Response to treatment in patients with partial androgen insensitivity due to mutations in the DNA-binding domain of the androgen receptor

The androgen insensitivity syndrome is a disorder caused by deficient funct ion of the androgen receptor, characterized by varying degrees of undermasc ulinization in karyotypic males. We have identified four mutations in the a ndrogen receptor gene, in the region encoding the DNA-binding domain of the protein. Two mutations, R607X and R615G, were found in patients with compl ete insensitivity to androgens, whereas the other two, S578T and A596T, wer e found in patients with partial insensitivity. The functional consequences of the three missense mutations were assayed in vitro after transient expr ession of the receptors in COS cells. All mutants showed normal androgen bi nding but abnormal abilities to stimulate transcription of an androgen-resp onsive reporter gene. R615G abolished transactivation whereas S578T and A59 6T were partially malfunctional, The function of A596T, but not of S578T, w as normalized at high androgen concentrations in vitro, reflecting the in v ivo situation. Thus, patients with specific mutations in the DNA-binding do main of the androgen receptor may benefit from androgen treatment. Copyrigh t (C) 2000 S. Karger AG, Basel.