CHARACTERIZATION OF MUTANT ANDROGEN RECEPTORS CAUSING PARTIAL ANDROGEN INSENSITIVITY SYNDROME

The androgen insensitivity syndrome (AIS) is an X-linked disorder caus ed by mutations of the androgen receptor (AR) gene resulting in a spec trum of sex phenotypes that ranges from complete female (complete AIS) to nearly complete male (partial AIS). Using the polymerase chain rea ction and denaturing gradient gel electrophoresis, we have analyzed th e AR gene in three 46,XY individuals with partial AIS. In one subject whose androgen insensitivity was manifest at birth by clitoromegaly, p osterior labial fusion, and a urogenital sinus, androgen-binding affin ity in genital skin fibroblasts was similar to that of the control. In this subject, a mutation was identified in exon C encoding the second zinc finger of the androgen receptor. The mutation converted a leucin e residue at position 616 to arginine, causing greatly reduced binding of receptor to an androgen-response element DNA sequence. However, th e mutant AR retained a low level of transcriptional activity at physio logical androgen concentrations in keeping with the subject's phenotyp e of partial AIS. In the second subject, who also had an ambiguous ext ernal genital phenotype, a single base mutation was identified in exon G, converting arginine at position 840 to histidine. Androgen-binding affinity in genital skin fibroblasts of this subject was 7-fold lower than control, and the mutant receptor had reduced transcriptional act ivity. In the third subject, who had a female phenotype with normal pu bic hair reflecting a low degree of androgen responsiveness, the valin e residue at position 889 was replaced by methionine. This mutant rece ptor had apparent normal androgen-binding affinity but reduced androge n-binding capacity when examined by expression of the recreated mutant AR in COS 7 cells. These results demonstrate the clinical, functional , and molecular heterogeneity in the syndrome of partial androgen inse nsitivity.