ASSESSMENT OF ANDROGEN RECEPTOR FUNCTION IN GENITAL SKIN FIBROBLASTS USING A RECOMBINANT ADENOVIRUS TO DELIVER AN ANDROGEN-RESPONSIVE REPORTER GENE

Mutations of the androgen receptor (AR) cause defects in virilization and can result in a spectrum of phenotypic abnormalities of male sexua l development that includes patients with a completely female phenotyp e (complete testicular feminization) and individuals with less severe defects of virilization, such as Reifenstein syndrome. These phenotype s are not specific for mutations of the AR gene, however, and defects in other genes can also result in similar abnormalities of male develo pment. For this reason, the diagnosis of an AR defect is laborious and requires data from endocrine studies, the family history, and in vitr o binding experiments. To assist in the evaluation of patients with po ssible AR defects, we previously employed the use of a recombinant ade novirus to deliver an androgen-responsive gene into fibroblast culture s to assay AR function in normal subjects and patients with complete f orms of androgen resistance. Although these studies demonstrated measu rable differences between these two groups of subjects, we did not ass ay samples from patients with partial defects of androgen action. In t he current study, we have modified this method to examine AR function in three groups of patients with known or suspected defects of AR func tion: patients with Reifenstein syndrome, patients with spinobulbar mu scular atrophy, and patients with severe forms of isolated hypospadias . When assayed using this method, the AR function of patients with Rei fenstein syndrome was intermediate between that of normal control subj ects and that of patients with complete testicular feminization. Using the parameters established by the aforementioned experiments, we foun d that defective AR function can be detected in fibroblasts establishe d from patients with spinobulbar muscular atrophy and in some patients with severe forms of isolated hypospadias, including two with a norma l AR gene sequence. These results suggest that this method may have so me utility in screening samples to detect defects of AR function, part icularly when viewed in the context of other AR assays results.