Abstract
Premature 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, elevated gonadotrophins, and low estradiol levels. 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 truncated variants associated with POI have been reported; there have been no reports of an in-frame variant of STAG3 causing POI. In this study, two novel homozygous in-frame variants (c.877_885del, p.293_295del; c.891_893dupTGA, p.297_298insAsp) in STAG3 were identified in two sisters with POI from a five-generation consanguineous Han Chinese family. To evaluate the effects of these two variants, we performed fluorescence localization and co-immunoprecipitation analyses using in vitro cell model. The two variants were shown to be pathogenic, as neither STAG3 nor REC8 entered nuclei, and interactions between mutant STAG3 and REC8 or SMC1A were absent. To the best of our knowledge, this is the first report on in-frame variants of STAG3 that cause POI. This finding extends the spectrum of variants in STAG3 and sheds new light on the genetic origins of POI.
Highlights
Premature ovarian insufficiency (POI), known as premature ovarian failure, refers to hypergonadotropic hypogonadism in women younger than 40 years and is one of the major causes of female infertility, affecting at least 1–3% of adult women in the world (Bannatyne et al, 1990)
P.297_298insAsp) of Stromal antigen 3 (STAG3) were identified in a consanguineous Han Chinese family with POI
A fluorescence localization analysis was employed to evaluate the effects of the two variants and revealed that the mutant STAG3 proteins led to aberrant localization of REC8
Summary
Premature ovarian insufficiency (POI), known as premature ovarian failure, refers to hypergonadotropic hypogonadism in women younger than 40 years and is one of the major causes of female infertility, affecting at least 1–3% of adult women in the world (Bannatyne et al, 1990). Variants of STAG3 are rare, and only six truncated variants, three frameshift variants, two nonsense variants, and one splicing variant (Caburet et al, 2014; Stabej et al, 2016; Colombo et al, 2017; He et al, 2018a; Franca et al, 2019) (Table 1) associated with POI have been reported to date. It remains enigmatic whether in-frame variants of STAG3 can cause POI and female infertility
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