Abstract
Androgen insensitivity syndrome (AIS) is a rare disease associated with inactivating mutations of AR that disrupt male sexual differentiation, and cause a spectrum of phenotypic abnormalities having as a common denominator loss of reproductive viability. No established treatment exists for these conditions, however there are sporadic reports of patients (or recapitulated mutations in cell lines) that respond to administration of supraphysiologic doses (or pulses) of testosterone or synthetic ligands. Here, we utilize a novel high content analysis (HCA) approach to study AR function at the single cell level in genital skin fibroblasts (GSF). We discuss in detail findings in GSF from three historical patients with AIS, which include identification of novel mechanisms of AR malfunction, and the potential ability to utilize HCA for personalized treatment of patients affected by this condition.
Highlights
Androgen action is mediated by the intracellular androgen receptor (AR), a transcription factor member of the nuclear receptor superfamily
The common denominator of the experiments with AR-P766S was that doses of 200 nM of T, DHT, Mib or R1881 were able to rescue the NH2-COOH-Terminal Domain Interaction (NC-TDI) response to the levels observed with wt AR at concentrations of 0.2 nM (Fig. 3)
NC-TDI Experiments were performed to establish if the three mutants were affected by an impairment of the NH2-COOH terminal interaction, and if so, if this impairment would be amenable to normalization using conditions that enhance stability of binding, for instance by increasing concentrations of natural or synthetic AR agonists
Summary
Androgen action is mediated by the intracellular androgen receptor (AR), a transcription factor member of the nuclear receptor superfamily. AR action is a conditio sine qua non for the normal development and function of the entire male genital tract; varyingly degrees of impaired AR action from mutation is causative in individuals affected by androgen insensitivity syndrome (AIS) [1,2]. Three main clinical phenotypes in humans define AIS: Complete, Partial and Minimal Androgen Insensitivity (CAIS, PAIS and MAIS), and they range from complete lack of virilization of the internal and external genitalia (CAIS), to intermediate virilization (PAIS), to apparently normal virilization in infertile males (MAIS) [1]. The degree of abnormality caused by each individual mutation is usually related to the patient phenotype, the 3H-DHT binding characteristics, and the amount of residual reporter gene activity present in cells transfected with an AR carrying that particular mutation; in general, in the more feminized phenotypes, lack of 3H-DHT binding and abnormal transcriptional activity parallel increasing
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