Overexpression of a DENND1A isoform produces a polycystic ovary syndrome theca phenotype

McAllister, Jan M.; Modi, Bhavi P.; Miller, Brent W.; Biegler, Jessica M.; Bruggeman, Richard; Legro, Richard S.; Strauss, Jerome F.

doi:10.1073/pnas.1400574111

Cited by 192 publications

(173 citation statements)

References 54 publications

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“…The GCs used in the present study were collected from patients undergoing IVF (in vitro fertilization). On the other hand, much of the production of testosterone occurs in the theca cells (24) that surround the follicle and the GCs. Therefore, it is of significance to further confirm our findings in unstimulated and nonluteinized GCs and theca cells.…”

Section: Discussionmentioning

confidence: 99%

Alternative splicing of the androgen receptor in polycystic ovary syndrome

Wang

Pan

Liu

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Polycystic ovary syndrome (PCOS) is one of the most common female endocrine disorders and a leading cause of female subfertility. The mechanism underlying the pathophysiology of PCOS remains to be illustrated. Here, we identify two alternative splice variants (ASVs) of the androgen receptor (AR), insertion and deletion isoforms, in granulosa cells (GCs) in ∼62% of patients with PCOS. AR ASVs are strongly associated with remarkable hyperandrogenism and abnormalities in folliculogenesis, and are absent from all control subjects without PCOS. Alternative splicing dramatically alters genome-wide AR recruitment and androgeninduced expression of genes related to androgen metabolism and folliculogenesis in human GCs. These findings establish alternative splicing of AR in GCs as the major pathogenic mechanism for hyperandrogenism and abnormal folliculogenesis in PCOS.n ovarian follicles, oocytes are surrounded by granulosa cells (GCs), which have crucial endocrine functions. Polycystic ovary syndrome (PCOS) is a heterogeneous hormonal disorder affecting one in 15 women, and is one of the most common causes of female infertility (1). Hyperandrogenism and abnormal follicle development, associated with excessively small follicles and ovulatory dysfunction largely due to GCs dysfunction, characterize the pathogenesis of PCOS. Although the underlying etiology remains unclear, androgens and the androgen receptor (AR) are considered important on account of their critical roles in the prevalence of hyperandrogenism and ovarian folliculogenesis in this disorder (1-3).Androgens elicit their effects upon binding to AR, and AR functions primarily via genomic activities as a nuclear receptor. In the ovary, AR is predominantly expressed by GCs throughout most stages of follicular development. Nearly all reproductive phenotypes observed in global AR knockout mice have been attributed to a lack of AR expression in GCs (3). Haploinsufficiency for exon 3-deleted mutant AR is associated with a premature reduction in female fecundity (4), verifying the crucial role of classical genomic AR activity in normal ovarian function. Clinical studies have suggested that PCOS might be associated with AR (CAG)n repeats (5) and rs6152A (6) gene polymorphisms. These studies promoted interest in investigating the effects of AR in GC dysfunction in PCOS women. We therefore hypothesized that abnormally expressed and/or dysfunctional AR plays an important role in the pathogenesis of PCOS. ResultsAlternative Splice Variants of AR in GCs of PCOS Women. Nested RT-PCR (Fig. S1A) was used to amplify AR cDNAs from GCs of Southeastern Han Chinese women undergoing in vitro fertilization and embryo transfer. We identified two alternative splice variants (ASVs) expressed exclusively in PCOS women. One ASV inserted 69 bp into intron 2 (ivs2) between exons 2 and 3 (insertion isoform, ins) whereas the other skipped exon 3 (deletion isoform, del), as demonstrated by agarose gel electrophoresis (Fig. 1A) and PCR product sequencing (Fig. 1B). AR ASVs were not detected in ...

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Section: Discussionmentioning

confidence: 99%

Alternative splicing of the androgen receptor in polycystic ovary syndrome

Wang

Pan

Liu

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Expression of one variant, DENND1A.V2 , is greater in PCOS theca cells. Curiously, knockdown of this variant recapitulates a normal theca cell phenotype in PCOS ovaries, whereas overexpression in theca cells from normal women recapitulates PCOS phenotype [12]. The mechanism governing the regulation of the alternative splicing appears to reside outside of the DENND1A gene [13].…”

Section: A Pathophysiologymentioning

confidence: 99%

An International Consortium Update: Pathophysiology, Diagnosis, and Treatment of Polycystic Ovarian Syndrome in Adolescence

Ibáñez¹,

et al. 2017

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This paper represents an international collaboration of paediatric endocrine and other societies (listed in the Appendix) under the International Consortium of Paediatric Endocrinology (ICPE) aiming to improve worldwide care of adolescent girls with polycystic ovary syndrome (PCOS)¹. The manuscript examines pathophysiology and guidelines for the diagnosis and management of PCOS during adolescence. The complex pathophysiology of PCOS involves the interaction of genetic and epigenetic changes, primary ovarian abnormalities, neuroendocrine alterations, and endocrine and metabolic modifiers such as anti-Müllerian hormone, hyperinsulinemia, insulin resistance, adiposity, and adiponectin levels. Appropriate diagnosis of adolescent PCOS should include adequate and careful evaluation of symptoms, such as hirsutism, severe acne, and menstrual irregularities 2 years beyond menarche, and elevated androgen levels. Polycystic ovarian morphology on ultrasound without hyperandrogenism or menstrual irregularities should not be used to diagnose adolescent PCOS. Hyperinsulinemia, insulin resistance, and obesity may be present in adolescents with PCOS, but are not considered to be diagnostic criteria. Treatment of adolescent PCOS should include lifestyle intervention, local therapies, and medications. Insulin sensitizers like metformin and oral contraceptive pills provide short-term benefits on PCOS symptoms. There are limited data on anti-androgens and combined therapies showing additive/synergistic actions for adolescents. Reproductive aspects and transition should be taken into account when managing adolescents.

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“…Intrinsic abnormalities in ovarian steroidogenesis may underlie this ovarian dysfunction in some [7,8] . However, additional factors, such as insulin resistance and/or hyperinsulinemia, may play a major role.…”

Section: Introductionmentioning

confidence: 99%

The Diagnosis of Polycystic Ovary Syndrome during Adolescence

et al. 2015

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dress a series of questions regarding the diagnosis of PCOS during adolescence including the following: clinical and biochemical evidence of hyperandrogenism, criteria for oligoanovulation and polycystic ovary morphology, diagnostic criteria to exclude other causes of hyperandrogenism and amenorrhea, role of insulin resistance, and intervention. Results and Conclusion: Features of PCOS overlap normal pubertal development. Hence, caution should be taken before diagnosing PCOS without longitudinal evaluation. However, treatment may be indicated even in the absence of a definitive diagnosis. While obesity, insulin resistance, and hyperinsulinemia are common findings in adolescents with hyperandrogenism, these features should not be used to diagnose PCOS among adolescent girls. © 2015 S. Karger AG, Basel Key WordsHyperandrogenism · Ovarian hyperandrogenism · Ovary · Polycystic ovary syndrome · Puberty Abstract Background/Aims: The diagnostic criteria for polycystic ovary syndrome (PCOS) in adolescence are controversial, primarily because the diagnostic pathological features used in adult women may be normal pubertal physiological events. Hence, international pediatric and adolescent specialty societies have defined criteria that have sufficient evidence to be used for the diagnosis of PCOS in adolescents. Methods: The literature has been reviewed and evidence graded to ad-

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Overexpression of a DENND1A isoform produces a polycystic ovary syndrome theca phenotype

Cited by 192 publications

References 54 publications

Alternative splicing of the androgen receptor in polycystic ovary syndrome

Alternative splicing of the androgen receptor in polycystic ovary syndrome

An International Consortium Update: Pathophysiology, Diagnosis, and Treatment of Polycystic Ovarian Syndrome in Adolescence

The Diagnosis of Polycystic Ovary Syndrome during Adolescence

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