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Intrinsic androgen-dependent gene expression patterns revealed by comparison of genital fibroblasts from normal males and individuals with complete and partial androgen insensitivity syndrome

Paul-Martin Holterhus1*, Uta Deppe2, Ralf Werner2, Annette Richter-Unruh3, Jan-Hendrik Bebermeier2, Lutz Wünsch4, Susanne Krege5, Hans-Udo Schweikert6, Janos Demeter7, Felix Riepe1, Olaf Hiort2 and James D Brooks8

Author Affiliations

1 Department of Pediatrics, University-Hospital Schleswig-Holstein, Campus Kiel, Schwanenweg 20, Kiel, Germany

2 Department of Pediatric and Adolescent Medicine, University-Hospital Schleswig-Holstein, Campus Lübeck, Ratzeburger Allee 160, Lübeck, Germany

3 Endokrinologikum Ruhr, Alter Markt 4, Bochum, Germany

4 Department of Pediatric Surgery, University Hospital Schleswig-Holstein, Campus Lübeck, Ratzeburger Allee 160, Lübeck, Germany

5 Department of Urology, University of Essen, Essen, Germany

6 Department of Internal Medicine, University of Bonn, Bonn, Germany

7 Department of Genetics, Stanford University School of Medicine, CA, USA

8 Department of Urology, Stanford University School of Medicine, CA, USA

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BMC Genomics 2007, 8:376  doi:10.1186/1471-2164-8-376

Published: 18 October 2007



To better understand the molecular programs of normal and abnormal genital development, clear-cut definition of androgen-dependent gene expression patterns, without the influence of genotype (46, XX vs. 46, XY), is warranted. Previously, we have identified global gene expression profiles in genital-derived fibroblasts that differ between 46, XY males and 46, XY females with complete androgen insensitivity syndrome (CAIS) due to inactivating mutations of the androgen receptor (AR). While these differences could be due to cell autonomous changes in gene expression induced by androgen programming, recent work suggests they could also be influenced by the location from which the fibroblasts were harvested (topology). To minimize the influence of topology, we compared gene expression patterns of fibroblasts derived from identical urogenital anlagen: the scrotum in normally virilized 46, XY males and the labia majora from completely feminized 46, XY individuals with CAIS.


612 transcripts representing 440 unique genes differed significantly in expression levels between scrotum and CAIS labia majora, suggesting the effects of androgen programming. While some genes coincided with those we had identified previously (TBX3, IGFBP5, EGFR, CSPG2), a significant number did not, implying that topology had influenced gene expression in our previous experiments. Supervised clustering of gene expression data derived from a large set of fibroblast cultures from individuals with partial AIS revealed that the new, topology controlled data set better classified the specimens.


Inactivating mutations of the AR, in themselves, appear to induce lasting changes in gene expression in cultured fibroblasts, independent of topology and genotype. Genes identified are likely to be relevant candidates to decipher androgen-dependent normal and abnormal genital development.