Molecular genetics of androgen insensitivity

Abstract

Androgen insensitivity syndromes are the clinical manifestations of end-organ resistance to androgen actions. In this inborn error of sexual differentiation, the most common cause of end-organ resistance is altered androgen receptor function. The clinical features of androgen insensitivity range from phenotypic females with complete androgen insensitivity to minimally affected phenotypic males with partial androgen insensitivity. The mechanism of action of the androgen receptor involves binding of the ligand which promotes conformational changes to overcome the inhibition to dimerization. The receptor is translocated to the nucleus if it is not already located there. The receptor then binds to a specific region of DNA, the hormone response element, eliciting its actions within the target cell. Post-translation modification in terms of phosphorylation may occur. Hydroxyfluta-mide, an antiandrogen, is able to bind to the androgen receptor, but presumably does not achieve the correct conformation to promote DNA binding.

Analyzing the abnormal receptor gene in affected families has provided much information regarding the structure and function of the androgen receptor. In contrast to cystic fibrosis in which many affected individuals carry a deletion of phenylalanine at codon 508, the diversity of mutations in androgen insensitivity complicates the development of simple molecular screening tests. Nevertheless, for those instances of partial androgen insensitivity and significant genital ambiguity, phenotype/genotype correlations for previously recognized mutations may be helpful in predicting the natural history, i.e., magnitude of androgen resistance.