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Azoospermia Associated with a Mutation in the Ligand-Binding Domain of an Androgen Receptor Displaying Normal Ligand Binding, but Defective Trans-Activation¹

Department of Obstetrics and Gynecology, National University of Singapore, Republic of Singapore 119074; and the Institute for Reproduction and Development, Monash University (A.T., D.d.K.), and Prince Henry’s Institute of Medical Research (R.M.), Melbourne, Victoria 3168, Australia

Address all correspondence and requests for reprints to: Assoc. Prof. E. L. Yong, Department of Obstetrics and Gynecology, National University Hospital, Lower Kent Ridge Road, Republic of Singapore 119074. E-mail: obgyel{at}nus.edu.sg

Although male infertility affects a significant proportion of couples trying to conceive, the cause of defective spermatogenesis is not known in a large 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 identified an azoospermic (no sperm in any ejaculates) patient with an amino acid substitution (GlnGlu) in residue 798 of the AR gene. This germline mutation 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 caused a subtle, but significant, decrease in receptor trans-activation function in vitro that is consistent with the phenotype. Despite being located in the middle of the ligand-binding domain of the receptor, the Q798E mutation did not cause any ligand binding defect, indicating that this highly conserved 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 studies are required to determine the therapeutic relevance of this finding.

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