A missense in HSF2BP causing primary ovarian insufficiency affects meiotic recombination by its novel interactor C19ORF57/BRME1

  • Elife. 2020 Aug 26;9:e56996. doi: 10.7554/eLife.56996.
Natalia Felipe-Medina  #  1 ,  Sandrine Caburet  #  2  3 ,  Fernando Sánchez-Sáez  1 ,  Yazmine B Condezo  1 ,  Dirk G de Rooij  4 ,  Laura Gómez-H  1 ,  Rodrigo Garcia-Valiente  1 ,  Anne Laure Todeschini  2  3 ,  Paloma Duque  1 ,  Manuel Adolfo Sánchez-Martin  5  6 ,  Stavit A Shalev  7  8 ,  Elena Llano  1  9 ,  Reiner A Veitia  2  3  10 ,  Alberto M Pendás  1
Affiliations
  • 1. Molecular Mechanisms Program, Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer (CSIC-Universidad de Salamanca), Salamanca, Spain.
  • 2. Université de Paris, Paris Cedex, France.
  • 3. Institut Jacques Monod, Université de Paris, Paris, France.
  • 4. Reproductive Biology Group, Division of Developmental Biology, Department of Biology, Faculty of Science, Utrecht University, Utrecht, Netherlands.
  • 5. Transgenic Facility, Nucleus platform, Universidad de Salamanca, Salamanca, Spain.
  • 6. Departamento de Medicina, Universidad de Salamanca, Salamanca, Spain.
  • 7. The Genetic Institute, "Emek" Medical Center, Afula, Israel.
  • 8. Bruce and Ruth Rappaport Faculty of Medicine, Technion, Haifa, Israel.
  • 9. Departamento de Fisiología y Farmacología, Universidad de Salamanca, Salamanca, Spain.
  • 10. Université Paris-Saclay, Institut de Biologie F. Jacob, Commissariat à l'Energie Atomique, Fontenay aux Roses, France.
  • # Contributed equally.
PMID: 32845237 DOI: 10.7554/eLife.56996
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 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.

Keywords
cell biology; fertility; human genetics; meiosis; meiotic recombination; mouse; reproduction.