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

[EN]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 H...

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Detalles Bibliográficos
Autores: Felipe-Medina, Natalia, Caburet, Sandrine, Sánchez Sáez, Fernando, Condezo, Yazmine B, de Rooij, Dirk G, Gómez-H, Laura, Garcia-Valiente, Rodrigo, Todeschini, Anne Laure, Duque, Paloma, Sánchez Martín, Manuel Adolfo, Shalev, Stavit A, Llano Cuadra, María Elena, Veitia, Reiner A, Martín Pendás, Alberto
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2020
País:España
Institución:Universidad de Salamanca (USAL)
Repositorio:GREDOS. Repositorio Institucional de la Universidad de Salamanca
OAI Identifier:oai:gredos.usal.es:10366/168742
Acceso en línea:http://hdl.handle.net/10366/168742
Access Level:acceso abierto
Palabra clave:meiosis POI
Meiosis
Mutation
Primary Ovarian Insufficiency
Animals
Rad51 Recombinase
DNA-Binding Proteins
Mice
meiosis
insuficiencia ovárica primaria
animales
ratones
mutación
proteínas de unión al ADN
rad51 recombinasa
Descripción
Sumario:[EN]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.

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