A missense in HSF2BP causing Primary Ovarian Insufficiency affects meiotic recombination by its novel interactor C19ORF57/BRME1
- Centro de Investigación del Cáncer, Spain
- Université Paris Diderot, France
- Instituto de Biologia Molecular y Celular del Cancer, Spain
- Academic Medical Center Amsterdam/Utrecht University, Netherlands
- Instituto de Biologia Molecular y Celular del Cancer-CSIC-Universidad de Salamanca, Spain
- Institut Jacques Monod, Universite de Paris, CNRS, France
- Instituto de Biologia Molecular y Celular del Cancer (CSIC-Universidad de Salamanca), Spain
- University of Salamanca, Spain
- Genetic Institute, Emek Medical Center, Israel
- Campus Miguel de Unamúno, Spain
Abstract
Primary Ovarian Insufficiency (POI) is a major cause of infertility, but its etiology remains poorly understood. Using whole-exome sequencing in a family with 3 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.
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All data generated or analysed during this study are included in the manuscript and supporting files.
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Author details
Rodrigo Garcia-Valiente
Funding
Ministerio de Economía y Competitividad
- Alberto M Pendás
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All the experiments were approved by the Ethics Committee for Animal Experimentation of the University of Salamanca (USAL) and the Ethics committee of the Spanish Research Council (CSIC) under protocol #00-245. Accordingly, all the mouse protocols used in this work have been approved by the above mentioned Animal Experimentation committees. Specifically, mice were always housed in a temperature-controlled facility (specific pathogen free, spf) using individually ventilated cages, standard diet and a 12 h light/dark cycle, according to EU law (63/2010/UE) and the Spanish royal law (53/2013) at the "Servicio de Experimentación Animal, SEA. In addition, animal suffering was always minimized and we made every effort to improve animal welfare during the life of the animals.
Copyright
© 2020, Felipe-Medina et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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A missense in HSF2BP causing Primary Ovarian Insufficiency affects meiotic recombination by its novel interactor C19ORF57/BRME1
eLife 9:e56996.
https://doi.org/10.7554/eLife.56996
