer Res., September 1, 2000; 60(18): 5111 - 5116.
[Abstract] [Full Text]

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 J. Clin. Endocrinol. Metab.Home page
O. Hiort, P.-M. Holterhus, T. Horter, W. Schulze, B. Kremke, M. Bals-Pratsch, G. H. G. Sinnecker, and K. Kruse
Significance of Mutations in the Androgen Receptor Gene in Males with Idiopathic Infertility
J. Clin. Endocrinol. Metab., August 1, 2000; 85(8): 2810 - 2815.
[Abstract] [Full Text]

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 Mol. Endocrinol.Home page
J. Lim, F. J. Ghadessy, A. A. R. Abdullah, L. Pinsky, M. Trifiro, and E. L. Yong
Human Androgen Receptor Mutation Disrupts Ternary Interactions between Ligand, Receptor Domains, and the Coactivator TIF2 (Transcription Intermediary Factor 2)
Mol. Endocrinol., August 1, 2000; 14(8): 1187 - 1197.
[Abstract] [Full Text]

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 Hum Mol GenetHome page
H.N. Lim, H. Chen, S. McBride, A.M. Dunning, R.M. Nixon, I.A. Hughes, and J.R. Hawkins
Longer polyglutamine tracts in the androgen receptor are associated with moderate to severe undermasculinized genitalia in XY males
Hum. Mol. Genet., March 22, 2000; 9(5): 829 - 834.
[Abstract] [Full Text] [PDF]

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 Mol Hum ReprodHome page
S. Dadze, C. Wieland, S. Jakubiczka, K. Funke, E. Schroder, B. Royer-Pokora, R. Willers, and P.F. Wieacker
The size of the CAG repeat in exon 1 of the androgen receptor gene shows no significant relationship to impaired spermatogenesis in an infertile Caucasoid sample of German origin
Mol. Hum. Reprod., March 1, 2000; 6(3): 207 - 214.
[Abstract] [Full Text] [PDF]

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 Hum Mol GenetHome page
R. A. Irvine, H. Ma, M. C. Yu, R. K. Ross, M. R. Stallcup, and G. A. Coetzee
Inhibition of p160-mediated coactivation with increasing androgen receptor polyglutamine length
Hum. Mol. Genet., January 22, 2000; 9(2): 267 - 274.
[Abstract] [Full Text] [PDF]

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 CarcinogenesisHome page
A. M. Dunning, S. McBride, J. Gregory, F. Durocher, N. A. Foster, C. S. Healey, N. Smith, P. D. P. Pharoah, R. N. Luben, D. F. Easton, et al.
No association between androgen or vitamin D receptor gene polymorphisms and risk of breast cancer
Carcinogenesis, November 1, 1999; 20(11): 2131 - 2135.
[Abstract] [Full Text] [PDF]

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 J. Clin. Endocrinol. Metab.Home page
D. M. de Kretser and H. W. G. Baker
Infertility in Men: Recent Advances and Continuing Controversies
J. Clin. Endocrinol. Metab., October 1, 1999; 84(10): 3443 - 3450.
[Full Text] [PDF]

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 JNCI J Natl Cancer InstHome page
A. B. Spurdle, G. S. Dite, X. Chen, C. J. Mayne, M. C. Southey, L. E. Batten, H. Chy, L. Trute, M. R. E. McCredie, G. G. Giles, et al.
Androgen Receptor Exon 1 CAG Repeat Length and Breast Cancer in Women Before Age Forty Years
J Natl Cancer Inst, June 2, 1999; 91(11): 961 - 966.
[Abstract] [Full Text] [PDF]

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 Mol Hum ReprodHome page
F.J. Ghadessy, S.L. Liow, and E.L. Yong
Mutations in the promoter region of the androgen receptor gene are not common in males with idiopathic infertility
Mol. Hum. Reprod., March 1, 1999; 5(3): 287 - 290.
[Abstract] [Full Text] [PDF]

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 Mol Hum ReprodHome page
S. Komori, H. Kasumi, R.-i. Kanazawa, K. Sakata, Y. Nakata, H. Kato, and K. Koyama
CAG repeat length in the androgen receptor gene of infertile Japanese males with oligozoospermia
Mol. Hum. Reprod., January 1, 1999; 5(1): 14 - 16.
[Abstract] [Full Text] [PDF]


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