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1.
J Ovarian Res ; 17(1): 32, 2024 Feb 03.
Artículo en Inglés | MEDLINE | ID: mdl-38310280

RESUMEN

BACKGROUND: The etiology of premature ovarian insufficiency, that is, the loss of ovarian activity before 40 years of age, is complex. Studies suggest that genetic factors are involved in 20-25% of cases. The aim of this study was to explore the oligogenic basis of premature ovarian insufficiency. RESULTS: Whole-exome sequencing of 93 patients with POI and whole-genome sequencing of 465 controls were performed. In the gene-burden analysis, multiple genetic variants, including those associated with DNA damage repair and meiosis, were more common in participants with premature ovarian insufficiency than in controls. The ORVAL-platform analysis confirmed the pathogenicity of the RAD52 and MSH6 combination. CONCLUSIONS: The results of this study indicate that oligogenic inheritance is an important cause of premature ovarian insufficiency and provide insights into the biological mechanisms underlying premature ovarian insufficiency.


Asunto(s)
Menopausia Prematura , Insuficiencia Ovárica Primaria , Femenino , Humanos , Insuficiencia Ovárica Primaria/genética , Menopausia Prematura/genética
2.
Front Endocrinol (Lausanne) ; 14: 1285667, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-38149096

RESUMEN

Introduction: The number of primordial follicles (PFs) in mammals determines the ovarian reserve, and impairment of primordial follicle formation (PFF) will cause premature ovarian insufficiency (POI). Methods: By analyzing public single-cell RNA sequencing performed during PFF on mice and human ovaries, we identified novel functional genes and novel ligand-receptor interaction during PFF. Based on immunofluorescence and in vitro ovarian culture, we confirmed mechanisms of genes and ligand-receptor interaction in PFF. We also applied whole exome sequencing (WES) in 93 cases with POI and whole genome sequencing (WGS) in 465 controls. Variants in POI patients were further investigated by in silico analysis and functional verification. Results: We revealed ANXA7 (annexin A7) and GTF2F1 (general transcription factor IIF subunit 1) in germ cells to be novel potentially genes in promoting PFF. Ligand Mdk (midkine) in germ cells and its receptor Sdc1 (syndecan 1) in granulosa cells are novel interaction crucial for PFF. Based on immunofluorescence, we confirmed significant up-regulation of ANXA7 in PFs compared with germline cysts, and uniform expression of GTF2F1, MDK and SDC1 during PFF, in 25 weeks human fetal ovary. In vitro investigation indicated that Anxa7 and Gtf2f1 are vital for mice PFF by regulating Jak/Stat3 and Jnk signaling pathways, respectively. Ligand-receptor (Mdk-Sdc1) are crucial for PFF by regulating Pi3k-akt signaling pathway. Two heterozygous variants in GTF2F1, and one heterozygous variants in SDC1 were identified in cases, but no variant were identified in controls. The protein level of GTF2F1 or SDC1 in POI cases are significantly lower than that of controls, indicating the pathogenic effects of the two genes on ovarian function were dosage dependent. Discussion: Our study identified novel genes and novel ligand-receptor interaction during PFF, and further expanding the genetic architecture of POI.


Asunto(s)
Menopausia Prematura , Insuficiencia Ovárica Primaria , Femenino , Humanos , Animales , Ratones , Secuenciación del Exoma , Fosfatidilinositol 3-Quinasas/metabolismo , Ligandos , Análisis de Expresión Génica de una Sola Célula , Folículo Ovárico/metabolismo , Insuficiencia Ovárica Primaria/genética , Mamíferos/genética
3.
Cell Cycle ; 22(21-22): 2436-2448, 2023 11.
Artículo en Inglés | MEDLINE | ID: mdl-38146657

RESUMEN

Endometriosis is a benign high prevalent disease exhibiting malignant features. However, the underlying pathogenesis and key molecules of endometriosis remain unclear. By integrating and analysis of existing expression profile datasets, we identified coxsackie and adenovirus receptor (CXADR), as a novel key gene in endometriosis. Based on the results of immunohistochemistry (IHC), we confirmed significant down-regulation of CXADR in ectopic endometrial tissues obtained from women with endometriosis compared with healthy controls. Further in vitro investigation indicated that CXADR regulated the stability and function of the phosphatases and AKT inhibitors PHLPP2 (pleckstrin homology domain and leucine-rich repeat protein phosphatase 2) and PTEN (phosphatase and tensin homolog). Loss of CXADR led to phosphorylation of AKT and glycogen synthase kinase-3ß (GSK-3ß), which resulted in stabilization of an epithelial-mesenchymal transition (EMT) factor, SNAIL1 (snail family transcriptional repressor 1). Therefore, EMT processs was induced, and the proliferation, migration and invasion of Ishikawa cells were enhanced. Over-expression of CXADR showed opposite effects. These findings suggest a previously undefined role of AKT/GSK-3ß signaling axis in regulating EMT and reveal the involvement of a CXADR-induced EMT, in pathogenic progression of endometriosis.


Asunto(s)
Endometriosis , Proteínas Proto-Oncogénicas c-akt , Femenino , Humanos , Moléculas de Adhesión Celular , Línea Celular Tumoral , Movimiento Celular , Endometriosis/genética , Transición Epitelial-Mesenquimal , Glucógeno Sintasa Quinasa 3 beta , Fosfoproteínas Fosfatasas/farmacología , Monoéster Fosfórico Hidrolasas , Proteínas Proto-Oncogénicas c-akt/metabolismo , Factores de Transcripción de la Familia Snail/genética , Factores de Transcripción de la Familia Snail/metabolismo
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