Deleterious variants in RNF111 impair female fertility and induce premature ovarian insufficiency in humans and mice  

作　　者：Chengcheng Song Yingying Qin Yan Li Bingyi Yang Ting Guo Wenqing Ma Dian Xu Keyan Xu Fangfang Fu Li Jin Yanhua Wu Shuyan Tang Xiaojun Chen Feng Zhang 

机构地区：[1]Obstetrics and Gynecology Hospital,State Key Laboratory of Genetic Engineering,Institute of Medical Genetics and Genomics,Fudan University,Shanghai 200011,China [2]Human Phenome Institute,Zhangjiang Fudan International Innovation Center,Fudan University,Shanghai 201203,China [3]Center for Reproductive Medicine,Cheeloo College of Medicine,Shandong University,Jinan 250021,China [4]State Key Laboratory of Reproductive Medicine and Offspring Health,Key Laboratory of Reproductive Endocrinology of Ministry of Education,National Research Center for Assisted Reproductive Technology and Reproductive Genetics,Shandong Key Laboratory of Reproductive Medicine,Shandong Provincial Clinical Research Center for Reproductive Health,Shandong University,Jinan 250021,China [5]Department of Obstetrics and Gynecology,Tongji Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan 430030,China [6]National Demonstration Center for Experimental Biology Education,School of Life Sciences,Fudan University,Shanghai 200433,China [7]Department of Gynecology,the Tenth People’s Hospital of Tongji University,Shanghai 200072,China [8]Soong Ching Ling Institute of Maternity and Child Health,International Peace Maternity and Child Health Hospital of China Welfare Institute,Shanghai 200030,China

出　　处：《Science China(Life Sciences)》2024年第7期1325-1337,共13页中国科学（生命科学英文版）

基　　金：supported by the National Natural Science Foundation of China(32288101);the National Key Research and Development Program of China(2021YFC2701400);Shenkang Clinical Technology Innovation Project(SHDC22021219)。

摘　　要：Premature ovarian insufficiency(POI)is a heterogeneous female disorder characterized by the loss of ovarian function before the age of 40.It represents a significant detriment to female fertility.However,the known POI-causative genes currently account for only a fraction of cases.To elucidate the genetic factors underlying POI,we conducted whole-exome sequencing on a family with three fertile POI patients and identified a deleterious missense variant in RNF111.In a subsequent replication study involving 1,030 POI patients,this variant was not only confirmed but also accompanied by the discovery of three additional predicted deleterious RNF111 variants.These variants collectively account for eight cases,representing 0.78%of the study cohort.A further study involving 500 patients with diminished ovarian reserve also identified two additional RNF111 variants.Notably,RNF111 encodes an E3 ubiquitin ligase with a regulatory role in the TGF-β/BMP signaling pathway.Our analysis revealed that RNF111/RNF111 is predominantly expressed in the oocytes of mice,monkeys,and humans.To further investigate the functional implications of RNF111 variants,we generated two mouse models:one with a heterozygous missense mutation(Rnf111+/M)and another with a heterozygous null mutation(Rnf111^(+/-)).Both mouse models exhibited impaired female fertility,characterized by reduced litter sizes and small ovarian reserve.Additionally,RNA-seq and quantitative proteomics analysis unveiled that Rnf111 haploinsufficiency led to dysregulation in female gonad development and negative regulation of the BMP signaling pathway within mouse ovaries.In conclusion,our findings strongly suggest that monoallelic deleterious variants in RNF111 can impair female fertility and induce POI in both humans and mice.

关 键 词：POI RNF111 female fertility ovarian reserve 

分 类 号：R711.75[医药卫生—妇产科学]