Androgen Receptor Point Mutations as the Underlying Molecular Defect in 2 Patients With Androgen Insensitivity Syndrome

PURPOSE: We have detected androgen receptor (AR) gene mutations as the underlying molecular defect in male pseudohermaphroditism patients. The functional properties of these mutant receptors regarding hormone binding and transactivation were characterized in 2 patients and offered a possible treatment modality for a male pseudohermaphroditism newborn. MATERIALS AND METHODS: Specific binding of dihydrotestosterone, thermostability of the receptor-hormone complex and 5alpha-reductase activity were measured in their genital skin fibroblasts. AR gene mutations were detected by direct sequencing. The ability of the mutant receptors to activate androgen responsive elements in the deoxyribonucleic acid was determined by transactivation experiments. Screening techniques that distinguish between normal and mutant ARs were developed for rapid detection of the mutation in other family members. RESULTS: The 2 patients showed a qualitative and quantitative binding defect. In both patients, point mutations in the ligand binding domain were identified as the underlying cause. Transactivation assays demonstrated that in the newborn increasing androgen concentrations can restore the mutated receptor's function completely, whereas in the patient with complete androgen insensitivity, excessive amounts of synthetic androgens were necessary. Therefore, the newborn received androgen stimulation and underwent surgical correction in the male direction. These experiments revealed that the functional difference between a mutant AR that causes a partial and one that causes a complete androgen insensitivity may be very small. CONCLUSIONS: Identification of the molecular mechanisms that cause the various forms of sex ambiguity will greatly improve both diagnosis and therapy in affected patients. Exact characterization of AR activation and function may offer a possible treatment modality in affected patients.