TY - JOUR T1 - Haploinsufficiency in non-homologous end joining factor 1 induces ovarian dysfunction in humans and mice JF - Journal of Medical Genetics JO - J Med Genet DO - 10.1136/jmedgenet-2020-107398 SP - jmedgenet-2020-107398 AU - Guoqing Li AU - Xi Yang AU - Lingbo Wang AU - Yuncheng Pan AU - Siyuan Chen AU - Lingyue Shang AU - Yicheng Zhang AU - Yucheng Wu AU - Zixue Zhou AU - Qing Chen AU - Xue Zhang AU - Ling Zhang AU - Yingchen Wang AU - Jinsong Li AU - Li Jin AU - Yanhua Wu AU - Xiaojin Zhang AU - Feng Zhang Y1 - 2021/04/22 UR - http://jmg.bmj.com/content/early/2021/04/21/jmedgenet-2020-107398.abstract N2 - Background Premature ovarian insufficiency (POI) is a common disease in women that leads to a reduced reproductive lifespan. The aetiology of POI is genetically heterogeneous, with certain double-strand break (DSB) repair genes being implicated in POI. Although non-homologous end joining (NHEJ) is an efficient DSB repair pathway, the functional relationship between this pathway and POI remains unknown.Methods and results We conducted whole-exome sequencing in a Chinese family and identified a rare heterozygous loss-of-function variant in non-homologous end joining factor 1 (NHEJ1): c.532C>T (p.R178*), which co-segregated with POI and irregular menstruation. The amount of NHEJ1 protein in the proband was half of the normal level, indicating a link between NHEJ1 haploinsufficiency and POI. Furthermore, another rare heterozygous NHEJ1 variant c.500A>G (p.Y167C) was identified in one of 100 sporadic POI cases. Both variants were predicted to be deleterious by multiple in silico tools. In vitro assays showed that knock-down of NHEJ1 in human KGN ovarian cells impaired DNA repair capacity. We also generated a knock-in mouse model with a heterozygous Nhej1 variant equivalent to NHEJ1 p.R178* in familial patients. Compared with wild-type mice, heterozygous Nhej1-mutated female mice required a longer time to first birth, and displayed reduced numbers of primordial and growing follicles. Moreover, these mice exhibited higher sensitivity to DSB-inducing drugs. All these phenotypes are analogous to the progressive loss of ovarian function observed in POI.Conclusions Our observations in both humans and mice suggest that NHEJ1 haploinsufficiency is associated with non-syndromic POI, providing novel insights into genetic counselling and clinical prevention of POI.All data relevant to the study are included in the article or uploaded as supplementary information. ER -