title: Alternative splicing of the androgen receptor in polycystic ovary syndrome.
abstract: 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 androgen-induced 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.
authors.affiliation: The Key Laboratory of Reproductive Genetics, Ministry of Education (Zhejiang University), Hangzhou 310058, China;
authors.forename: Fangfang
authors.initials: F
authors.lastname: Wang
authors.affiliation: The Key Laboratory of Reproductive Genetics, Ministry of Education (Zhejiang University), Hangzhou 310058, China;
authors.forename: Jiexue
authors.initials: J
authors.lastname: Pan
authors.affiliation: The Key Laboratory of Reproductive Genetics, Ministry of Education (Zhejiang University), Hangzhou 310058, China;
authors.forename: Ye
authors.initials: Y
authors.lastname: Liu
authors.affiliation: The Key Laboratory of Reproductive Genetics, Ministry of Education (Zhejiang University), Hangzhou 310058, China;
authors.forename: Qing
authors.initials: Q
authors.lastname: Meng
authors.affiliation: The Key Laboratory of Reproductive Genetics, Ministry of Education (Zhejiang University), Hangzhou 310058, China;
authors.forename: Pingping
authors.initials: P
authors.lastname: Lv
authors.affiliation: The Key Laboratory of Reproductive Genetics, Ministry of Education (Zhejiang University), Hangzhou 310058, China;
authors.forename: Fan
authors.initials: F
authors.lastname: Qu
authors.affiliation: The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China;
authors.forename: Guo-Lian
authors.initials: GL
authors.lastname: Ding
authors.affiliation: Department of Obstetrics and Gynecology, Child and Family Research Institute, University of British Columbia, Vancouver, BC, Canada V5Z 4H4;
authors.forename: Christian
authors.initials: C
authors.lastname: Klausen
authors.affiliation: Department of Obstetrics and Gynecology, Child and Family Research Institute, University of British Columbia, Vancouver, BC, Canada V5Z 4H4;
authors.forename: Peter C K
authors.initials: PC
authors.lastname: Leung
authors.affiliation: Epithelial Cell Biology Research Center, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong 999077, China; and.
authors.forename: Hsiao Chang
authors.initials: HC
authors.lastname: Chan
authors.affiliation: Women's Hospital and.
authors.forename: Weimiao
authors.initials: W
authors.lastname: Yao
authors.affiliation: Women's Hospital and.
authors.forename: Cai-Yun
authors.initials: CY
authors.lastname: Zhou
authors.affiliation: Women's Hospital and.
authors.forename: Biwei
authors.initials: B
authors.lastname: Shi
authors.affiliation: The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China;
authors.forename: Junyu
authors.initials: J
authors.lastname: Zhang
authors.affiliation: The Key Laboratory of Reproductive Genetics, Ministry of Education (Zhejiang University), Hangzhou 310058, China; Department of Pathology and Pathophysiology, School of Medicine, Zhejiang University, Hangzhou 310058, China.
authors.forename: Jianzhong
authors.initials: J
authors.lastname: Sheng
authors.affiliation: The Key Laboratory of Reproductive Genetics, Ministry of Education (Zhejiang University), Hangzhou 310058, China; The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China; huanghefg@hotmail.com.
authors.forename: Hefeng
authors.initials: H
authors.lastname: Huang
mesh_terms: D000328:Adult; D017398:Alternative Splicing; D001483:Base Sequence; D002478:Cells, Cultured; D003687:Dehydroepiandrosterone / Q000097:blood; D005260:Female; D020869:Gene Expression Profiling; D055106:Genome-Wide Association Study; D006107:Granulosa Cells / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D017588:Hyperandrogenism / Q000097:blood / Q000235:genetics; D054643:INDEL Mutation; D009866:Oogenesis / Q000235:genetics; D006080:Ovarian Follicle / Q000503:physiopathology; D011085:Polycystic Ovary Syndrome / Q000097:blood / Q000235:genetics* / Q000503:physiopathology; D020033:Protein Isoforms / Q000235:genetics; D011944:Receptors, Androgen / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013739:Testosterone / Q000097:blood
chemical_list: C410798:AR protein, human; D020033:Protein Isoforms; D011944:Receptors, Androgen; D013739:Testosterone; D003687:Dehydroepiandrosterone
keywords: AR; PCOS; folliculogenesis; hyperandrogenism; splicing
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