Novel pathogenic mutations in minichromosome maintenance complex component 9 (MCM9) responsible for premature ovarian insufficiency.

To investigate whether mutations in the minichromosome maintenance complex component 9 (MCM9) gene were present in 192 patients with sporadic premature ovarian insufficiency (POI) of Chinese descent. Genetic and functional study. University-based reproductive medicine center. A total of 192 patients with sporadic POI and 192 control women with regular menstruation. Sanger sequencing performed in 192 sporadic POI patients, and potential pathogenic variants were excluded in matched controls. Functional effects of mutations on MCM9 were explored based on etoposide-induced DNA damage response, and DNA repair capacity was evaluated by histone H2AX phosphorylation level. Sanger sequencing and functional characteristics. Three novel heterozygous mutations in MCM9, c.C1423T (p.L475F), c.T2921C (p.L974S), and c.G3388A (p.A1130T), were identified in three POI patients separately, which were absent in 192 controls. Functional studies showed that the human embryonic kidney 293 (HEK293) cells overexpressing mutant MCM9 presented with diminished DNA repair capacity compared with wild type. This study identified novel mutations in MCM9 that are potentially causative for sporadic POI in Chinese women and further highlighted the role of DNA repair capacity in maintenance of ovarian function.

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