Lin Zhao-Jing, Zhu Lei, Dong Yi, Yun Jiao, Zhi Ya-Nan, Zhang Wei, Sun Yan-Mei, Jiang Yu-Jie, Liu Shu, Fan Liang-Liang, Li Ya-Li, Guo Shuai
Department of Cell Biology, Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, China.
Department of Anesthesiology, The Second Xiangya Hospital of Central South University, Changsha, China.
J Clin Lab Anal. 2025 Mar;39(6):e70011. doi: 10.1002/jcla.70011. Epub 2025 Mar 11.
This study aimed to identify genetic variants and their functional consequences underlying Unexplained Recurrent Pregnancy Loss (uRPL) through comprehensive genomic and transcriptomic analyses.
We recruited 13 Chinese uRPL patients and performed Whole Exome Sequencing (WES) on chorionic villi samples from miscarriage tissues. Additionally, we conducted an integrative analysis using single-cell RNA sequencing data from decidual immune cells to examine expression patterns.
WES analysis pinpointed variants in the four MUC genes (MUC4, MUC6, MUC16, and MUC17), six lipid metabolism genes in immune cells (ABCA4, ABCA7, ABCB5, ABCC8, ADGRV1, and ANK3), and two structural genes (PIEZO1 and PKD1), whose variants impair mucosal barriers and lipid homeostasis, thereby leading to immune dysregulation and contributing to uRPL. To delve deeper into the effects of these genetic variants on cellular expression patterns, we undertook an integrative analysis using a single-cell dataset from decidual immune cells in uRPL cases. We observed significant dysregulation of lipid metabolism within immune cells, reduced heat shock protein expression, and enhanced chemokine signaling in uRPL samples, indicating a pro-inflammatory state.
In summary, our study reveals a complex interplay between genetic variants and immune cell dysfunctions in uRPL, emphasizing the role of identified genetic variants in driving pro-inflammatory states. These findings provide a comprehensive view of the molecular mechanisms underlying uRPL, opening paths for novel therapeutic interventions and improved clinical management.
本研究旨在通过全面的基因组和转录组分析，确定不明原因复发性流产（uRPL）潜在的基因变异及其功能后果。
我们招募了13名中国uRPL患者，并对流产组织的绒毛样本进行了全外显子组测序（WES）。此外，我们利用来自蜕膜免疫细胞的单细胞RNA测序数据进行综合分析，以检查表达模式。
WES分析确定了四个MUC基因（MUC4、MUC6、MUC16和MUC17）、免疫细胞中的六个脂质代谢基因（ABCA4、ABCA7、ABCB5、ABCC8、ADGRV1和ANK3）以及两个结构基因（PIEZO1和PKD1）中的变异，这些变异损害了黏膜屏障和脂质稳态，从而导致免疫失调并促成uRPL。为了更深入地研究这些基因变异对细胞表达模式的影响，我们利用uRPL病例中蜕膜免疫细胞的单细胞数据集进行了综合分析。我们观察到uRPL样本中免疫细胞内脂质代谢显著失调、热休克蛋白表达降低以及趋化因子信号增强，表明处于促炎状态。
总之，我们的研究揭示了uRPL中基因变异与免疫细胞功能障碍之间的复杂相互作用，强调了已确定的基因变异在驱动促炎状态中的作用。这些发现提供了uRPL潜在分子机制的全面视图，为新型治疗干预和改善临床管理开辟了道路。
