ANALYSIS OF A MUTANT ANDROGEN RECEPTOR OFFERS A TREATMENT MODALITY INA PATIENT WITH PARTIAL ANDROGEN INSENSITIVITY SYNDROME

Objectives: In male pseudohermaphroditism patients, we have detected a ndrogen receptor (AR) gene mutations as the underlying molecular defec t. The properties of these mutant receptors regarding hormone binding and transactivation were characterized. In a newborn patient with part ial androgen insensitivity syndrome caused by an AR gene point mutatio n, the functional analysis of the mutated AR offers a possible treatme nt modality. Methods: Specific binding of dihydrotestosterone in the p atient's genital skin fibroblasts, thermostability, and Sa-reductase a ctivity were evaluated. Furthermore, an AR gene mutation was detected by direct sequencing. The ability of the mutant receptor to activate a ndrogen-responsive elements in the DNA was determined by recreating an AR expression vector and cotransfection experiments. Results: The new born patient with partial androgen insensitivity showed a qualitative and quantitative binding defect. A point mutation in the ligand bindin g domain was identified as the underlying cause. Transactivation assay s demonstrated that increasing androgen concentrations can restore the function of the mutated receptor completely. Therefore, the patient r eceived androgen stimulation which resulted in good growth of his exte rnal genitalia and underwent surgical correction in the male direction . Conclusions: Diagnosis and therapy in affected patients will be impr oved identifying the molecular mechanisms that cause the various forms of sex ambiguity. Exact characterization of AR activation and functio n may offer a possible treatment modality in patients with the androge n insensitivity syndrome. Our results led to a surgical correction of our newborn patient in the male direction.