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Increased Transcription and Increased Messenger Ribonucleic Acid (mRNA) Stability Contribute to Increased GATA6 mRNA Abundance in Polycystic Ovary Syndrome Theca Cells

Center for Research on Reproduction and Women’s Health (C.K.M.H., J.R.W., Z.Z., J.F.S.) and Department of Genetics (D.R.S., K.E., W.A., R.S.), University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104; Departments of Cellular and Molecular Physiology (J.W., V.N.-D., J.M.M.) and Obstetrics and Gynecology (R.S.L.), Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033; and Division of Endocrinology, Metabolism, and Molecular Medicine (A.D.), Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611

Address all correspondence and requests for reprints to: Jerome F. Strauss III, M.D., Ph.D., Dean, School of Medicine, Virginia Commonwealth University, Sanger Hall, 1101 East Marshall Street, Room 1-071, P.O. Box 980565, Richmond, Virginia 23298. E-mail: jfstrauss{at}vcu.edu.

Context: Polycystic ovary syndrome (PCOS) theca cells secrete increased levels of androgens. The mRNA and protein levels of the transcription factor GATA6, which regulates expression of several steroidogenic enzymes, are increased in PCOS theca cells. Thus, GATA6 is a PCOS candidate gene.

Objective: The objective of the study was to explore mechanisms by which GATA6 mRNA levels are increased in PCOS theca cells.

Design: Theca cell cDNA and genomic DNA from normal individuals and PCOS patients were subjected to quantitative RT-PCR and sequence analysis, respectively.

Setting: The experiments were performed in a university laboratory.

Participants: Four hundred sixty-nine families that contain at least one PCOS patient were ascertained for genetic studies. Theca cells were obtained from four normal individuals and four PCOS patients.

Results: Nascent GATA6 transcript levels, which reflect GATA6 gene transcription, were significantly increased in PCOS theca cells. In normal theca cells, GATA6 mRNA has a short half-life, which was attributed to an AU-rich 3'-untranslated region sequence. The half-life of GATA6 transcripts was also significantly longer in the PCOS theca cells. However, no sequence variations in the GATA6 gene locus were associated with PCOS.

Conclusions: In PCOS theca cells, GATA6 gene transcription and the stability of the GATA6 mRNA are increased. Because there is no sequence variation in the GATA6 gene locus, which is associated with PCOS, it is likely that the increased gene transcription and mRNA stability are due to intrinsic differences in PCOS theca cells.

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