Alternative splicing of the androgen receptor in polycystic ovary syndrome

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 112; no. 15; pp. 4743 - 4748
• Main Authors: Wang, Fangfang, Pan, Jiexue, Liu, Ye, Meng, Qing, Lv, Pingping, Qu, Fan, Ding, Guo-Lian, Klausen, Christian, Leung, Peter C. K., Chan, Hsiao Chang, Yao, Weimiao, Zhou, Cai-Yun, Shi, Biwei, Zhang, Junyu, Sheng, Jianzhong, Huang, Hefeng
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 14.04.2015; National Acad Sciences
• Subjects: Adult; Alternative Splicing; androgen receptors; Androgens; animal ovaries; Base Sequence; Biological Sciences; Cells; Cells, Cultured; Dehydroepiandrosterone - blood; Endocrine system; etiology; Female; Gene Expression Profiling; Genes; Genome-Wide Association Study; Granulosa Cells - metabolism; HEK293 Cells; Humans; Hyperandrogenism - blood; Hyperandrogenism - genetics; INDEL Mutation; metabolism; Oogenesis - genetics; Ovarian Follicle - physiopathology; Polycystic ovary syndrome; Polycystic Ovary Syndrome - blood; Polycystic Ovary Syndrome - genetics; Polycystic Ovary Syndrome - physiopathology; Protein Isoforms - genetics; Receptors, Androgen - genetics; Reverse Transcriptase Polymerase Chain Reaction; Testosterone - blood; women; Womens health; AR; folliculogenesis; PCOS; splicing; hyperandrogenism
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1418216112

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. Significance Excess androgens and abnormal follicle development, largely due to ovarian granulosa cell (GC) dysfunction, characterize polycystic ovary syndrome (PCOS), a common endocrinopathy of women predisposing to infertility. Thus, it is important to understand GC dysfunction. The androgen receptor (AR) is widely believed to be an essential regulator of GC biology. High expression of AR in GCs is primarily considered to associate with PCOS. However, we show that AR alternative splice variants in GCs disturb androgen metabolism and follicle growth, leading to PCOS because of impaired transcription factor function. These data considerably change our understanding of the role of AR in the etiology of PCOS, and inform the development of clinical diagnostic and classification tests as well as novel therapeutic interventions.