Partial androgen resistance due to a distinctive qualitative defect of the androgen receptor.

Using whole genital skin fibroblasts, we have characterized a novel androgen receptor mutation in a family with partial androgen resistance. The proposita was born with bilateral labioscrotal folds and a single perineal urogenital orifice. Her similarly affected maternal aunt was raised as a female with the support of gonadectomy and vaginoplasty. The mutant androgen receptor has a normal maximum binding capacity (Bmax), but an increased apparent equilibrium dissociation constant (Kd) with 5 alpha-dihydrotestosterone (DHT) and 2 synthetic androgens, methyltrienolone (MT) and mibolerone (MB). Preformed mutant DHT-receptor complexes dissociate (k) at a near-normal rate, but their MT and MB counterparts dissociate twice as quickly as normal. The native free mutant receptor is not more thermolabile than normal, but its recently dissociated counterpart is. Prolonged incubation of the cells with each of the 3 androgens causes the mutant receptor to acquire a normal increment of increased androgen-receptor activity. This androgen-sensitive pattern of misbehavior of the present mutant receptor distinguishes it from those responsible for 3 other families with partial androgen resistance studied previously. These differences will help to identify structure-function domains on the androgen receptor protein, particularly in conjunction with the use of DNA probes to analyze mutations at the X-linked androgen receptor locus.