Androgen insensitivity

The androgen receptor (AR) protein regulates transcription of certain genes . Usually, this activity depends upon a central DNA-binding domain that per mits the binding of androgen-AR complexes to regulatory DNA sequences near or in a target gene. The AR also has a C-terminal androgen-binding domain ( ABD) and an N-terminal modulatory domain. These domains interact among them selves and with coregulatory, nonreceptor proteins to determine vector cont rol over a gene's transcription rate. The precise roles of these proteins a re active research areas. Severe X-linked androgen receptor gene (AR) mutat ions cause complete androgen insensitivity, mild ones impair virilization w ith or without infertility, and moderate ones sometimes yield a wide phenot ypic spectrum among sibs. Different expressivity may reflect variability of AR-interactive proteins. The family history must identify heterozygous XX females with sparse, delayed, or asymmetric pubic/axillary hair or delayed menarche and infertile XY maternal aunts or uncles, Mutation type and densi ty vary along the length of the AR. N-terminal polyglutamine tract expansio n limits AR transactivation, causing a form of mild androgen insensitivity. Analysis of ABD mutations that do not impair androgen binding or impair it selectively will illuminate its intradomain properties. For partial androg en Insensitivity and mild androgen insensitivity, pharmacotherapy with cert ain androgens or other steroids may overcome some dysfunction of certain mu tant ARs. Experience with this approach is limited; outcomes have been gene rally disappointing. (C) 2000 Wiley-Liss, Inc.