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The A645D Mutation in the Hinge Region of the Human Androgen Receptor (AR) Gene Modulates AR Activity, Depending on the Context of the Polymorphic Glutamine and Glycine Repeats

Departments of Pediatric and Adolescent Medicine (R.W., D.S., C.M., O.H.), University of Lübeck, 23538 Lübeck, Germany; Departments of Pediatric and Adolescent Medicine (P.-M.H.), Christian-Albrechts University, D-24105 Kiel, Germany; Departments of Pediatric and Adolescent Medicine (G.B.), Eberhard-Karls-University of Tübingen, D-72076 Tübingen, Germany; Departments of Pediatric and Adolescent Medicine (H.-P.S.), Ludwig-Maximilians University of Munich, D-80539 Munich, Germany; and Departments of Pediatric and Adolescent Medicine (M.M.), Endokrinologikum, D-30161 Hannover, Germany

Address all correspondence and requests for reprints to: Professor Dr. Olaf Hiort, Department of Pediatric and Adolescent Medicine, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany. E-mail: hiort{at}paedia.ukl.mu-luebeck.de.

Background: Sufficient androgen receptor (AR) activity is crucial for normal male sexual differentiation. Here we report on two unrelated 46, XY patients suffering from undervirilization and genital malformations. Both patients had a short polyglycine (polyG) repeat of 10 residues and a relatively long polyglutamine (polyQ) repeat of 28 and 30 residues within the transactivation domain of the AR. In addition, they also harbor a rare A645D substitution.

Objective: We made a set of AR expression plasmid constructs with varying polyQ and polyG tract sizes in context with or without the A645D substitution and analyzed their in vitro transactivation capacity in transfected CHO cells.

Results: We found that a short polyG repeat downmodulated AR activity to approximately 60–65% of the wild-type receptor. This effect was aggravated by A645D in context of a long polyQ repeat to less than 50% activity. In contrast, in the context of a short polyQ and a short polyG repeat, the A645D mutation rescues AR activity to almost wild-type levels, demonstrating a contradictory effect of this mutation, depending on the size of the polymorphic repeats.

Conclusions: A combination of a short polyG repeat with a long polyQ repeat and an A645D substitution might contribute to the development of virilization disorders and explain the observed phenotypes of our patients as a form of androgen insensitivity. The whole recreation of AR sequence variations including individual polymorphic repeat sizes could unravel possible interference of mutations and variations on AR activity by in vitro transfection.

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