Objectives: In male pseudohermaphroditism patients, we have detected androgen receptor (AR) gene mutations as the underlying molecular defect. The properties of these mutant receptors regarding hormone binding and transactivation were characterized. In a newborn patient with partial androgen insensitivity syndrome caused by an AR gene point mutation, the functional analysis of the mutated AR offers a possible treatment modality.
Methods: Specific binding of dihydrotestosterone in the patient's genital skin fibroblasts, thermostability, and 5 alpha-reductase activity were evaluated. Furthermore, an AR gene mutation was detected by direct sequencing. The ability of the mutant receptor to activate androgen-responsive elements in the DNA was determined by recreating an AR expression vector and cotransfection experiments.
Results: The newborn patient with partial androgen insensitivity showed a qualitative and quantitative binding defect. A point mutation in the ligand binding domain was identified as the underlying cause. Transactivation assays demonstrated that increasing androgen concentration can restore the function of the mutated receptor completely. Therefore, the patient received androgen stimulation which resulted in good growth of his external genitalia and underwent surgical correction in the male direction.
Conclusions: Diagnosis and therapy in affected patients will be improved identifying the molecular mechanisms that cause the various forms of sex ambiguity. Exact characterization of AR activation and function may offer a possible treatment modality in patients with the androgen insensitivity syndrome. Our results led to a surgical correction of our newborn patient in the male direction.