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Losing of ovarian functions prior to natural menopause age causes female infertility and early menopause. Premature ovarian insufficiency (POI) is defined as the loss of ovarian activity before 40 years of age. Known genetic causes account for 25–30% of POI cases, demonstrating the high genetic heterogeneity of POI and the necessity for further genetic explorations. Here we conducted genetic analyses using whole-exome sequencing in a Chinese non-syndromic POI family with the affected mother and at least four affected daughters. Intriguingly, a rare missense variant of  BUB1B  c.273A&gt;T (p.Gln91His) was shared by all the cases in this family. Furthermore, our replication study using targeted sequencing revealed a novel stop-gain variant of  BUB1B  c.1509T&gt;A (p.Cys503 * ) in one of 200 sporadic POI cases. Both heterozygous  BUB1B  variants were evaluated to be deleterious by multiple  in silico  tools.  BUB1B  encodes BUBR1, a crucial spindle assembly checkpoint component involved in cell division. BUBR1 insufficiency may induce vulnerability to oxidative stress. Therefore, we generated a mouse model with a loss-of-function mutant of  Bub1b , and also employed D-galactose-induced aging assays for functional investigations. Notably,  Bub1b  +/−  female mice presented late-onset subfertility, and they were more sensitive to oxidative stress than wild-type female controls, mimicking the clinical phenotypes of POI cases affected by deleterious  BUB1B  variants. Our findings in human cases and mouse models consistently suggest, for the first time, that heterozygous deleterious variants of  BUB1B  are involved in late-onset POI and related disorders.

Rare deleterious BUB1B variants induce premature ovarian insufficiency and early menopause