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

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

doi:10.1016/j.jgg.2021.03.014

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

J Genet Genomics. 2021 May 20;48(5):384-395. doi: 10.1016/j.jgg.2021.03.014. Epub 2021 May 1.

Authors

Li Yu¹, Lina Wang², Wufan Tao³, Wenxiang Zhang⁴, Shuanghao Yang⁵, Jian Wang⁶, Jia Fei⁷, Rui Peng⁸, Yiming Wu⁹, Xiumei Zhen¹⁰, Hong Shao¹¹, Weiyue Gu⁵, Rong Li¹², Bai-Lin Wu¹³, Hongyan Wang¹⁴

Affiliations

¹ Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China; Children's Hospital, Institutes of Reproduction and Development, Fudan University, Shanghai 201102, China; Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
² Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing 100191, China; Boston Children's Hospital and NGS collaboration, Harvard Medical School, Boston MA 02115, USA; National Clinical Research Center for Obstetrics and Gynecology, Peking University Third Hospital, Beijing 100191, China. Electronic address: bwanglina@sina.com.
³ 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; Institute of Developmental Biology & Molecular Medicine, Fudan University, Shanghai 200433, China.
⁴ Boston Children's Hospital and NGS collaboration, Harvard Medical School, Boston MA 02115, USA; Reproductive Medicine Centre, Anhui Medical University, Hefei 230032, China.
⁵ Boston Children's Hospital and NGS collaboration, Harvard Medical School, Boston MA 02115, USA; Chigene Translational Medicine Research Center, Beijing 100875, China.
⁶ Boston Children's Hospital and NGS collaboration, Harvard Medical School, Boston MA 02115, USA; Shanghai Children's Medical Center, Shanghai Jiaotong University, Shanghai 200127, China.
⁷ Boston Children's Hospital and NGS collaboration, Harvard Medical School, Boston MA 02115, USA; Zhongke Genetics and Reproductive Medicine Institute, Beijing 102600, China.
⁸ 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.
⁹ Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China; Children's Hospital, Institutes of Reproduction and Development, Fudan University, Shanghai 201102, China; Boston Children's Hospital and NGS collaboration, Harvard Medical School, Boston MA 02115, USA.
¹⁰ Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing 100191, China; Boston Children's Hospital and NGS collaboration, Harvard Medical School, Boston MA 02115, USA; National Clinical Research Center for Obstetrics and Gynecology, Peking University Third Hospital, Beijing 100191, China.
¹¹ Boston Children's Hospital and NGS collaboration, Harvard Medical School, Boston MA 02115, USA.
¹² Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing 100191, China; National Clinical Research Center for Obstetrics and Gynecology, Peking University Third Hospital, Beijing 100191, China.
¹³ Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China; Children's Hospital, Institutes of Reproduction and Development, Fudan University, Shanghai 201102, China; Boston Children's Hospital and NGS collaboration, Harvard Medical School, Boston MA 02115, USA. Electronic address: Wu_b@fudan.edu.cn.
¹⁴ Children's Hospital, Institutes of Reproduction and Development, Fudan University, Shanghai 201102, China; 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. Electronic address: wanghy@fudan.edu.cn.

PMID: 34147365
DOI: 10.1016/j.jgg.2021.03.014

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^+/L642PAlms1^+/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.

Keywords: ALMS1; Anovulation; Hyperandrogenemia; LHCGR; PCOS.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alleles
Animals
Biosynthetic Pathways
Cell Cycle Proteins / genetics
Cell Cycle Proteins / metabolism
DNA Mutational Analysis
Disease Models, Animal
Exome Sequencing
Female
Gene Frequency
Genetic Association Studies
Genetic Predisposition to Disease*
Humans
Immunohistochemistry
Mice
Mice, Knockout
Mutation*
Pedigree
Phenotype
Polycystic Ovary Syndrome / diagnosis
Polycystic Ovary Syndrome / genetics*
Polycystic Ovary Syndrome / metabolism
Receptors, LH / genetics*
Receptors, LH / metabolism
Steroids / biosynthesis

Substances

Alms1 protein, mouse
Cell Cycle Proteins
LHCGR protein, mouse
Receptors, LH
Steroids