Detailed Functional Studies On Androgen Receptor Mild Mutations Demonstrate Their Association With Male Infertility

Main Category: Fertility
Also Included In: Men's health;  Endocrinology;  Clinical Trials / Drug Trials
Article Date: 21 Nov 2007 - 0:00 PDT

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Mutations in the androgen receptor (AR) gene can cause the androgen insensitivity syndrome (AIS). For complete and severe partial AIS well-characterized in vitro functional assays can be used for genotype-phenotype correlation, however for mild forms of AIS, as associated with male infertility, experimental evidence is scarce or lacking. In particular, optimal in vitro functional tests informative about the genotype phenotype relation have not been described.

The objective of this study was to investigate the association among genotype and phenotype for AR mutations found in infertile males by conventional functional assays and additional in-depth studies performed with several gene-reporters. To this aim we selected 4 AR missense mutations associated with isolated male infertility (L547F and two novel mutations A474V and S650G) or partial AIS (Y571H). After introduction of the specific mutations in AR expression plasmid we performed classical in vitro studies (western immunoblotting, electrophoretic mobility shift assay, hormone-response curves) and transactivation assays with different reporter constructs (MMTV, Sc-ARU-TK, TAT-GRE-2X, Slp-ARU-TK, PEM).

Our results showed that standard functional tests (hormone dose-response curve and western immunoblotting) provide sufficient information only for severe AR mutations, found almost exclusively in CAIS and in some PAIS patients, whereas for AR mutations found in MAIS patients only an extensive analysis with different in vitro systems can lead to a comprehension of the "functional trend" of the receptor's response and therefore it can assess the association among the mutation and the infertile phenotype. If we would limit the analysis of AR mutations to the standard functional tests, we would lose the significance of 3 out of 4 mutations, and in particular of all the 3 mutations associated with male infertility. In the cases of mild AR mutations associated with male infertility, such a large number of different functional assays is needed because seminological, clinical and laboratory data cannot distinguish between patients with and without AR mutations. In fact, only 25% of the patients (2 out of 8) showed an elevated androgen insensitivity index which is considered the best parameter of androgen sensitivity. Among the different in vitro functional studies, transactivation assays with PEM promoter seems to be the most informative in these cases.

Written by:

D. Zuccarello, A. Ferlin, C. Vinanzi, E. Prana, A. Garolla, L. Callewaert, F. Claessens, A.O. Brinkmann, C. Foresta.

Reference:

Clin Endocrinol (Oxf). 2007 Oct 29; [Epub ahead of print]

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