Mol. Hum. Reprod. Advance Access published online on May 29, 2009
Molecular Human Reproduction, doi:10.1093/molehr/gap035
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PDE8A Genetic Variation, Polycystic Ovary Syndrome and Androgen Levels in Women
1Department of Obstetrics and Gynecology, Virginia Commonwealth University, Virginia, USA 2Department of Molecular Physiology, Penn State Hershey Medical Center, Pennsylvania, USA 3Department of Genetics, University of Pennsylvania School of Medicine, Pennsylvania, USA 4Department of Obstetrics & Gynecology, Penn State Hershey Medical Center, Pennsylvania, USA 5Department of Medicine, Northwestern University School of Medicine, Illinois, USA
* Correspondence to: Jerome F. Strauss III, M.D., Ph.D. Virginia Commonwealth University, School of Medicine, Richmond, Virginia, 23298 USA Email: jfstrauss{at}vcu.edu
Polycystic ovary syndrome (PCOS) is characterized by excessive theca cell androgen secretion, dependent upon LH, which acts through the intermediacy of adenosine 3’, 5’-cyclic monophosphate (cAMP). cAMP signaling pathways are controlled through regulation of its synthesis by adenylyl cyclases, and cAMP degradation by phosphodiesterases (PDEs). PDE8A, a high-affinity cAMP-specific PDE is expressed in ovary and testis cells. Leydig cells from mice with a targeted mutation in the PDE8A gene are sensitized to the action of LH in terms of testosterone production. These observations led us to evaluate the human PDE8A gene as a PCOS candidate gene and the hypothesis that reduced PDE8A activity or expression would contribute to excessive ovarian androgen production. We identified a rare variant (R136Q; NM_002605.2 [GenBank] c.407 G>A) and studied another known single nucleotide polymorphism (SNP) (rs62019510, N401S) in the PDE8A coding sequence causing non-synonymous amino acid substitutions, and a new SNP in the promoter region (NT_010274 [GenBank] .16:g.490155G>A). Although PDE8A kinetics were consistent with reduced activity in theca cell lysates, study of the expressed variants did not confirm reduced activity in cell-free assays. Cellular localization of the enzyme was also not different among the coding sequence variants. The PDE8A promoter SNP and a previously described promoter SNP did not affect promoter activity in vitro assays. The more common coding sequence SNP (N401S), and the promoter SNPs were not associated with PCOS in our transmission/disequilibrium test (TDT)-based analysis, nor where they associated with total testosterone or hydroepiandrosterone sulphate (DHEAS) levels. These findings exclude a significant role for PDE8A as a PCOS candidate gene and a major determinant of androgen levels in women.
Key Words: PDE8A/Polycystic Ovary Syndrome (PCOS)/Androgens/Theca/SNP
Submitted on April 17, 2009; resubmitted on May 16, 2009; accepted on May 18, 2009.