A missense in HSF2BP causing Primary Ovarian Insufficiency affects meiotic recombination by its novel interactor C19ORF57/BRME1

  1. Natalia Felipe-Medina
  2. Sandrine Caburet
  3. Fernando Sánchez-Sáez
  4. Yazmine B Condezo
  5. Dirk G de Rooij
  6. Laura Gómez-H
  7. Rodrigo Garcia-Valiente
  8. Anne Laure Todeschini
  9. Paloma Duque
  10. Manuel Adolfo Sánchez-Martin
  11. Stavit A Shalev
  12. Elena Llano
  13. Reiner A Veitia  Is a corresponding author
  14. Alberto M Pendás  Is a corresponding author
  1. Centro de Investigación del Cáncer, Spain
  2. Université Paris Diderot, France
  3. Instituto de Biologia Molecular y Celular del Cancer, Spain
  4. Academic Medical Center Amsterdam/Utrecht University, Netherlands
  5. Instituto de Biologia Molecular y Celular del Cancer-CSIC-Universidad de Salamanca, Spain
  6. Institut Jacques Monod, Universite de Paris, CNRS, France
  7. Instituto de Biologia Molecular y Celular del Cancer (CSIC-Universidad de Salamanca), Spain
  8. University of Salamanca, Spain
  9. Genetic Institute, Emek Medical Center, Israel
  10. 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

  1. Natalia Felipe-Medina

    l9, Centro de Investigación del Cáncer, Salamanca, Spain
    Competing interests
    The authors declare that no competing interests exist.
  2. Sandrine Caburet

    Molecular Oncology and Ovarian Pathologies, Institut Jacques Monod, Université Paris Diderot, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7404-8213
  3. Fernando Sánchez-Sáez

    l9, Instituto de Biologia Molecular y Celular del Cancer, Salamanca, Spain
    Competing interests
    The authors declare that no competing interests exist.
  4. Yazmine B Condezo

    l9, Centro de Investigación del Cáncer, Salamanca, Spain
    Competing interests
    The authors declare that no competing interests exist.
  5. Dirk G de Rooij

    reproduction, Academic Medical Center Amsterdam/Utrecht University, Utrecht, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  6. Laura Gómez-H

    l9, Instituto de Biologia Molecular y Celular del Cancer-CSIC-Universidad de Salamanca, salamanca, Spain
    Competing interests
    The authors declare that no competing interests exist.
  7. Rodrigo Garcia-Valiente

    L9, Instituto de Biologia Molecular y Celular del Cancer-CSIC-Universidad de Salamanca, Salamanca, Spain
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0444-5587
  8. Anne Laure Todeschini

    Institut Jacques Monod, Universite de Paris, CNRS, paris, France
    Competing interests
    The authors declare that no competing interests exist.
  9. Paloma Duque

    l9, Instituto de Biologia Molecular y Celular del Cancer (CSIC-Universidad de Salamanca), Salamanca, Spain
    Competing interests
    The authors declare that no competing interests exist.
  10. Manuel Adolfo Sánchez-Martin

    University of Salamanca, Salamanca, Spain
    Competing interests
    The authors declare that no competing interests exist.
  11. Stavit A Shalev

    OBGYN, Genetic Institute, Emek Medical Center, Afula, Israel
    Competing interests
    The authors declare that no competing interests exist.
  12. Elena Llano

    Instituto de Biología Molecular y Celular del Cáncer (CSIC-USAL), Campus Miguel de Unamúno, Salamanca, Spain
    Competing interests
    The authors declare that no competing interests exist.
  13. Reiner A Veitia

    Institut Jacques Monod, Université Paris Diderot, Paris, France
    For correspondence
    reiner.veitia@ijm.fr
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4100-2681
  14. Alberto M Pendás

    Instituto de Biología Molecular y Celular del Cáncer de Salamanca, Campus Miguel de Unamúno, Salamanca, Spain
    For correspondence
    amp@usal.es
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9264-3721

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.

Reviewing Editor

  1. Bernard de Massy, CNRS UM, France

Publication history

  1. Received: March 17, 2020
  2. Accepted: August 26, 2020
  3. Accepted Manuscript published: August 26, 2020 (version 1)
  4. Version of Record published: September 17, 2020 (version 2)

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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  1. Natalia Felipe-Medina
  2. Sandrine Caburet
  3. Fernando Sánchez-Sáez
  4. Yazmine B Condezo
  5. Dirk G de Rooij
  6. Laura Gómez-H
  7. Rodrigo Garcia-Valiente
  8. Anne Laure Todeschini
  9. Paloma Duque
  10. Manuel Adolfo Sánchez-Martin
  11. Stavit A Shalev
  12. Elena Llano
  13. Reiner A Veitia
  14. Alberto M Pendás
(2020)
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