Context: The androgen insensitivity syndrome (AIS) is caused by molecular defects in the androgen receptor (AR). Clinically, the partial form (PAIS) has a variable phenotype. Many mechanisms explain the phenotype in AIS. A crucial step in AR action is the interaction of the N and C termini.

Objective: The role of the hinge region of the AR is not as well understood as other parts of the receptor. We aim to study the role of this region in the N/C termini interaction.

Patient & method: We report a patient with severe undermasculinisation and poor response to exogenous androgens. Androgen binding was performed and the AR gene was sequenced. The mutation was re-created, and transfected in COS-1 cells. Transactivation was studied. N/C termini interaction was studied using a mammalian 2-hybrid assay. Nuclear localisation study was performed.

Results: Androgen binding was normal and a novel mutation (Arg629Trp) in the AR hinge region was identified. Mutant AR transactivation was 40% higher compared to wild-type (WT). A 3-fold increase in transcription occurred when both WT N and C terminal domains were co-transfected; no response occurred when the mutated region of the AR was included (P<0.001). Cells with mutant AR showed a comparable nuclear localization to the WT AR.

Conclusions: A mutation in the hinge region impaired N/C domain interaction in the presence of normal AR binding and nuclear localisation. It resulted in severe undermasculinisation at birth and resistance to androgens. The findings confirm a unique regulatory role for the hinge region in AR function.