A novel mutation F826L in the human androgen receptor in partial androgen insensitivity syndrome; increased NH2-/COOH-terminal domain interaction and TIF2 co-activation

Abstract

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.

Coregulator Control of Androgen Receptor Action by a Novel Nuclear Receptor-binding Motif

“…7A). However, this was not the case for the Bag-1L (61)(62)(63)(64)(65)(66)(67)(68)(69)(70)(71)(72)(73)(74)(75)(76)(77)(78)(79)(80) peptide, where only the exchange of the penultimate two amino acids XXXRPX to alanine decreased binding (Fig. 7B).…”

“…Residues in the BF-3 pocket are also targets for prostate cancer and androgen insensitivity syndrome mutations (63)(64)(65)(66)(67). Our finding that the GARRPR motifs of Bag-1L bind to the BF-3 would therefore strongly implicate Bag-1L in the development or progression of androgen insensitivity syndrome and/or prostate cancer.…”

Association of a Tagging Single Nucleotide Polymorphism in the<b> Androgen Receptor </b>Gene Region with Susceptibility to Severe Hypospadias in a Caucasian Population

“…This gene includes 8 exons, in which exon 1 codes for the transactivation domain, exons 2 and 3 encode the DNA binding domain, and the 3 ′ part of exon 4 including exons 5-8, code for the ligand binding domain [Quigley et al, 1995]. Previous studies have reported the presence of rare mutations in this gene, however, only in very few hypospadias patients [Hiort et al, 1994;Alléra et al, 1995;Sutherland et al, 1996;Nordenskjöld et al, 1999;Wang et al, 2004;Thai et al, 2005;Wong et al, 2008]. In our present study, we screened a much larger cohort and identified one SNP (rs5919436, g.67024320C>G) that was significantly associated with an increased risk of severe hypospadias.…”

“…The complex is subsequently translocated to the nucleus where it recognizes the canonical androgen response elements and affects the expression of androgen-regulated genes critical for the development of the male sexual phenotype [Mooradian et al, 1987]. Mutations of the AR gene causes the syndrome of partial or complete androgen insensitivity, but mutations in isolated hypospadias patients have been reported in relatively few cases [Hiort et al, 1994;Alléra et al, 1995;Sutherland et al, 1996;Nordenskjöld et al, 1999;Wang et al, 2004;Thai et al, 2005;Wong et al, 2008].…”

Functional Impact of Novel Androgen Receptor Mutations on the Clinical Manifestation of Androgen Insensitivity Syndrome

“…The hydrophobic pocket serves as a binding site for coactivators and promotes the LBD-NTD interaction. The coactivator interactions increase transcriptional activity of the AR [He and Wilson, 2002;Werner et al, 2008;Wong et al, 2008].…”