Molecular Mechanisms Program, Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer (CSIC-Universidad de Salamanca), Salamanca, Spain.
Université de Paris, Paris Cedex, France.
Elife. 2020 Aug 26;9:e56996. doi: 10.7554/eLife.56996.
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 , 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. 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.
原发性卵巢功能不全 (POI) 是不孕的主要原因，但病因仍知之甚少。我们对一个有三例 POI 的家族进行全外显子组测序，发现了 中一个重要的减数分裂基因 S167L 的候选错义变异。HSF2BP-S167L 变异在小鼠中的功能分析表明，与新的功能丧失（敲除）小鼠模型相比，它表现为一个功能降低的等位基因。HSF2BP-S167L 杂合突变的 雌性小鼠的生育力降低，产仔数减少。为了获得机制上的见解，我们鉴定了 C19ORF57/BRME1 是 HSF2BP 的一个强相互作用物和稳定剂，并表明 BRME1/HSF2BP 蛋白复合物与 BRCA2、RAD51、RPA 和 PALB2 共免疫沉淀。携带 HSF2BP-S167L 变异的减数分裂细胞在重组结节处 HSF2BP 和 BRME1 的染色明显减少，并且由重组酶 RAD51/DMC1 形成的焦点数量减少，从而导致交叉频率降低。我们的研究结果为人类卵巢功能不全和亚（低）生育力中 HSF2BP-S167L 的分子机制提供了新的见解。
