This Article Full Text Full Text (PDF) All Versions of this Article: 20/6/1248    most recent Author Manuscript (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager NURSA Molecule Pages Link Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Albertelli, M. A. Articles by Robins, D. M. Search for Related Content PubMed PubMed Citation Articles by Albertelli, M. A. Articles by Robins, D. M.

Replacing the Mouse Androgen Receptor with Human Alleles Demonstrates Glutamine Tract Length-Dependent Effects on Physiology and Tumorigenesis in Mice

Department of Human Genetics, University of Michigan Medical School, Ann Arbor, Michigan 48109-0618

Address all correspondence and requests for reprints to: Diane M. Robins, Department of Human Genetics, 4909 Buhl Bldg, University of Michigan Medical School, Ann Arbor, Michigan 48109-0618. E-mail: drobins{at}umich.edu.

Polymorphism in the length of the N-terminal glutamine (Q) tract in the human androgen receptor (AR) has been implicated in affecting aspects of male health ranging from fertility to cancer. Extreme expansion of the tract underlies Kennedy disease, and in vitro the AR Q tract length correlates inversely with transactivation capacity. However, whether normal variation influences physiology or the etiology of disease has been controversial. To assess directly the functional significance of Q tract variation, we converted the mouse AR to the human sequence by germline gene targeting, introducing alleles with 12, 21, or 48 glutamines. These three "humanized" AR (h/mAR) mouse lines were grossly normal in growth, behavior, fertility, and reproductive tract morphology. Phenotypic analysis revealed traits that varied subtly with Q tract length, including body fat amount and, more notably, seminal vesicle weight. Upon molecular analysis, tissue-specific differences in AR levels and target gene expression were detected between mouse lines. In the prostate, probasin, Nkx3.1, and clusterin mRNAs trended in directions predicted for inverse correlation of Q tract length with AR activation. Remarkably, when crossed with transgenic adenocarcinoma of mouse prostate (TRAMP) mice, striking genotype-dependent differences in prostate cancer initiation and progression were revealed. This link between Q tract length and prostate cancer, likely due to differential activation of AR targets, corroborates human epidemiological studies. This h/mAR allelic series in a homogeneous mouse genetic background allows examination of numerous physiological traits for Q tract influences and provides an animal model to test novel drugs targeted specifically to human AR.

NURSA Molecule Pages Link:

Nuclear Receptors:   AR

This article has been cited by other articles:

				O. A. O'Mahony, M. P. Steinkamp, M. A. Albertelli, M. Brogley, H. Rehman, and D. M. Robins Profiling Human Androgen Receptor Mutations Reveals Treatment Effects in a Mouse Model of Prostate Cancer Mol. Cancer Res., November 1, 2008; 6(11): 1691 - 1701. [Abstract] [Full Text] [PDF]

				M. A. Albertelli, O. A. O'Mahony, M. Brogley, J. Tosoian, M. Steinkamp, S. Daignault, K. Wojno, and D. M. Robins Glutamine tract length of human androgen receptors affects hormone-dependent and -independent prostate cancer in mice Hum. Mol. Genet., January 1, 2008; 17(1): 98 - 110. [Abstract] [Full Text] [PDF]

				M. Zitzmann and E. Nieschlag Androgen Receptor Gene CAG Repeat Length and Body Mass Index Modulate the Safety of Long-Term Intramuscular Testosterone Undecanoate Therapy in Hypogonadal Men J. Clin. Endocrinol. Metab., October 1, 2007; 92(10): 3844 - 3853. [Abstract] [Full Text] [PDF]

				P. Crabbe, V. Bogaert, D. De Bacquer, S. Goemaere, H. Zmierczak, and J. M. Kaufman Part of the Interindividual Variation in Serum Testosterone Levels in Healthy Men Reflects Differences in Androgen Sensitivity and Feedback Set Point: Contribution of the Androgen Receptor Polyglutamine Tract Polymorphism J. Clin. Endocrinol. Metab., September 1, 2007; 92(9): 3604 - 3610. [Abstract] [Full Text] [PDF]

				B Lapauw, S Goemaere, P Crabbe, J M Kaufman, and J B Ruige Is the effect of testosterone on body composition modulated by the androgen receptor gene CAG repeat polymorphism in elderly men? Eur. J. Endocrinol., March 1, 2007; 156(3): 395 - 401. [Abstract] [Full Text] [PDF]