RT Journal Article
SR Electronic
T1 A missense in HSF2BP causing Primary Ovarian Insufficiency affects meiotic recombination by its novel interactor C19ORF57/MIDAP
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.03.05.978007
DO 10.1101/2020.03.05.978007
A1 Felipe-Medina, Natalia
A1 Caburet, Sandrine
A1 Sánchez-Sáez, Fernando
A1 Condezo, Yazmine B.
A1 de Rooij, Dirk
A1 Gómez-H, Laura
A1 García-Valiente, Rodrigo
A1 Todeschini, Anne-Laure
A1 Duque, Paloma
A1 Sánchez-Martín, Manuel
A1 Shalev, Stavit A.
A1 Llano, Elena
A1 Veitia, Reiner
A1 Pendás, Alberto M.
YR 2020
UL http://biorxiv.org/content/early/2020/03/05/2020.03.05.978007.abstract
AB 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.