LHCGR and ALMS1 defects likely cooperate in the development of polycystic ovary syndrome indicated by double-mutant mice  

作　　者：Li Yu Lina Wang Wufan Tao Wenxiang Zhang Shuanghao Yang Jian Wang Jia Fei Rui Peng Yiming Wu Xiumei Zhen Hong Shao Weiyue Gu Rong Li Bai-Lin Wu Hongyan Wang 

机构地区：[1]Institutes of Biomedical Sciences,Fudan University,Shanghai 200032,China [2]Children’s Hospital,Institutes of Reproduction and Development,Fudan University,Shanghai 201102,China [3]Department of Laboratory Medicine,Zhongshan Hospital,Fudan University,Shanghai 200032,China [4]Center for Reproductive Medicine,Department of Obstetrics and Gynecology,Peking University Third Hospital,Beijing 100191,China [5]Boston Children's Hospital and NGS collaboration,Harvard Medical School,Boston MA 02115,USA [6]National Clinical Research Center for Obstetrics and Gynecology,Peking University Third Hospital,Beijing 100191,China [7]Obstetrics and Gynecology Hospital,NHC Key Laboratory of Reproduction Regulation(Shanghai Institute of Planned Parenthood Research),State Key Laboratory of Genetic Engineering at School of Life Sciences,Institute of Metabolism and Integrative Biology,Fudan University,Shanghai 200011,China [8]Institute of Developmental Biology&Molecular Medicine,Fudan University,Shanghai 200433,China [9]Reproductive Medicine Centre,Anhui Medical University,Hefei 230032,China [10]Chigene Translational Medicine Research Center,Beijing 100875,China [11]Shanghai Children’s Medical Center,Shanghai Jiaotong University,Shanghai 200127,China [12]Zhongke Genetics and Reproductive Medicine Institute,Beijing 102600,China

出　　处：《Journal of Genetics and Genomics》2021年第5期384-395,共12页遗传学报（英文版）

基　　金：jointly supported by the National Key Research and Development Program of China(2018YFC1002104 to L.W.,2018YFC1004904 to B.-L.W.and J.F.,2016YFC1000500 to H.Y.W.and W.F.T.);the National Natural Science Foundation of China([81930036,31521003,31771669]to H.Y.W.);the Commission for Science and Technology of Shanghai Municipality(17JC1400902to H.Y.W.);the MDA-CHB Research Grant to B.-L.W。

摘　　要：Polycystic ovary syndrome(PCOS)is a heterogeneous disorder with evidence of polygenetic components,and obesity may be a risk factor for hyperandrogen ism.Previous studies have shown that LHCGR is en riched 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 LHCGRL638 P in granulosa-like tumor cell line(KGN)cells promoted cyclic adenosine monophosphate production and granulosa cell proliferation,indicating that LHCGRL638 P is an activating mutation.Lhcgr~(L642 P/L642 P)mice showed an irregular estrous cycle,reduced follicles with dynamic folliculogenesis,and increased testosterone(T),estradiol(E2),and dehydroepiandrosterone.Lhcgr~(+/L642 P)AIms1~(+/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.

关 键 词：LHCGR ALMS1 ANOVULATION Hyperandrogenemia PCOS 

分 类 号：R711.75[医药卫生—妇产科学]