Abstract
BackgroundGenetic causes of premature ovarian insufficiency (POI) account for approximately 20 ~ 25% of patients. So far, only a few genes have been identified.ResultsHere, we first identified the c.1840C > A on G-protein signaling modulator 1 (GPSM1) as a susceptibility locus for POI in 10 sporadic POI patients by whole-exome sequencing. The frequency of GPSM1 c.1840C > A was then verified as 3/20 in a POI sample of 20 patients (including the above 10 patients) by Sanger sequencing. RT-PCR and western blot analysis showed the expression of GPSM1 in rat ovaries was increased in the large antral follicle stage compared to the primordial follicle stage (P < 0.01). The cell proliferation assay (CCK8) and flow cytometry suggested that the small-interfering RNA-induced silencing of Gpsm1 significantly increased apoptosis and decreased proliferation of rat ovarian granulosa cells (GCs) (P < 0.01). Furthermore, suppression of Gpsm1 in GCs reduced levels of cAMP, PKAc, p-CREB as well as the ratio of Bcl-2/Bax, and increased the expression of Caspase-3 and Cleaved Caspase-3 (P < 0.01).ConclusionsIn summary, this study identified a susceptibility variant GPSM1 c.1840C > A of POI for the first time. Gpsm1 was related to rat follicle development, and silencing of Gpsm1 increased apoptosis and decreased proliferation in rat GCs, possibly through inhibition of the cAMP-PKA-CREB pathway.
Highlights
Premature ovarian insufficiency (POI) is a clinical syndrome characterized by the loss of ovarian activity before the age of 40 years, which results in hypergonadotropic hypogonadism [1]
Downregulating of Gpsm1 alters the expression of the cAMP-cAMPresponse element binding protein (CREB)-protein kinase A (PKA) signaling molecules in granulosa cells (GCs) we investigated the effect of Gpsm1-knockdown on intracellular signaling in rat GCs
We confirmed the anti-apoptotic and proliferative functions of G-protein signaling modulator 1 (GPSM1) in rat GCs, and found that the possible mechanism of action might be through regulation of the Bcl-2/Bax ratio through cAMP-PKA-CREB signaling, which affects the activation of apoptosis protein, Caspase-3
Summary
Premature ovarian insufficiency (POI) is a clinical syndrome characterized by the loss of ovarian activity before the age of 40 years, which results in hypergonadotropic hypogonadism [1]. It affects approximately 1% women under 40 years old [2]. Only several genes have been confirmed to be associated with the pathogenesis of POI, including FOXL2, BMP2, NOBOX, FIGLA, and GDF9 [5]. Most of the research on POI-pathogenesis genes is focused on pedigree studies [6, 7]. Genetic causes of premature ovarian insufficiency (POI) account for approximately 20 ~ 25% of patients.
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