AUTHOR=Xiao Wen-Juan , He Wen-Bin , Zhang Ya-Xin , Meng Lan-Lan , Lu Guang-Xiu , Lin Ge , Tan Yue-Qiu , Du Juan 

TITLE=In-Frame Variants in STAG3 Gene Cause Premature Ovarian Insufficiency

JOURNAL=Frontiers in Genetics

VOLUME=Volume 10 - 2019

YEAR=2019

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2019.01016

DOI=10.3389/fgene.2019.01016

ISSN=1664-8021

ABSTRACT=Primary ovarian insufficiency (POI) is a severe clinical syndrome defined by ovarian dysfunction in women less than 40 years old who generally manifest with infertility, menstrual disturbance, raised gonadotrophins, and low oestradiol. STAG3 is considered a genetic aetiology of POI, which facilitates entry of REC8 into the nucleus of a cell and plays an essential role in gametogenesis. At present, only six truncating mutations associated with POI have been reported; there have been no reports of an in-frame mutation of STAG3 causing POI. In this study, two novel homozygous in-frame mutations (c.877_885del, p.293_295del; c.891_893dup, p.297_298insAsp) in STAG3 were identified in two sisters with POI from a four-generation consanguineous Han Chinese family. To evaluate the effects of these two mutations, we performed fluorescence localization and co-immunoprecipitation analyses using in vitro cell model. The two mutations were proved to be pathogenic, as neither STAG3 nor REC8 entered nuclei, and interactions between mutant STAG3 and REC8 or SMC1A were absent. This is the first report on in-frame mutations in STAG3 that cause POI. The finding extends the spectrum of mutations in STAG3 and sheds new light on the genetic origins of POI.