2. Academic Validation
  3. A missense in HSF2BP causing primary ovarian insufficiency affects meiotic recombination by its novel interactor C19ORF57/BRME1

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

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.

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