Functional Genetic Variation in the Anti-Müllerian Hormone Pathway in Women With Polycystic Ovary Syndrome

The Journal of Clinical Endocrinology and Metabolism
Lidija K GorsicMargrit Urbanek

Abstract

Polycystic ovary syndrome (PCOS) is a highly heritable, common endocrine disorder characterized by hyperandrogenism, irregular menses, and polycystic ovaries. PCOS is often accompanied by elevated levels of anti-Müllerian hormone (AMH). AMH inhibits follicle maturation. AMH also inhibits steroidogenesis through transcriptional repression of CYP17A1. We recently identified 16 rare PCOS-specific pathogenic variants in AMH. To test whether additional members of the AMH signaling pathway also contribute to the etiology of PCOS. Targeted resequencing of coding and regulatory regions of AMH and its specific type 2 receptor, AMHR2, was performed on 608 women affected with PCOS and 142 reproductively normal control women. Prediction tools of deleteriousness and in silico evidence of epigenetic modification were used to prioritize variants for functional evaluation. Dual-luciferase reporter assays and splicing assays were used to measure the impact of genetic variants on function. We identified 20 additional variants in/near AMH and AMHR2 with significantly reduced signaling activity in in vitro assays. Collectively, from our previous study and as reported herein, we have identified a total of 37 variants with impaired activity in/near ...Continue Reading

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May 1, 2019·The Journal of Clinical Endocrinology and Metabolism·Matthew DapasM Geoffrey Hayes
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Jul 8, 2019·Neuroendocrinology·Anne-Laure BarbotinPaolo Giacobini

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