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

Version 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.

Metrics

  • 1,548
    Page views
  • 287
    Downloads
  • 21
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

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)

  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

Further reading

    1. Biochemistry and Chemical Biology
    2. Cell Biology
    Maria Körner, Susanne R Meyer ... Alexander Buchberger
    Research Article Updated

    The ATPase p97 (also known as VCP, Cdc48) has crucial functions in a variety of important cellular processes such as protein quality control, organellar homeostasis, and DNA damage repair, and its de-regulation is linked to neuromuscular diseases and cancer. p97 is tightly controlled by numerous regulatory cofactors, but the full range and function of the p97–cofactor network is unknown. Here, we identify the hitherto uncharacterized FAM104 proteins as a conserved family of p97 interactors. The two human family members VCP nuclear cofactor family member 1 and 2 (VCF1/2) bind p97 directly via a novel, alpha-helical motif and associate with p97-UFD1-NPL4 and p97-UBXN2B complexes in cells. VCF1/2 localize to the nucleus and promote the nuclear import of p97. Loss of VCF1/2 results in reduced nuclear p97 levels, slow growth, and hypersensitivity to chemical inhibition of p97 in the absence and presence of DNA damage, suggesting that FAM104 proteins are critical regulators of nuclear p97 functions.

    1. Cell Biology
    2. Neuroscience
    Elisabeth Jongsma, Anita Goyala ... Collin Yvès Ewald
    Research Article Updated

    The amyloid beta (Aβ) plaques found in Alzheimer’s disease (AD) patients’ brains contain collagens and are embedded extracellularly. Several collagens have been proposed to influence Aβ aggregate formation, yet their role in clearance is unknown. To investigate the potential role of collagens in forming and clearance of extracellular aggregates in vivo, we created a transgenic Caenorhabditis elegans strain that expresses and secretes human Aβ1-42. This secreted Aβ forms aggregates in two distinct places within the extracellular matrix. In a screen for extracellular human Aβ aggregation regulators, we identified different collagens to ameliorate or potentiate Aβ aggregation. We show that a disintegrin and metalloprotease a disintegrin and metalloprotease 2 (ADM-2), an ortholog of ADAM9, reduces the load of extracellular Aβ aggregates. ADM-2 is required and sufficient to remove the extracellular Aβ aggregates. Thus, we provide in vivo evidence of collagens essential for aggregate formation and metalloprotease participating in extracellular Aβ aggregate removal.