Details

Autor(en) / Beteiligte

• Duan, Yuwei
• Cai, Bing
• Guo, Jing
• Wang, Chen
• Mai, Qingyun
• Xu, Yan
• Zeng, Yang
• Shi, Yue
• Wang, Boyan
• Ding, Chenhui
• Chen, Minghui
• Zhou, Canquan
• Xu, Yanwen

Titel

GDF9His209GlnfsTer6/S428T and GDF9Q321X/S428T bi-allelic variants caused female subfertility with defective follicle enlargement

Ist Teil von

• Cell communication and signaling, 2024-04, Vol.22 (1), p.1-235, Article 235

Ort / Verlag

London: BioMed Central Ltd

Erscheinungsjahr

2024

Quelle

Springer Online Journals

Beschreibungen/Notizen

• Antral follicles consist of an oocyte cumulus complex surrounding by somatic cells, including mural granulosa cells as the inner layer and theca cells as the outsider layer. The communications between oocytes and granulosa cells have been extensively explored in in vitro studies, however, the role of oocyte-derived factor GDF9 on in vivo antral follicle development remains elusive due to lack of an appropriate animal model. Clinically, the phenotype of GDF9 variants needs to be determined. Whole-exome sequencing (WES) was performed on two unrelated infertile women characterized by an early rise of estradiol level and defect in follicle enlargement. Besides, WES data on 1,039 women undergoing ART treatment were collected. A Gdf9.sup.Q308X/S415T mouse model was generated based on the variant found in one of the patients. Two probands with bi-allelic GDF9 variants (GDF9.sup.His209GlnfsTer6/S428T, GDF9.sup.Q321X/S428T) and eight GDF9.sup.S428T heterozygotes with normal ovarian response were identified. In vitro experiments confirmed that these variants caused reduction of GDF9 secretion, and/or alleviation in BMP15 binding. Gdf9.sup.Q308X/S415T mouse model was constructed, which recapitulated the phenotypes in probands with abnormal estrogen secretion and defected follicle enlargement. Further experiments in mouse model showed an earlier expression of STAR in small antral follicles and decreased proliferative capacity in large antral follicles. In addition, RNA sequencing of granulosa cells revealed the transcriptomic profiles related to defective follicle enlargement in the Gdf9.sup.Q308X/S415T group. One of the downregulated genes, P4HA2 (a collagen related gene), was found to be stimulated by GDF9 protein, which partly explained the phenotype of defective follicle enlargement. GDF9 bi-allelic variants contributed to the defect in antral follicle development. Oocyte itself participated in the regulation of follicle development through GDF9 paracrine effect, highlighting the essential role of oocyte-derived factors on ovarian response.