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Differential gene-expression patterns in genital fibroblasts of normal males and 46,XY females with androgen insensitivity syndrome: evidence for early programming involving the androgen receptor

Paul-Martin Holterhus13*, Olaf Hiort3, Janos Demeter2, Patrick O Brown4* and James D Brooks1*

Author Affiliations

1 Department of Urology, Stanford University School of Medicine, Stanford, CA, 94305, USA

2 Department of Genetics, Stanford University School of Medicine, Stanford, CA, 94305, USA

3 Department of Pediatrics, University of Lübeck, 23538 Lübeck, Germany

4 Department of Biochemistry and the Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, 94305, USA

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Genome Biology 2003, 4:R37  doi:10.1186/gb-2003-4-6-r37

Published: 15 May 2003



Androgen insensitivity syndrome (AIS) comprises a range of phenotypes from male infertility to complete feminization. Most individuals with AIS carry germline mutations of the androgen receptor (AR) that interfere with or ablate its function. As genital fibroblasts retain expression of the AR in vitro, we used genital skin fibroblasts from normal males and 46,XY females with complete AIS due to known AR mutations to gain insights into the role of the AR in human genital differentiation.


Using DNA microarrays representing 32,968 different genes, we identified 404 transcripts with significant differences in transcription levels between genital skin fibroblasts cultured from normal and AIS-affected individuals. Gene-cluster analyses uncovered coordinated expression of genes involved in key processes of morphogenesis. On the basis of animal studies and human genetic syndromes, several of these genes are known to have specific roles in genital differentiation. Remarkably, genital fibroblasts from both normal and AIS-affected individuals showed no transcriptional response to dihydrotestosterone treatment despite expression of the AR.


The results suggest that in addition to differences in the anatomic origin of the cells, androgen signaling during prenatal development contributes to setting long-lasting, androgen-independent transcriptional programs in genital fibroblasts. Our findings have broad implications in understanding the establishment and the stability of sexual dimorphism in human genital development.