Family-Based Analysis of Candidate Genes for Polycystic Ovary Syndrome

Ewens, Kathryn G.; Stewart, Douglas R.; Ankener, Wendy; Urbanek, Margrit; McAllister, Jan M.; Chen, Chen; Baig, K. Maravet; Parker, Stephen C. J.; Margulies, Elliot H.; Legro, Richard S.; Dunaif, Andrea; Strauss, Jerome F.; Spielman, Richard S.

doi:10.1210/jc.2009-2703

Cited by 105 publications

(59 citation statements)

References 39 publications

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“…Androgens might have their effect on PCOS offspring in a more indirect manner such as fetal programming. This is in line with twin (7,22) and genetic (8,9,10,11) studies that demonstrate high heritability of PCOS and particularly hyperandrogenism (12). Furthermore, it remains questionable how closely cord blood reflects actual fetal androgen exposure during gestation (53).…”

Section: Discussionmentioning

confidence: 67%

“…PCOS is characterized by at least two of the following criteria: oligo-or amenorrhoea, signs of PCOS is a complex genetic disease and the phenotype is likely the result of the interplay of variation in a number of different genes with environmental factors. Twin (7) and genetic studies (8,9,10,11) show high heritability of PCOS, and particularly hyperandrogenism (12). The pathophysiology of PCOS is still poorly understood.…”

Section: Introductionmentioning

confidence: 99%

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Mass spectrometry methods measured androgen and estrogen concentrations during pregnancy and in newborns of mothers with polycystic ovary syndrome

Caanen

Kuijper

Hompes

et al. 2016

European Journal of Endocrinology

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Objective: Little is known about the aetiology of polycystic ovary syndrome (PCOS). Some suggest that elevated maternal androgens during gestation play a causative role. This implies placental passage of androgens during pregnancy. The aim of this study is to compare androgen and estrogen concentrations in maternal serum during pregnancy and in umbilical cord blood, between mothers with PCOS and their offspring compared to controls. Design: Prospective case-control study. Methods: Maternal blood samples were collected around 20 weeks of gestation and at delivery. Umbilical cord blood was also taken at delivery. Androgens (testosterone (T), androstenedione (ADION), dehydroepiandrostenedione (DHEA)) and estrogens (estrone (E 1 ), estradiol (E 2 ), estriol (E 3 )) were measured using the liquid chromatography tandem mass spectrometry (LC-MS/MS) methods. Results: At 20 weeks of gestation: T (PZ0.019) and ADION (PZ0.034) were higher in the PCOS mothers (pregnant with a girl), whereas DHEA, E 1 , E 2 , and E 3 were not different. Maternal concentration at birth: T (PZ0.004) and ADION (PZ0.009) were also higher in the subgroup of PCOS mothers that were pregnant with a girl compared to the girl pregnancy controls. DHEA, E 1 , E 2 and E 3 were not different. In umbilical cord blood, no differences were found for T, ADION, DHEA, E 2 , E 3 , and AMH between the PCOS mothers and the controls respectively. E 1 was lower in girls from PCOS mothers (PZ0.007). Conclusions: Despite elevated maternal androgen concentrations during pregnancy in PCOS mothers, offspring showed no signs of elevated androgen concentrations in cord blood at birth using the latest highly specific LC-MS/MS methods.

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Section: Discussionmentioning

confidence: 67%

Section: Introductionmentioning

confidence: 99%

Mass spectrometry methods measured androgen and estrogen concentrations during pregnancy and in newborns of mothers with polycystic ovary syndrome

Caanen

Kuijper

Hompes

et al. 2016

European Journal of Endocrinology

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“…However, subsequently mutations leading to recessive Weill-Marchesani syndrome were identified in ADAMTS10 (Dagoneau et al, 2004). Linkage and immunohistochemical analyses strongly suggests a role for fibrillin-3 in the pathogenesis of polycystic ovary syndrome (Urbanek et al, 2005;Stewart et al, 2006;Ewens et al, 2010;Jordan et al, 2010). Functional single nucleotide polymorphism analysis, however, argued against this possibility (Prodoehl et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Fibrillin-3 expression in human development

et al. 2011

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Fibrillin proteins are the major components of extracellular microfibrils found in many connective tissues. Fibrillin-1 and fibrillin-2 are well studied and mutations in these proteins cause a number of fibrillinopathies including Marfan syndrome and congenital contractural arachnodactyly, respectively. Fibrillin-3 was more recently discovered and is much less well characterized. Fibrillin-1 is expressed throughout life, whereas fibrillin-2 and -3 are thought to be primarily present during development. Here, we report detailed fibrillin-3 expression patterns in early human development.A polyclonal antiserum against a C-terminal recombinant half of human fibrillin-3 was produced in rabbit. Anti-fibrillin-3 antibodies were affinity-purified and antibodies cross-reacting with the other fibrillins were removed by absorption resulting in specific anti-fibrillin-3 antibodies. Immunohistochemical analyses with these purified antibodies demonstrate that fibrillin-3 is temporally expressed in numerous tissues relatively evenly from the 6 th to the 12 th gestational week. Fibrillin-3 was found spatially expressed in perichondrium, perineurium, perimysium, skin, developing bronchi, glomeruli, pancreas, kidney, heart and testis and at the prospective basement membranes in developing epithelia and endothelia. Double immunohistochemical analyses showed that all fibrillins are globally expressed in the same organs, with a number of differences on the tissue level in cartilage, perichondrium and developing bronchi. These results suggest that fibrillin-3, compared to the other fibrillins, fulfills both overlapping and distinct functions in human development.

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“…Genes that map to within 100 kb of D19S884 are FBN3 (encoding fibrillin-3), ELAVL1 (encoding an mRNA-binding protein), and CCL25 (encoding a thymus-expressed chemokine) (Urbanek et al 2005). The dinucleotide repeat D19S884, which maps to intron 55 of the FBN3, was identified as the most likely PCOS susceptibility locus, and this polymorphic variant within FBN3 confers an increased risk of PCOS (Urbanek et al 2005;Stewart et al 2006;Ewens et al 2010). The PCOS susceptibility allele, A8, is also associated with metabolic consequences seen in both the women with PCOS and their brothers (Urbanek et al 2007).…”

mentioning

confidence: 99%

Fibrillins in Adult Human Ovary and Polycystic Ovary Syndrome: Is Fibrillin-3 Affected in PCOS?

Jordan

Bohling

Charbonneau

et al. 2010

J Histochem Cytochem.

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(LYS) S U M M A R Y Polycystic ovary syndrome (PCOS) is a common endocrinopathy in women of reproductive age. Although genetic linkage analyses have demonstrated a susceptibility locus for PCOS mapping to the fibrillin-3 gene, the presence of fibrillin proteins in normal and polycystic ovaries has not been characterized. This study compared and contrasted fibrillin-1, -2, and -3 localization in normal and polycystic ovaries. Immunohistochemical stainings of ovaries from 21 controls and 9 patients with PCOS were performed. Fibrillin-1 was ubiquitous in ovarian connective tissue. Fibrillin-2 localized around antral follicles and in areas of folliculolysis. Fibrillin-3 was present in a restricted distribution within the specialized perifollicular stroma of follicles in morphological transition from primordial to primary type [transitional follicles (TFs)]. Fibrillin-1 and -2 stainings of PCOS ovaries were similar to those of the controls. However, in eight of the nine PCOS ovaries, there was a decrease in the number of TFs associated with fibrillin-3, including no staining in five PCOS samples; decreased number of fibrillin-3-associated TFs/mm 2 was confirmed by quantitative analysis. Our findings support a role for fibrillin-3 in the pathogenesis of PCOS and suggest fibrillin-3 may function in primordial to primary follicle transition. We propose that loss of fibrillin-3 during folliculogenesis may be an important factor in PCOS pathogenesis. (J Histochem Cytochem 58:903-915, 2010)

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Family-Based Analysis of Candidate Genes for Polycystic Ovary Syndrome

Abstract: A polymorphic variant, D19S884, in FBN3 is associated with risk of PCOS. POMC is also a candidate gene of interest.

Cited by 105 publications

References 39 publications

Mass spectrometry methods measured androgen and estrogen concentrations during pregnancy and in newborns of mothers with polycystic ovary syndrome

Mass spectrometry methods measured androgen and estrogen concentrations during pregnancy and in newborns of mothers with polycystic ovary syndrome

Fibrillin-3 expression in human development

Fibrillins in Adult Human Ovary and Polycystic Ovary Syndrome: Is Fibrillin-3 Affected in PCOS?

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