Lang Qin1,2,3,4,5, Shigang Zhao1,2,3,4,5, Ping Yang1,2,3,4,5, Yongzhi Cao1,2,3,4,5, Jiangtao Zhang1,2,3,4,5, Zi-Jiang Chen6,7,8,9,10,11, Andrea Dunaif12, Han Zhao13,14,15,16,17. 1. Center for Reproductive Medicine, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China. 2. Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, Shandong, China. 3. Shandong Key Laboratory of Reproductive Medicine, Jinan, Shandong, China. 4. Shandong Provincial Clinical Research Center for Reproductive Health, Jinan, Shandong, China. 5. National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, Shandong, China. 6. Center for Reproductive Medicine, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China. chenzijiang@hotmail.com. 7. Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, Shandong, China. chenzijiang@hotmail.com. 8. Shandong Key Laboratory of Reproductive Medicine, Jinan, Shandong, China. chenzijiang@hotmail.com. 9. Shandong Provincial Clinical Research Center for Reproductive Health, Jinan, Shandong, China. chenzijiang@hotmail.com. 10. National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, Shandong, China. chenzijiang@hotmail.com. 11. Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Center for Reproductive Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. chenzijiang@hotmail.com. 12. Division of Endocrinology, Metabolism, and Molecular Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. andrea.dunaif@mssm.edu. 13. Center for Reproductive Medicine, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China. hanzh80@yahoo.com. 14. Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, Shandong, China. hanzh80@yahoo.com. 15. Shandong Key Laboratory of Reproductive Medicine, Jinan, Shandong, China. hanzh80@yahoo.com. 16. Shandong Provincial Clinical Research Center for Reproductive Health, Jinan, Shandong, China. hanzh80@yahoo.com. 17. National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, Shandong, China. hanzh80@yahoo.com.
Abstract
PURPOSE: Anti-Müllerian hormone (AMH) is crucial for folliculogenesis. Prenatal exposure to AMH in mice produces a phenocopy of polycystic ovary syndrome (PCOS) in the adult female offspring. The aim of this study was to determine whether genetic variation in AMH gene contribute to PCOS in women of Chinese ancestry. METHODS: We conducted a case-control genetic study in 383 PCOS case and 433 control women of Chinese ancestry. The exons and the 5' flanking region of AMH were sanger sequenced. Bioinformatic prediction of variant deleteriousness was performed. RESULTS: Seven novel heterozygous variants along with 15 rare known variants in AMH were identified in women with PCOS but not in controls. The novel variants included one frameshift variant (c.125_129delACTTG), one synonymous variant (c.1095C>T), one variant (c.-14T>C) in the 5'-untranslated region (UTR), four variants(c.-775C>T, c.-682C>T, c.-333A>G, c.-137A>T) in 5' flanking sequence. Of all the AMH variants identified in women with PCOS, eight were predicted to be deleterious by bioinformatic analysis. The PCOS carriers of predicted-to-be-deleterious PCOS-specific AMH variants had increased total follicle numbers compared to PCOS noncarriers (p = 0.021). CONCLUSIONS: Our findings suggest the AMH plays a role in the development of PCOS. The exact mechanisms by which the predicted-to-be-deleterious novel and rare AMH variants described in our study affect AMH function requires further study.
PURPOSE: Anti-Müllerian hormone (AMH) is crucial for folliculogenesis. Prenatal exposure to AMH in mice produces a phenocopy of polycystic ovary syndrome (PCOS) in the adult female offspring. The aim of this study was to determine whether genetic variation in AMH gene contribute to PCOS in women of Chinese ancestry. METHODS: We conducted a case-control genetic study in 383 PCOS case and 433 control women of Chinese ancestry. The exons and the 5' flanking region of AMH were sanger sequenced. Bioinformatic prediction of variant deleteriousness was performed. RESULTS: Seven novel heterozygous variants along with 15 rare known variants in AMH were identified in women with PCOS but not in controls. The novel variants included one frameshift variant (c.125_129delACTTG), one synonymous variant (c.1095C>T), one variant (c.-14T>C) in the 5'-untranslated region (UTR), four variants(c.-775C>T, c.-682C>T, c.-333A>G, c.-137A>T) in 5' flanking sequence. Of all the AMH variants identified in women with PCOS, eight were predicted to be deleterious by bioinformatic analysis. The PCOS carriers of predicted-to-be-deleterious PCOS-specific AMH variants had increased total follicle numbers compared to PCOS noncarriers (p = 0.021). CONCLUSIONS: Our findings suggest the AMH plays a role in the development of PCOS. The exact mechanisms by which the predicted-to-be-deleterious novel and rare AMH variants described in our study affect AMH function requires further study.
Authors: Christien Weenen; Joop S E Laven; Anne R M Von Bergh; Mark Cranfield; Nigel P Groome; Jenny A Visser; Piet Kramer; Bart C J M Fauser; Axel P N Themmen Journal: Mol Hum Reprod Date: 2004-02 Impact factor: 4.025
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Authors: M Geoffrey Hayes; Margrit Urbanek; David A Ehrmann; Loren L Armstrong; Ji Young Lee; Ryan Sisk; Tugce Karaderi; Thomas M Barber; Mark I McCarthy; Stephen Franks; Cecilia M Lindgren; Corrine K Welt; Evanthia Diamanti-Kandarakis; Dimitrios Panidis; Mark O Goodarzi; Ricardo Azziz; Yi Zhang; Roland G James; Michael Olivier; Ahmed H Kissebah; Elisabet Stener-Victorin; Richard S Legro; Andrea Dunaif Journal: Nat Commun Date: 2015-08-18 Impact factor: 14.919