LHCGR and ALMS1 defects likely cooperate in the development of polycystic ovary syndrome indicated by double-mutant mice. (20th May 2021)

• Record Type: Journal Article
• Authors: Yu, Li; Wang, Lina; Tao, Wufan; Zhang, Wenxiang; Yang, Shuanghao; Wang, Jian; Fei, Jia; Peng, Rui; Wu, Yiming; Zhen, Xiumei; Shao, Hong; Gu, Weiyue; Li, Rong; Wu, Bai-Lin; Wang, Hongyan
• Is Part Of: Journal of genetics and genomics. Volume 48:Number 5(2021)
• Page Start: 384
• Page End: 395
• Publication Date: 2021-05-20
• Subjects: LHCGR -- ALMS1 -- Anovulation -- Hyperandrogenemia -- PCOS; Genetics -- Periodicals; Genomics -- Periodicals; 576.505
• DOI: 10.1016/j.jgg.2021.03.014
• Languages: English
• ISSNs: 1673-8527

Abstract

Abstract: Polycystic ovary syndrome (PCOS) is a heterogeneous disorder with evidence of polygenetic components, and obesity may be a risk factor for hyperandrogenism. Previous studies have shown that LHCGR is enriched in the ovary and LHCGR deficiency causes infertility without typical PCOS phenotypes. ALMS1 is implicated in obesity and hyperandrogenism, the common phenotypes among PCOS patients. Through whole-exome sequencing of 22 PCOS families and targeted candidate gene sequencing of additional 65 sporadic PCOS patients, we identified potential causative mutations in LHCGR and ALMS1 in a sibling-pair PCOS family and three sporadic PCOS patients. The expression of LHCGR L638P in granulosa-like tumor cell line (KGN) cells promoted cyclic adenosine monophosphate production and granulosa cell proliferation, indicating that LHCGR L638P is an activating mutation. Lhcgr L642P/L642P mice showed an irregular estrous cycle, reduced follicles with dynamic folliculogenesis, and increased testosterone (T), estradiol (E2), and dehydroepiandrosterone. Lhcgr +/L642P Alms1 +/PB mice displayed increased T and E2 but decreased late secondary and preovulatory follicles. We showed that activating mutation of LHCGR likely plays important roles in the pathophysiology of PCOS involving abnormal reproductive physiology, whereas ALMS1 deficiency may promote anovulatory infertility via elevated androgens, suggesting that the disturbed LHCGR and ALMS1 cooperatively induce PCOS phenotypes, characterized as anovulation and hyperandrogenemia frequently observed in PCOS patients with obesity.