Two compound heterozygous MEIOSIN (likely) pathogenic variants cause female infertility with premature ovarian insufficiency through the disruption of meiosis-related gene transcription

BACKGROUND: Premature ovarian insufficiency (POI) is a major contributor to female infertility; however, its genetic basis remains insufficiently understood. MEIOSIN is crucial for initiating meiosis by activating a subset of key meiotic genes that regulate the transition from mitosis to meiosis in mammalian germ cells. Recent studies suggest that biallelic MEIOSIN variant may contribute to POI in humans, yet further analysis is required to confirm and clarify this role. METHODS: To identify potential pathogenic variants associated with POI, whole-exome sequencing was conducted in the affected individuals, followed by Sanger sequencing for variant validation. To evaluate the functional consequences of these variants, a series of in vitro assays was performed, including Western blotting, immunostaining, and structural modeling of mutant proteins. Additionally, a dual-luciferase reporter assay was utilized to assess whether the identified variants influenced the transcriptional activity of MEIOSIN. RESULTS: Two compound heterozygous variants in MEIOSIN-c.980T > C (p.Leu327Pro) and c.1068_1092del (p.His356fs*14)-were identified in two affected sisters, with the latter representing a novel variant. Sanger sequencing confirmed that the two variants were inherited from each parent, thereby establishing compound heterozygosity. Functional characterization revealed that the frameshift variant resulted in a truncated MEIOSIN protein with aberrant intracellular localization. While the missense variant did not impact MEIOSIN expression or localization, it disrupted the protein's 3D structure. Furthermore, dual-luciferase assays demonstrated that both variants impaired MEIOSIN's transcriptional regulation of downstream meiotic genes. According to the ACMG/AMP guidelines, the frameshift variant was classified as pathogenic, while the missense variant was classified as likely pathogenic. CONCLUSION: These findings provide compelling evidence that pathogenic biallelic variants in MEIOSIN represent a recurrent genetic cause of POI in humans.