ANDROGEN RECEPTOR DEFECTS IN PATIENTS WITH MINIMAL AND PARTIAL ANDROGEN RESISTANCE CLASSIFIED ACCORDING TO A MODEL OF ANDROGEN-RECEPTOR COMPLEX ENERGY-STATES

We have characterized intracellularly the androgen-receptor (A-R) complexes formed by genital skin fibroblasts from 2 unrelated males with qualitative defects of the androgen receptor: One has a small nonhypospadic penis as part of a syndrome of mild androgen resistance; the other was born with ambiguous external genitalia. The dissociation rate constants of testosterone, methyltrienolone (MT). dihydrotestosterone (DHT) and mibolerone (MB) from normal androgen receptors were determined at various temperatures: When plotted by the method of Arrhenius, they yielded a linear hierarchy of dissociation states with energies of state IV > III > II > I, respectively. Relative to this hierarchy, patient A-R complexes were displaced to higher, androgen-inappropriate energies in a mutant-distinctive pattern. MB- or MT-R complexes of both patients were thermolabile; however, both up-regulated normally in response to prolonged incubation with either hormone. Apparent equilibrium affinity constants (Kd) of the DHT- and MB-R complexes formed by both patients were normal; however, the binding capacity (Bmax) for MB in 1 case was subnormal. The distinctive biochemical phenotypes of A-R complexes in these 2 patients with androgen resistance will facilitate the definition of structure-function relations in the androgen receptor, a classical DNA- binding, transcription-regulating protein. © 1990 S. Karger AG, Basel.