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.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files.
Article and author information
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.
Metrics
-
- 1,754
- views
-
- 314
- downloads
-
- 36
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Citations by DOI
-
- 36
- citations for umbrella DOI https://doi.org/10.7554/eLife.56996
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
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
