The Molecular Basis of Androgen Insensitivity

Androgen action is mediated in the peripheral target cell via the androgen receptor (AR). The AR is a nuclear transcription factor, combining a DNA-binding and a hormone-binding domain with a large transactivation unit. Androgen insensitivity syndrome (AIS) as the clinical entity of defective androgen action with variable phenotypes in 46,XY patients is caused by mutations of the X-chromosomal AR gene. Most variations in the AR gene are point mutations inhibiting either hormone or DNA binding. However, even within the same family, the phenotype for a given mutation can vary widely. Only few influential factors have been identified for the phenotypic diversity. For mutations affecting hormone binding, ligand concentration variability during fetal life may be an important influence on residual androgen action. A second factor is the occurrence of postzygotic de novo mutations, which are present at a high rate in single-case families. These somatic mutations lead to expression of both mutant and wild-type AR in a single patient and thus allow androgen action despite a deleterious mutation of the AR gene. Third, residual androgen response may be mediated by additional transcripts of the AR gene which are present in several cell types and can be affected in a different pattern by splice-site mutations. Whether differential expression of AR-interacting proteins has an influence on phenotype has not yet been proven. Moreover, little is known about the regulation of AR-dependent genes. Their identification is needed to understand post-AR action and, hence, androgenic control of sexual differentiation and maturation.