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Keywords:

  • XY sex primary amenorrhea reversal;
  • primary amenorrhea;
  • androgens;
  • complete androgen insensitivity syndrome;
  • Leydig cell hyperplasia;
  • ligand binding

ABSTRACT: Androgens drive male secondary sexual differentiation and maturation. Mutations in the androgen receptor (AR) gene cause an array of abnormal sex differentiation phenotypes in humans, ranging from mild through partial to complete androgen insensitivity. Earlier, we reported a C3693T missense mutation in the AR gene in a familial case of complete androgen insensitivity syndrome (CAIS), resulting in the replacement of a highly conserved leucine residue with phenylalanine (L859F) in ligand-binding domain (LBD) of the receptor. In silico analysis and the information from the crystal structure of AR-LBD indicated that the residue L859, located in helix 10 of AR protein, plays a significant role in overall architecture of the ligand-binding pocket. From this information we anticipated that the mutation might have resulted in the loss of the ligand binding to the receptor. In the present study, we have conducted the in vitro functional assays for this mutation. The mutation resulted in highly significant loss of the ligand binding to the receptor. The loss of ligand binding and subsequent AR function was confirmed by the transactivation assay, in which we observed very little activation of the reporter gene expressed under the control of the ligand-AR complex.