Haploinsufficiency in non-homologous end joining factor 1 induces ovarian dysfunction in humans and mice

Premature ovarian insufficiency (POI) is a common disease in women that leads to a reduced reproductive lifespan. By utilizing whole-exome sequencing, we identified a rare heterozygous loss-of-function variant of non-homologous end joining factor 1 (NHEJ1) co-segregating with POI in a three-generation Chinese family. The loss-of-function variant caused an approximately 50% reduction in NHEJ1 protein amount in human. Knock-down of NHEJ1 in KGN ovarian cells significantly impaired DNA repair capacity. By constructing a knock-in mouse model, we found that haploinsufficiency of Nhej1 lead to reduced number of follicles in ovaries and impaired female fertility. Our studies provided novel insights into genetic counseling and clinical prevention of POI. (By Prof. Feng Zhang and Prof. Yanhua Wu, https://jmg.bmj.com/content/early/2021/04/21/jmedgenet-2020-107398 )

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