ANDROGEN RECEPTOR ALTERATIONS IN PATIENTS WITH DISTURBANCES IN MALE SEXUAL DEVELOPMENT AND IN PROSTATIC-CARCINOMA

The androgen receptor, a ligand-activated nuclear transcription factor belonging to the large superfamily of nuclear receptors, mediates the intracellular action of androgens. It plays a central role in male se xual development and in prostatic carcinoma as a target of endocrine t herapy. We have looked for androgen receptor mutations as a cause of m ale sexual ambiguity and as a possible reason for failure of androgen ablation therapy on prostatic carcinoma. In 5 patients of 2 families w ith perineoscrotal hypospadia and undescended testes, we have identifi ed a mutation ala(596)-->thr in the DNA-binding domain of the androgen receptor. This mutation interferes with DNA binding of the receptor. Reactivation of this mutant receptor by binding of an antibody or by i nteraction with other proteins and by exchange of the amino acid thr(6 02)-->ala indicates that the dimerization step is affected. A point mu tation ser(703)-->gly was detected in a newborn male child with perine oscrotal hypospadias. This mutation decreased receptor-hormone affinit y. As a consequence its transactivation activity was dependent on the androgen concentration. Although the molecular mechanisms of these two mutations are completely different, both resulted in partial androgen insensitivity and interfered with virilization in the affected patien ts. A different kind of mutation was present in a tumor specimen deriv ed from an advanced therapy-resistant prostatic carcinoma. This point mutation resulted in exchange of valine-->methionine at amino acid pos ition 715 in the receptor protein. In contrast to the former two mutat ions this receptor showed a gain in function. In transactivation assay s it was activated not only by testicular androgens but also by the ad renal androgens, androstenedione and dehydroepiandrosterone, and by pr ogesterone. This aberrant transactivation spectrum may contribute to p rogressive tumor growth.