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

Natalia Felipe-Medina, View ORCID ProfileSandrine Caburet, Fernando Sánchez-Sáez, Yazmine B. Condezo, Dirk de Rooij, Laura Gómez-H, Rodrigo García-Valiente, Anne-Laure Todeschini, Paloma Duque, Manuel Sánchez-Martín, Stavit A. Shalev, Elena Llano, View ORCID ProfileReiner Veitia, View ORCID ProfileAlberto M. Pendás
doi: https://doi.org/10.1101/2020.03.05.978007
Natalia Felipe-Medina
1Molecular Mechanisms Program, Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer (CSIC-Universidad de Salamanca), Salamanca, Spain
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Sandrine Caburet
2Université de Paris, 75205 Paris Cedex 13, France
3Institut Jacques Monod, Université de Paris, CNRS UMR7592, Paris 75013, France
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  • ORCID record for Sandrine Caburet
Fernando Sánchez-Sáez
1Molecular Mechanisms Program, Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer (CSIC-Universidad de Salamanca), Salamanca, Spain
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Yazmine B. Condezo
1Molecular Mechanisms Program, Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer (CSIC-Universidad de Salamanca), Salamanca, Spain
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Dirk de Rooij
4Reproductive Biology Group, Division of Developmental Biology, Department of Biology, Faculty of Science, Utrecht University, Utrecht 3584CM, The Netherlands
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Laura Gómez-H
1Molecular Mechanisms Program, Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer (CSIC-Universidad de Salamanca), Salamanca, Spain
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Rodrigo García-Valiente
1Molecular Mechanisms Program, Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer (CSIC-Universidad de Salamanca), Salamanca, Spain
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Anne-Laure Todeschini
2Université de Paris, 75205 Paris Cedex 13, France
3Institut Jacques Monod, Université de Paris, CNRS UMR7592, Paris 75013, France
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Paloma Duque
1Molecular Mechanisms Program, Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer (CSIC-Universidad de Salamanca), Salamanca, Spain
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Manuel Sánchez-Martín
5Departamento de Medicina, Universidad de Salamanca, Spain
6Transgenic Facility, Nucleus platform, Universidad de Salamanca, Spain
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Stavit A. Shalev
7Bruce and Ruth Rappaport Faculty of Medicine, Technion, Haifa, Israel
8The Genetic Institute, “Emek” Medical Center, Afula, Israel
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Elena Llano
1Molecular Mechanisms Program, Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer (CSIC-Universidad de Salamanca), Salamanca, Spain
9Departamento de Fisiología y Farmacología, Universidad de Salamanca, Salamanca, Spain
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Reiner Veitia
2Université de Paris, 75205 Paris Cedex 13, France
3Institut Jacques Monod, Université de Paris, CNRS UMR7592, Paris 75013, France
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  • For correspondence: amp@usal.es reiner.veitia@ijm.fr
Alberto M. Pendás
1Molecular Mechanisms Program, Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer (CSIC-Universidad de Salamanca), Salamanca, Spain
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  • For correspondence: amp@usal.es reiner.veitia@ijm.fr
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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, compared to a new HSF2BP knock-out mouse showed that it behaves as a hypomorphic allele. HSF2BP-S167L females show reduced fertility with small litter sizes. To obtain mechanistic insights, we identified C19ORF57/MIDAP as a strong interactor and stabilizer of HSF2BP by forming a higher-order macromolecular structure involving BRCA2, RAD51, RPA and PALB2. Meiocytes bearing the HSF2BP-S167L mutation showed a strongly decreased expression of both MIDAP and HSF2BP at the recombination nodules. Although HSF2BP-S167L does not affect heterodimerization between HSF2BP and MIDAP, it promotes a lower expression of both proteins and a less proficient activity in replacing RPA by the recombinases RAD51/DMC1, thus leading to a lower frequency of cross-overs. Our results provide insights into the molecular mechanism of two novel actors of meiosis underlying non-syndromic ovarian insufficiency.

Summary Felipe-Medina et al. describe a missense variant in the meiotic gene HSF2BP in a consanguineous family with Premature Ovarian Insufficiency, and characterize it as an hypormorphic allele, that in vivo impairs its dimerization with a novel meiotic actor, MIDAP/ C19ORF57, and affect recombination at double-strand DNA breaks.

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Posted March 05, 2020.
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A missense in HSF2BP causing Primary Ovarian Insufficiency affects meiotic recombination by its novel interactor C19ORF57/MIDAP
Natalia Felipe-Medina, Sandrine Caburet, Fernando Sánchez-Sáez, Yazmine B. Condezo, Dirk de Rooij, Laura Gómez-H, Rodrigo García-Valiente, Anne-Laure Todeschini, Paloma Duque, Manuel Sánchez-Martín, Stavit A. Shalev, Elena Llano, Reiner Veitia, Alberto M. Pendás
bioRxiv 2020.03.05.978007; doi: https://doi.org/10.1101/2020.03.05.978007
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A missense in HSF2BP causing Primary Ovarian Insufficiency affects meiotic recombination by its novel interactor C19ORF57/MIDAP
Natalia Felipe-Medina, Sandrine Caburet, Fernando Sánchez-Sáez, Yazmine B. Condezo, Dirk de Rooij, Laura Gómez-H, Rodrigo García-Valiente, Anne-Laure Todeschini, Paloma Duque, Manuel Sánchez-Martín, Stavit A. Shalev, Elena Llano, Reiner Veitia, Alberto M. Pendás
bioRxiv 2020.03.05.978007; doi: https://doi.org/10.1101/2020.03.05.978007

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