Congenital androgen insensitivity due to a qualitatively abnormal androgen receptor

Complete or incomplete androgen insensitivity (AI) not associated with deficient specific 5α‐dihydrotestosterone (DHT)‐receptor activity in cultured genital skin fibroblasts may result from a qualitative receptor abnormality or a postreceptor defect in target cell sensitivity to DHT. We have studied a sporadic patient with complete AI whose mean receptor capacity (Bmax) is 34 fmol/mg protein and a second with incomplete AI, multiple affected maternal relatives, and a mean Bmax of 40 (normal: 15 – 50). Each has normal 5α‐reductase activity. The following qualities of the receptor activity are normal in each: Equilibrium dissociation constant (Kd), elution profile on gel chromatography, nuclear translocation of the DHT‐receptor complex, and 0.4 M KCl extractability of the nuclear complex. When preincubated at 37°C and assayed at 42°C (compared with the usual 37°C) the receptor activity in cells of the “complete AI” patient decreased much more (60%) than that of any of 7 control cell lines (± 20%); the activity in cells of the “incomplete AI” patient, in contrast, decreased to a variable, questionably abnormal extent. When preincubated, assayed, and chased at 37°C with excess radioinert DHT, the androgen‐receptor complexes in both patients dissociated with a rate constant (k−1) about 18 × 10−3 min−1 compared with a normal of 5.9 ± 0.32 × 10−3 min−1 (± SEM; n = 15). We have thus defined novel qualitative defects of the androgen receptor activity in two patients who have different clinical degrees of congenital AI despite normal levels of androgen binding. These defects will be useful as markers for genetic studies and as molecular models for steroid‐resistant cancer in man.