A truncating variant of RAD51B associated with primary ovarian insufficiency provides insights into its meiotic and somatic functions
Yazmine Bejarano
Centro de Investigación del Cáncer
Primary ovarian insufficiency (POI) causes female infertility by abolishing normal ovarian function. Although its genetic etiology has been extensively investigated, most POIs remain unexplained. Using whole-exome sequencing, we identified a homozygous variant in RAD51B – (c.92delT:p.Leu31Tyrfs*9) in two sisters with severe POI. In vitro studies revealed that this variant led to translation reinitiation at Met39. In mice, we showed that this is a pathogenic hypomorphic variant. Rad51bc.92delT/c.92delT mice exhibited meiotic DNA repair defects due to RAD51 and HSF2BP/BMRE1 accumulation in the chromosome axes leading to a reduction in crossovers. Interestingly, RAD51B-c.92delT interaction with RAD51C and with its newly identified interactors RAD51 and HELQ was abrogated or diminished. Repair of mitomycin-C-induced chromosomal aberrations was impaired in RAD51B/Rad51b-c.92delT human and mouse somatic cells in vitro and in mouse bone marrow cells in vivo. Accordingly, Rad51b-c.92delT variant decreased the reprogramming efficiency of primary MEFs to induced pluripotent stem cells. Finally, Rad51bc.92delT/c.92delT mice displayed increased incidence of hyperplasia of the pituitary gland. These results provide new mechanistic insights into the role of RAD51B in meiosis and in the maintenance of somatic genome stability.