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 greater than III greater than II greater than 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.
Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, Montreal, Canada.
M
M
Kaufman
L
L
Pinsky
B
B
Gottlieb
M
M
Schweitzer
A
A
Brezezinski
C
C
von Westarp
J
J
Ginsberg
D000293:Adolescent; D000728:Androgens / Q000378:metabolism*; D002675:Child, Preschool; D013196:Dihydrotestosterone / Q000378:metabolism; D004351:Drug Resistance; D005347:Fibroblasts / Q000378:metabolism; D005837:Genitalia, Male; D006801:Humans; D008297:Male; D015741:Metribolone / Q000378:metabolism; D009277:Nandrolone / Q000031:analogs & derivatives / Q000378:metabolism; D011944:Receptors, Androgen / Q000172:deficiency* / Q000378:metabolism; D013739:Testosterone / Q000378:metabolism; D013816:Thermodynamics
D000728:Androgens; D011944:Receptors, Androgen; D013196:Dihydrotestosterone; D015741:Metribolone; D013739:Testosterone; D009277:Nandrolone; C100075:mibolerone