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 sexual development and in prostatic carcinoma as a target of endocrine therapy. We have looked for androgen receptor mutations as a cause of male sexual ambiguity and as a possible reason for failure of androgen ablation therapy on prostatic carcinoma. In 5 patients of 2 families with perineoscrotal hypospadia and undescended testes, we have identified a mutation ala596-->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 interaction with other proteins and by exchange of the amino acid thr602-->ala indicates that the dimerization step is affected. A point mutation ser703-->gly was detected in a newborn male child with perineoscrotal hypospadias. This mutation decreased receptor-hormone affinity. 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 patients. A different kind of mutation was present in a tumor specimen derived from an advanced therapy-resistant prostatic carcinoma. This point mutation resulted in exchange of valine-->methionine at amino acid position 715 in the receptor protein. In contrast to the former two mutations this receptor showed a gain in function.(ABSTRACT TRUNCATED AT 250 WORDS)