Complete androgen insensitivity due to mutations in the probable -helical segments of the DNA-binding domain in the human androgen receptor

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Abstract
We describe different single-amlno acid aberrations in the DNA-binding domain (DBD) of the human androgen receptor (hAR) in three families with complete androgen Insensitivity. No additional alteration was found in the translated portion of each mutant gene. In one family, an in-frame 3 nt deletion removes codon 581 (or 582) and, thereby, one of two phenylalanines that invariably occupy adjacent positions in the N-terminal α-hellcal region of the DBD in the steroid/thyroid/vitamin D receptor superfamily. In the second, an in-frame 3 nt loss deletes Arg614, an invariant residue in the C-terminal α-helix of the DBD. In the third, a G— A transition causes Arg614His. Following transient transfection of COS cells with each mutant AR plasmid, there is a normal concentration of specific androgen-binding activity that has a reduced ability to bind two types of androgen response element (ARE), and to transregulate an androgen-responsive human growth hormone reporter gene. In genital skin fibroblasts withΔ Phe581 or Arg614His, androgen-binding, AR protein and AR mRNA are markedly reduced; in gonadal fibroblasts with ΔArg614, AR mRNA may be reduced. Our data substantlate the primary contributions of Phe581 and Arg614 to normal hAR-ARE binding, and expose important secondary effects of the mutations affecting each residue.

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