A novel sequence variation in the transactivation regulating domain of the human androgen receptor.

OBJECTIVE

To study a novel sequence variation within the androgen receptors' N-terminal CAG repeat region and possible resulting consequences for the receptors' three-dimensional (3D) protein structure.

DESIGN

Controlled clinical study.

SETTING

University research and andrology clinic.

PATIENT(S): Twenty-one adult infertile men.

INTERVENTION(S): Ultraviolet laser-assisted microdissection (PALM, Microlaser Technology AG, Bernried, Germany), cloning into pGEM-T vector (Promega, Madison, WI), automated sequencing (Gene Scan 3.7 ABI Prim, Applied Biosystems, Foster City, CA), and Assisted Model Building with Energy Refinement (AMBER).

MAIN OUTCOME MEASURE(S): Determination of the sequence of the CAG repeat of the androgen receptor gene and analysis of the 3D protein structure.

RESULTS(S): In one hypergonadotropic azoospermic patient with Sertoli-cell-only syndrome, we found a punctual sequence variation of 212A-->G in the CAG repeat resulting in a glutamine-arginine substitution, which leads to a moderate conformational change of the alpha-helix from 34 A in length and 16 A in diameter (without mutation) to a slightly longer helix (43 A) with a smaller diameter (15 A).

CONCLUSION(S): Whether the novel 212A-->G exchange in the CAG repeat leading to a glutamine-->arginine substitution and a change in alpha-helix structure may causally be related to the Sertoli-cell-only phenotype of the patient remains to be elucidated.