A truncating variant of RAD51B associated with primary ovarian insufficiency provides insights into its meiotic and somatic functions

Primary ovarian insufficiency (POI) causes female infertility by abolishing normal ovarian function. Although its genetic etiology has been extensively investigated, most POI cases remain unexplained. Using whole-exome sequencing, we identified a homozygous variant in RAD51B –(c.92delT) in two sisters with POI. In vitro studies revealed that this variant leads to translation reinitiation at methionine 64. Here, we show that this is a pathogenic hypomorphic variant in a mouse model. 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 the number of crossovers. Interestingly, the interaction of RAD51B-c.92delT 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 explanted mouse bone marrow cells. Accordingly, Rad51b-c.92delT variant reduced replication fork progression of patient-derived lymphoblastoid cell lines and pluripotent reprogramming efficiency of primary mouse embryonic fibroblasts. Finally, Rad51bc.92delT/c.92delT mice displayed increased incidence of pituitary gland hyperplasia. These results provide new mechanistic insights into the role of RAD51B not only in meiosis but in the maintenance of somatic genome stability.This work was supported by the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Grant 2014/14231-0 (to MMF); FAPESP Grant 2013/02162-8, Nucleo de Estudos e Terapia Celular e Molecular (NETCEM), Conselho Nacional de Desenvolvimento Científico e Tecnológico Grant 303002/2016- 6 (to BBM); and FAPESP Grant 2014/50137-5 (to SELA). This work was supported by MINECO (PID2020-120326RB-I00) and by Junta de Castilla y León (CSI239P18 and CSI148P20). NFM, FSS, and MRMH are supported by European Social Fund/JCyLe grants (EDU/310/2015, EDU/556/2019 and EDU/1992/2020). YBC and RSU are funded by a grant from MINECO (BS-2015–073993 and BFU2017-89408-R). Experiments performed at CNIO were supported by grant PID2019-106707-RB to JM, co-sponsored by EU ERDF funds. SM was supported by an international postdoctoral contract “CNIO Friends”. The proteomic analysis was performed in the Proteomics Facility of Centro de Investigación del Cáncer, Salamanca, Grant PRB3(IPT17/0019 -ISCIII-SGEFI/ERDF). CIC-IBMCC is supported by the Programa de Apoyo a Planes Estratégicos de Investigación de Estructuras de Investigación de Excelencia cofunded by the Castilla–León autonomous government and the European Regional Development Fund (CLC–2017–01). Veitia’s Lab is supported by the University of Paris and the Centre National de la Recherche Scientifique

The genetic make-up of ovarian development and function: the focus on the transcription factor FOXL2.

International audienceIn a 46 XY individual, the presence of the Y chromosome harboring the testis-determining factor (SRY) triggers testis determination and differentiation. In a 46 XX individual, the absence of SRY and the activation of genes associated with the female pathway lead to ovarian development. The latter process has long been considered as a default pathway. However, recent studies have cast doubts on this dogma. Here, after a brief overview of the main steps of ovarian development, we focus on three genes WNT4, RSPO1 and FOXL2 that are essential for ovarian determination, differentiation and/or maintenance. Special attention is paid to FOXL2 whose mutations are responsible for the blepharophimosis syndrome, often associated with female infertility, and for cancer. We highlight the cooperation of WNT4, RSPO1 and FOXL2 within a regulatory network and the need for further research to better understand their role in defining and maintaining ovarian identity