A missense in HSF2BP causing primary ovarian insufficiency affects meiotic recombination by its novel interactor C19ORF57/BRME1
Open accessPublished version of a preprint
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. Hsf2bp S167L/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.
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Cites
Global quantification of mammalian gene expression control
Schwanhäusser, B., Busse, D., Li, N., Dittmar, G., Schuchhardt, J., Wolf, J., Chen, W., & Selbach, M. (2011) · Nature · doi:10.1038/nature10098 · Cited by 6,566 · cited 2× · see citing works
“Proteins were quantified using iBAQ (Schwanhäusser et al., 2011).”
MethodPromotion of BRCA2-Dependent Homologous Recombination by DSS1 via RPA Targeting and DNA Mimicry
Zhao, W., Vaithiyalingam, S., San Filippo, J., Maranon, D. G., Jimenez-Sainz, J., Fontenay, G. V., Kwon, Y., Leung, S. G., Lu, L., Jensen, R. B., et al. (2015) · Molecular Cell · doi:10.1016/j.molcel.2015.05.032 · Cited by 177 · see citing works
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- Authors
- Felipe-Medina, N., Caburet, S., Sánchez-Sáez, F., Condezo, Y. B., de Rooij, D. G., Gómez-H, L., Garcia-Valiente, R., Todeschini, A. L., Duque, P., Sánchez-Martin, M. A., Shalev, S. A., Llano, E., Veitia, R. A., & Pendás, A. M.
- Affiliations
- Molecular Mechanisms Program, Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer (CSIC-Universidad de Salamanca), Salamanca, Spain
- Centre National de la Recherche Scientifique (FR)
- Consejo Superior de Investigaciones Científicas (ES)
- Reproductive Biology Group, Division of Developmental Biology, Department of Biology, Faculty of Science, Utrecht University, Utrecht, Netherlands
- Transgenic Facility, Nucleus platform, Universidad de Salamanca, Salamanca, Spain
- Technion – Israel Institute of Technology (IL)
- Corresponding author
- Veitia, Reiner A
- Pendás, Alberto M
- ORCID
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2020-08-26
- Volume
- 9
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC7498267
- OpenAlex
- W3080971197
- Cited by
- 45
- References
- 2
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 8 · 2023: 10 · 2022: 8 · 2021: 11 · 2020: 2
- FWCI
- 5.80
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Gredos (University of Salamanca) (publishedVersion, cc-by-nc-nd)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- Hispana (submittedVersion, cc-by-nc-nd)
- Funders
- Ministerio de Economía y Competitividad
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Reproductive Biology and Fertility
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
- Keywords
- primary ovarian insufficiency, meiotic recombination, crossover frequency, hypomorphic allele, protein-protein interaction, BRCA2, RAD51, DMC1, PALB2, RPA, mouse model
- MeSH terms
- Exome Sequencing, Animals, Carrier Proteins, DNA-Binding Proteins, Female, Heat-Shock Proteins, Meiosis, Recombination, Genetic, Primary Ovarian Insufficiency, Mice, Knockout, Mutation, Missense, Rad51 Recombinase, Mice
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