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Submitted on January 11, 2006
Accepted on March 30, 2006
Department of Human Genetics, University of Michigan Medical School., Ann Arbor, Michigan 48109-0618
* To whom correspondence should be addressed. E-mail: drobins{at}umich.edu.
Polymorphism in length of the N-terminal glutamine (Q) tract in the human androgen receptor (AR) has been implicated in affecting aspects of male health from fertility to cancer. Extreme expansion of the tract underlies Kennedy disease, while 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" (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.
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