Complete Androgen Insensitivity Syndrome Caused by a Novel Mutation in the Ligand-Binding Domain of the Androgen Receptor: Functional Characterization

Mutations in the X-linked androgen receptor (AR) gene cause the androgen insensitivity syndrome by impairing androgen-dependent male sexual differentiation to varying degrees. Complete androgen insensitivity (CAIS) yields an external female phenotype, whereas affected cases of partial androgen insensitivity have various ambiguities of the genitalia. Here we describe a 46,XY phenotypically female patient with all of the characteristics of CAIS, i.e. primary amenorrhea, no axillary or pubic hair, female external genitalia, no uterus, and undescended testes. Defects in testosterone and dihydrotestosterone synthesis were excluded. The molecular basis of the disease was clarified by means of direct sequencing of PCR-amplified exonic fragments of the AR gene. An A to C transition in exon 4 of the AR gene led to a novel missense His(689)Pro mutation in the ligand-binding domain of the AR protein. Functional studies demonstrated that the mutated AR is unable to efficiently bind its natural ligand dihydrotestosterone and to trans-activate known androgen response elements. Analysis of the structural consequences of the His(689)Pro substitution suggests that this mutation is likely to perturb the conformation of the second helix of the AR ligand-binding domain, which contains residues critical for androgen binding.