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.
Highlights
The process of gametogenesis is one of the most complex and highly regulated differentiation programs
In order to identify the genetic basis of this familial Primary Ovarian Insufficiency (POI) case, we performed whole exome sequencing on genomic DNA from two POI patients, III-2 and III-3, and their fertile sister III-10 (Supplementary file 1a)
We identified the S167L missense variant in HSF2BP in a consanguineous family with three cases of POI with secondary amenorrhea
Summary
The process of gametogenesis is one of the most complex and highly regulated differentiation programs. It involves a unique reductional cell division, known as meiosis, to generate highly specialized cells: the gametes. The outcome of meiosis is the production of oocytes and spermatozoa, which are the most distinctive cells of an adult organism and are essential for the faithful transmission of the genome across generations
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