A novel mutation F826L located within the ligand binding domain (LBD) of the human androgen receptor (AR) was investigated. This mutation was found in a boy with severe penoscrotal hypospadias (classified as 46,XY DSD). The AR mutant F826L appeared to be indistinguishable from the wild-type AR, with respect to ligand binding affinity, transcriptional activation of MMTV-luciferase and ARE2-TATA-luciferase reporter genes, protein level in genital skin fibroblasts (GSFs), and sub-cellular distribution in transfected cells. However, an at least two-fold higher NH2-/COOH-terminal domain interaction was found in luciferase and GST pull-down assays. A two-fold increase was also observed for TIF2 (transcription intermediary factor 2) co-activation of the AR F826L COOH-terminal domain. This increase could not be explained by a higher stability of the mutant protein, which was within wild-type range. Repression of transactivation by the nuclear receptor co-repressor (N-CoR) was not affected by the AR F826L mutation. The observed properties of AR F826L would be in agreement with an increased activity rather than with a partial defective AR transcriptional activation. It is concluded that the penoscrotal hypospadias in the present case is caused by an as yet unknown mechanism, which still may involve the mutant AR.

46,XY disorders of sex development, Androgen receptor, Hypospadias, Mutation, Testosterone, Transcriptional activation
dx.doi.org/10.1016/j.mce.2008.06.016, hdl.handle.net/1765/29654
Molecular and Cellular Endocrinology
Erasmus MC: University Medical Center Rotterdam

Wong, H.Y, Hoogerbrugge, J.W, Pang, K.L, van Leeuwen, M, Royen, M.E, Molier, M, … Brinkmann, A.O. (2008). A novel mutation F826L in the human androgen receptor in partial androgen insensitivity syndrome; increased NH2-/COOH-terminal domain interaction and TIF2 co-activation. Molecular and Cellular Endocrinology, 292(1-2), 69–78. doi:10.1016/j.mce.2008.06.016