Depletion of GPSM1 enhances ovarian granulosa cell apoptosis via cAMP-PKA-CREB pathway in vitro
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RESEARCH
Open Access
Depletion of GPSM1 enhances ovarian granulosa cell apoptosis via cAMP-PKACREB pathway in vitro Xuzi Cai, Huijiao Fu, Yan Wang, Qiwen Liu and Xuefeng Wang*
Abstract Background: Genetic causes of premature ovarian insufficiency (POI) account for approximately 20 ~ 25% of patients. So far, only a few genes have been identified. Results: Here, 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. RTPCR 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). Conclusions: In 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. Keywords: Premature ovarian insufficiency, Whole-exome sequencing, GPSM1, Ovarian granulosa cell, cAMP-PKACREB pathway
Introduction 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]. The opportunity to preserve fertility in women with POI is poor, which has a negative impact on both the psychological and reproductive health of women of childbearing age. As women are marrying at a later age, infertility caused by POI is becoming a greater * Correspondence: [email protected] Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Southern Medical University, No. 183 West Zhongshan Avenue, Guangzhou 510000, Guangdong, China
concern. Early detection of the high-risk population would allow for increased treatment options, and perhaps the POI-related infertility could be avoided. Research into the pathogenesis of POI is particularly important for molecular diagnosis and prevention. Although most POI cases are idiopathic, genetic factors are considered to be one of the main causes of POI [3], accounting for 20–25% [4]. Currently, only several genes have been confirmed to be associated with the pathogenesis of POI, including FOXL2, BMP2, NOBOX, FIGLA, and GDF9 [5]. The screening and validation of POI candidate genes is a large task. Currently, mos
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