In recent years, China has been grappling with a significant demographic challenge characterized by a declining birth rate and an increasing prevalence of infertility. Ovarian aging is one of the primary factors contributing to reduced female fertility. Premature ovarian insufficiency (POI) is a common ovarian aging disorder, but its etiologies and intervention strategies remain largely elusive. In 2023, Professor Zi-Jiang Chen's team from the Reproductive Medicine Center at Shandong University, in collaboration with Li Jin’s team from Fudan University, depicted the landscape of pathogenic variants in POI, revealing genetic factors account for 23.5% of the etiologies of POI (Nature Medicine, 2023). This work laid a foundation for further study of the genetic mechanisms underlying reproductive aging and the clinical management of POI. Recently, the two teams collaborated again and published a research paper titled “MGA loss-of-function variants cause premature ovarian insufficiency” in the Journal of Clinical Investigation, offering a new target for the intervention of POI.

This study utilized whole-exome sequencing data from 1,027 patients in the POI cohort of Shandong University. Based on the previous identifications published in Nature Medicine, the researchers expanded the scope of gene screening and conducted association analyses across 20,000 protein-coding genes. They found that loss-of-function (LoF) mutation in the MGA gene has a carrier rate of 2.6% among patients with POI, which has also been validated in multi-center and multi-ethnic POI cohorts globally. MGA is the known POI-causal gene with the highest mutation carrier rate. Functional experiments, including genetic co-segregation analysis in the patients’ families and knockout mouse models, demonstrated that heterozygous LoF mutations in MGA disrupt the expression of meiosis-related genes, leading to progressive follicle loss and ultimately causing POI. This study adopted an unbiased, data-driven whole-genome strategy to explore pathogenic genes for POI, offering a more comprehensive approach to exploring the genetic etiology of POI.

The research was supported by the National Natural Science Foundation of China, the National Key Research and Development Program of China, and the "Climbing" Program Innovation Team Project of Shandong University.