title: PDE8A genetic variation, polycystic ovary syndrome and androgen levels in women.
abstract: Polycystic ovary syndrome (PCOS) is characterized by excessive theca cell androgen secretion, dependent upon LH, which acts through the intermediacy of 3',5'-cyclic adenosine 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 the ovary and testis. 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 c.407G > 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_010274.16: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. Sub-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 in vitro assays. The more common coding sequence SNP (N401S), and the promoter SNPs were not associated with PCOS in our transmission/disequilibrium test-based analysis, nor where they associated with total testosterone or dehydroepiandrosterone sulfate levels. These findings exclude a significant role for PDE8A as a PCOS candidate gene, and as a Las major determinant of androgen levels in women.
authors.affiliation: Department of Obstetrics and Gynecology, Virginia Commonwealth University, School of Medicine, Richmond, VA 23298, USA.
authors.forename: Chen
authors.initials: C
authors.lastname: Chen
authors.forename: Jessica
authors.initials: J
authors.lastname: Wickenheisser
authors.forename: Kathryn G
authors.initials: KG
authors.lastname: Ewens
authors.forename: Wendy
authors.initials: W
authors.lastname: Ankener
authors.forename: Richard S
authors.initials: RS
authors.lastname: Legro
authors.forename: Andrea
authors.initials: A
authors.lastname: Dunaif
authors.forename: Jan M
authors.initials: JM
authors.lastname: McAllister
authors.forename: Richard S
authors.initials: RS
authors.lastname: Spielman
authors.forename: Jerome F
authors.initials: JF
authors.lastname: Strauss
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000235:genetics*; D000595:Amino Acid Sequence; D000728:Androgens / Q000097:blood*; D000818:Animals; D019556:COS Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D019314:Dehydroepiandrosterone Sulfate / Q000378:metabolism; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008969:Molecular Sequence Data; D011085:Polycystic Ovary Syndrome / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid; D013739:Testosterone / Q000378:metabolism; D013799:Theca Cells / Q000378:metabolism
chemical_list: D000728:Androgens; D013739:Testosterone; D019314:Dehydroepiandrosterone Sulfate; D015105:3',5'-Cyclic-AMP Phosphodiesterases; C112770:PDE8A protein, human