Molecular basis of androgen insensitivity syndromes

Individuals with complete androgen insensitivity syndrome show a female genital phenotype despite 46, XY gonosomes and the presence of androgen producing testes. This clinical observation indicates the resistance of the body and its cells to androgens like testosterone. At the molecular level, this hormone resistance is caused by hemizygous loss of function mutations in the X-chromosomal androgen receptor (AR) gene. Partial forms of androgen insensitivity syndrome (PAIS) show different degrees of virilisation largely depending on the remaining activity of the AR. Nevertheless, the phenotypic outcome can be variable even in presence of the same mutation and in the same kindred indicating the presence of further influencing factors. Importantly, the majority of clinically diagnosed PAIS individuals do not bear a mutation in their AR gene. A recent assay using the androgen regulated gene apolipoprotein D as biomarker is able to detect androgen insensitivity on the cellular level even in absence of an AR gene mutation. Using this assay a class of AIS without an AR-gene mutation was defined as AIS type II and suggests that unidentified cofactors of the AR are responsible for the PAIS phenotype. Here we outline the scientific progress made from the first clinical definition of AIS over biochemical and molecular characterizations to the concept of AIS type II. This review is based on publications in the PubMed database of the National Institutes of Health using the search terms androgen insensitivity syndrome and androgen receptor mutation.