A novel mutation F826L in the human androgen receptor in partial androgen insensitivity syndrome; increased NH 2 -/COOH-terminal domain interaction and TIF2 co-activation, Molecular and Cellular Endocrinology (2007), doi:10.1016/j.mce.2008 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Abbreviations: aa, amino acid; AD, activation domain; AF2, activation function 2; DHT, 5-dihydrotestosterone; DSD, disorders of sex development; GFP, green fluorescent protein; GSF, genital skin fibroblast; LBD, ligand binding domain; LBP, ligand binding pocket; N-CoR, nuclear receptor co-repressor; NC-TDI, NH 2 -/COOH-terminal domain interaction; NTD, N-terminal transactivation domain; T, testosterone; TIF2, transcriptional intermediary factor 2; wt, wild-type. However, an at least two-fold higher NH 2 -/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.