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A Novel Mutation in the Human Androgen Receptor Suggests a Regulatory Role for the Hinge Region in Amino-Terminal and Carboxy-Terminal Interactions

University Department of Paediatrics (A.D., J.J., I.A.H.), Addenbrooke’s Hospital, University of Cambridge, Cambridge CB2 2QQ, United Kingdom; Institute of Child Health and Great Ormond Street Hospital (M.D.), University College London, London WC1N 1EH, United Kingdom; Cancer Research United Kingdom Uro-Oncology Group (H.C.W.), Department of Oncology, University of Cambridge, Cambridge CB2 2XZ, United Kingdom; and Our Lady’s Hospital for Sick Children (C.C.), Crumlin, Dublin 12, Ireland

Address all correspondence and requests for reprints to: Professor I. A. Hughes, University Department of Pediatrics, Addenbrooke’s Hospital, Level 8, Box 116, Hills Road, Cambridge CB2 2QQ, United Kingdom. E-mail: iah1000{at}cam.ac.uk.

Context: The androgen insensitivity syndrome (AIS) is caused by molecular defects in the androgen receptor (AR). Clinically, the partial AIS has a variable phenotype. Many mechanisms explain the phenotype in the 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 and Method: We report a patient with severe undermasculinization and poor response to exogenous androgens. Androgen binding was performed, and the AR gene was sequenced. The mutation was recreated and transfected in COS-1 cells. Transactivation was studied. N/C-termini interaction was studied using a mammalian two-hybrid assay. A nuclear localization 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 with wild type (WT). A 3-fold increase in transcription occurred when both WT N and C-terminal domains were cotransfected; 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 localization. It resulted in severe undermasculinization at birth and resistance to androgens. The findings confirm a unique regulatory role for the hinge region in AR function.