Journal
JOURNAL OF GENETICS AND GENOMICS
Volume 48, Issue 5, Pages 384-395Publisher
SCIENCE PRESS
DOI: 10.1016/j.jgg.2021.03.014
Keywords
LHCGR; ALMS1; Anovulation; Hyperandrogenemia; PCOS
Funding
- National Key Research and Development Program of China [2018YFC1002104, 2018YFC1004904, 2016YFC1000500]
- National Natural Science Foundation of China [81930036, 31521003, 31771669]
- Commission for Science and Technology of Shanghai Municipality [17JC1400902]
- MDA-CHB Research Grant
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Activating mutation of LHCGR likely plays important roles in the pathophysiology of PCOS involving abnormal reproductive physiology, while 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.
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 LHCGRL638P in granulosa-like tumor cell line (KGN) cells promoted cyclic adenosine monophosphate production and granulosa cell proliferation, indicating that LHCGRL638P 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. Copyright (C) 2021, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, and Genetics Society of China. Published by Elsevier Limited and Science Press. All rights reserved.
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