Azoospermia associated with a mutation in the ligand-binding domain of an androgen receptor displaying normal ligand binding, but defective trans-activation

Although male infertility affects a significant proportion of couples tryin g to conceive, the cause of defective spermatogenesis is not known in a lar ge number of cases. Ligand binding studies indicate that a number of these subjects may have defects of the androgen receptor (AR). Genetic screening in subjects with defective spermatogenesis and in 110 fertile controls iden tified an azoospermic (no sperm in any ejaculates) patient with an amino ac id substitution (Gln-->Glu) in residue 798 of the AR gene. This germline mu tation was pathogenic because it was not observed in fertile controls, was associated with features of minimal androgen insensitivity in our patient, has been related to more severe grades of androgen insensitivity, and cause d a subtle, but significant, decrease in receptor trans-activation function in vitro that is consistent with the phenotype. Despite being located in t he middle of the ligand-binding domain of the receptor, the Q798E mutation did not cause any ligand binding defect, indicating that this highly conser ved residue has a trans-activation function but does not directly form part of the ligand binding pocket of the receptor. The trans-activation defect of the mutant receptor can be rectified in vitro with the androgenic drug, fluoxymesterone, but not with mesterolone or nortestosterone. Further studi es are required to determine the therapeutic relevance of this finding.