TY - JOUR TI - A missense in HSF2BP causing primary ovarian insufficiency affects meiotic recombination by its novel interactor C19ORF57/BRME1 AU - Felipe-Medina, Natalia AU - Caburet, Sandrine AU - Sánchez-Sáez, Fernando AU - Condezo, Yazmine B AU - de Rooij, Dirk G AU - Gómez-H, Laura AU - Garcia-Valiente, Rodrigo AU - Todeschini, Anne Laure AU - Duque, Paloma AU - Sánchez-Martin, Manuel Adolfo AU - Shalev, Stavit A AU - Llano, Elena AU - Veitia, Reiner A AU - Pendás, Alberto M A2 - de Massy, Bernard A2 - Struhl, Kevin A2 - de Massy, Bernard A2 - Jasin, Maria VL - 9 PY - 2020 DA - 2020/08/26 SP - e56996 C1 - eLife 2020;9:e56996 DO - 10.7554/eLife.56996 UR - https://doi.org/10.7554/eLife.56996 AB - Primary Ovarian Insufficiency (POI) is a major cause of infertility, but its etiology remains poorly understood. Using whole-exome sequencing in a family with three cases of POI, we identified the candidate missense variant S167L in HSF2BP, an essential meiotic gene. Functional analysis of the HSF2BP-S167L variant in mouse showed that it behaves as a hypomorphic allele compared to a new loss-of-function (knock-out) mouse model. Hsf2bpS167L/S167L females show reduced fertility with smaller litter sizes. To obtain mechanistic insights, we identified C19ORF57/BRME1 as a strong interactor and stabilizer of HSF2BP and showed that the BRME1/HSF2BP protein complex co-immunoprecipitates with BRCA2, RAD51, RPA and PALB2. Meiocytes bearing the HSF2BP-S167L variant showed a strongly decreased staining of both HSF2BP and BRME1 at the recombination nodules and a reduced number of the foci formed by the recombinases RAD51/DMC1, thus leading to a lower frequency of crossovers. Our results provide insights into the molecular mechanism of HSF2BP-S167L in human ovarian insufficiency and sub(in)fertility. KW - meiosis KW - meiotic recombination KW - fertility KW - reproduction KW - human genetics JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -