The length and location of CAG trinucleotide repeats in the androgen receptor N-terminal domain affect transactivation function

Abstract

Some transcription factors contain stretches of polyglutamine encoded by repeats of the trinucleotide CAG. Expansion of the CAG repeat in the androgen receptor (AR) has been correlated with the incidence and severity of X-linked spinal and bulbar muscular atrophy (Kennedy's disease). In order to understand the relationship of this mutation to AR function, we constructed ARs that varied in the position and size of the polyglutamine tract, and assayed for the abilities of these mutant receptors to bind androgen and to activate transcription of several different AR-responsive reporter genes. Elimination of the tract in both human and rat AR resulted in elevated transcriptional activation activity, strongly suggesting that the presence of the polyglutamine tract is inhibitory to transactivation. Progressive expansion of the CAG repeat in human AR caused a linear decrease of transactivation function. Importantly, expansion of the tract did not completely eliminate AR activity. We postulate that this residual AR activity may be sufficient for development of male primary and secondary sex characteristics, but may fall below a threshold level of activity necessary for normal maintenance of motor neuron function. This functional abnormality may be representative of other genetic diseases that are associated with CAG expansion mutations in open reading frames, such as spinocerebellar ataxia type I and Huntington's disease.

Anxiety, Sex-Linked Behaviors, and Digit Ratios (2D:4D)

“…Some evidence suggests that the 2D:4D ratio is a direct correlate of prenatal sex steroid levels (Lutchmaya, Baron-Cohen, Raggatt, Knickmeyer, & Manning, 2004;Manning et al, 1998). However, a recent proposal is that digit ratios may be better described as a measure of perinatal androgen action (McIntyre, 2006), consistent with findings that smaller digit ratios are associated with androgen receptor alleles showing fewer terminal domain CAG repeats (Manning, Bundred, Newton, & Flanagan, 2003), a marker of greater androgen sensitivity (Chamberlain, Driver, & Meisfeld, 1994;Kazemi-Esfarjani, Trifiro, & Pinski, 1995).…”

Effects of exogenous testosterone and mating context on men's preferences for female facial femininity

“…For instance, the trinucleotide CAG repeat polymorphism in the first exon of the androgen receptor (AR) gene could potentially play a role in T's influence on facial preferences. AR sensitivity appears to be negatively correlated with the length of CAG repeats, and as such, should produce larger phenotypic effects of androgens among those with relatively shorter CAG repeat lengths (Chamberlain et al, 1994;Choong et al, 1996). Indeed, recent evidence suggests that basal T concentrations are positively correlated with aggressive and non-aggressive risktaking behaviour, but only among individuals with short CAG repeats (Vermeersch et al, 2008).…”

A case-based evaluation of SRD5A1, SRD5A2, AR, and ADRA1A as candidate genes for severity of BPH

“…Given the importance of AR in the modulation of genes involved in cell proliferation and differentiation, the (CAG) n microsatellite has been intensely studied, in particular with respect to prostate cancer. 22 Both in vitro and in vivo studies have demonstrated that CAG repeat length is inversely related to transactivation activity of AR, [33][34][35][36] with additional evidence implicating AR in BPH severity coming from population-based observational studies. Using data from the Physicians' Health Study, it was determined that the risk of surgery for BPH increased linearly with decreasing CAG repeat length (OR ¼ 1.76, 95% CI (1.2, 2.7) for men with (CAG) p19 relative to men with (CAG) X25 ).…”