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


RESULTS
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.


CONCLUSIONS
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.
Holterhus
Paul-Martin
PM
Department of Pediatrics, University-Hospital Schleswig-Holstein, Campus Kiel, Schwanenweg 20, Kiel, Germany. holterhus@pediatrics.uni-kiel.de
Deppe
Uta
U
Werner
Ralf
R
Richter-Unruh
Annette
A
Bebermeier
Jan-Hendrik
JH
Wünsch
Lutz
L
Krege
Susanne
S
Schweikert
Hans-Udo
HU
Demeter
Janos
J
Riepe
Felix
F
Hiort
Olaf
O
Brooks
James D
JD
D000728:Androgens / Q000502:physiology*; D016000:Cluster Analysis; D005260:Female; D005347:Fibroblasts / Q000378:metabolism*; D020869:Gene Expression Profiling; D005837:Genitalia, Male / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D008297:Male; D012333:RNA, Messenger / Q000235:genetics
D000728:Androgens; D012333:RNA, Messenger