Wei Luo 1 , Ting Guo 1 , Guangyu Li 1 , Ran Liu 1 , Shidou Zhao 1 , Meihui Song 2,3 , Liangran Zhang 1,2,3 , Shunxin Wang 1 , Zi-Jiang Chen 1 , Yingying Qin 1 Show Affiliations »
Abstract
CONTEXT: Premature ovarian insufficiency (POI) is characterized by cessation of menstruation before 40 years of age and elevated serum level of FSH (>25 IU/L). Recent studies have found a few causative genes responsible for POI enriched in meiotic recombination and DNA damage repair pathways. OBJECTIVE: To investigate the role of variations in homologous recombination genes played in POI pathogenesis. METHODS: The whole exome sequencing was performed in 50 POI patients with primary amenorrhea. Functional characterizations of the novel variants were carried out in budding yeast and human cell line. RESULTS: We identified 8 missense variants in 7 homologous recombination genes, including EXO1, RAD51, RMI1, MSH5, MSH2, MSH6, and MLH1. The mutation p.Thr52Ser in EXO1 impaired the meiotic process of budding yeast and p.Glu68Gly in RAD51-altered protein localization in human cells, both of them impaired the efficiency of homologous recombination repair for DNA double-stranded breaks in human cells. CONCLUSIONS: Our study first linked the variants of EXO1 and RAD51 with POI and further highlighted the role of DNA repair genes in ovarian dysgenesis. © Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
CONTEXT: Premature ovarian insufficiency (POI) is characterized by cessation of menstruation before 40 years of age and elevated serum level of FSH (>25 IU/L). Recent studies have found a few causative genes responsible for POI enriched in meiotic recombination and DNA damage repair pathways. OBJECTIVE: To investigate the role of variations in homologous recombination genes played in POI pathogenesis. METHODS: The whole exome sequencing was performed in 50 POI patients with primary amenorrhea . Functional characterizations of the novel variants were carried out in budding yeast and human cell line. RESULTS: We identified 8 missense variants in 7 homologous recombination genes, including EXO1 , RAD51 , RMI1 , MSH5 , MSH2 , MSH6 , and MLH1 . The mutation p.Thr52Ser in EXO1 impaired the meiotic process of budding yeast and p.Glu68Gly in RAD51 -altered protein localization in human cells, both of them impaired the efficiency of homologous recombination repair for DNA double-stranded breaks in human cells. CONCLUSIONS: Our study first linked the variants of EXO1 and RAD51 with POI and further highlighted the role of DNA repair genes in ovarian dysgenesis . © Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
Entities: Disease
Gene
Mutation
Species
Keywords:
POI; DNA repair; EXO1; RAD51; whole exome sequencing
Year: 2020
PMID： 32772095 DOI： 10.1210/clinem/dgaa505
Source DB: PubMed Journal: J Clin Endocrinol Metab ISSN： 0021-972X Impact factor: 5.958