MOLECULAR-GENETICS OF ANDROGEN INSENSITIVITY

Androgen insensitivity syndromes are the clinical manifestations of en d-organ resistance to androgen actions. In this inborn error of sexual differentiation, the most common cause of end-organ resistance is alt ered androgen receptor function. The clinical features of androgen ins ensitivity range from phenotypic females with complete androgen insens itivity to minimally affected phenotypic males with partial androgen i nsensitivity. The mechanism of action of the androgen receptor involve s binding of the ligand which promotes conformational changes to overc ome the inhibition to dimerization. The receptor is translocated to th e nucleus if it is not already located there. The receptor then binds to a specific region of DNA, the hormone response element, eliciting i ts actions within the target cell. Post-translation modification in te rms of phosphorylation may occur. Hydroxyflutamide, an antiandrogen, i s able to bind to the androgen receptor, but presumably does not achie ve the correct conformation to promote DNA binding. Analyzing the abno rmal receptor gene in affected families has provided much information regarding the structure and function of the androgen receptor. In cont rast to cystic fibrosis in which many affected individuals carry a del etion of phenylalanine at codon 508, the diversity of mutations in and rogen insensitivity complicates the development of simple molecular sc reening tests. Nevertheless, for those instances of partial androgen i nsensitivity and significant genital ambiguity, phenotype/genotype cor relations for previously recognized mutations may be helpful in predic ting the natural history, i.e., magnitude of androgen resistance.