AN ANDROGEN RECEPTOR MUTATION CAUSING ANDROGEN RESISTANCE IN UNDERVIRILIZED MALE SYNDROME

The molecular basis of androgen resistance was investigated in a patie nt with undervirilized male syndrome. Binding studies of the androgen receptors in the patient's genital skin fibroblasts revealed a normal binding capacity of 5 alpha-dihydrotestosterone, although the affinity to androgen was slightly lower than the normal control value. The and rogen binding of the patient's receptor showed a moderate thermal inst ability when the assay temperature was raised from 30 to 41 C. Nucleot ide sequencing analysis of the androgen receptor gene revealed a singl e nucleotide substitution in exon F, resulting in an amino acid altera tion from leucine (CTC) to phenylalanine (TTC) at position 789 within the steroid-binding domain of androgen receptor. When expressed in COS -7 cells, the mutant androgen receptor harboring phenylalanine at posi tion 789 showed thermolabile androgen-binding properties similar to th ose observed in the patient's genital skin fibroblasts. Cotransfection experiments with an androgen-inducible reporter gene demonstrated a d ecreased transactivational capability of the mutant receptor. These re sults indicate that this point mutation modified the receptor function and caused androgen resistance in this patient. This mutation caused the mildest form of all androgen insensitivity syndromes ever examined for mutations in the androgen receptor gene.