Journal of Andrology
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Published-Ahead-of-Print May 23, 2007, DOI:10.2164/jandrol.107.002691

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L859F Mutation in Androgen Receptor Gene Results in Complete Loss of Androgen binding to the Receptor

Singh Rajender , Lalji Singh , and Kumarasamy Thangaraj *

* To whom correspondence should be addressed. E-mail: thangs{at}ccmb.res.in.

Androgens drive male secondary sexual differentiation and maturation. Mutations in androgen receptor (AR) gene cause an array of abnormal sex differentiation phenotypes in human, ranging from mild through partial to complete androgen insensitivity. Earlier, we reported a C3693T missense mutation in AR gene in a familial case of complete androgen insensitivity syndrome (CAIS), resulting in the replacement of a highly conserved leucine residue with phenylalanine (L859F) in ligand binding domain of the receptor. In silico analysis and the information from the crystal structure of AR-LBD indicated that the residue L859, located in helix 10 of AR protein plays a significant role in overall architecture of ligand binding pocket. From this information we anticipated that the mutation might have resulted in the loss of the ligand binding to the receptor. In the present study, we have conducted the in vitro functional assays for this mutation. The mutation resulted in highly significant loss of the ligand binding to the receptor. The loss of ligand binding and subsequent AR function was confirmed by the transactivation assay, where we observed very little activation of the reporter gene expressed under the control of the ligand-AR complex.


Key words: Androgen • Reproductive Genetics • 46,XY sex reversal • androgen insensitivity syndrome • androgen receptor






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Copyright © 2007 by The American Society of Andrology.