A missense in HSF2BP causing primary ovarian insufficiency affects meiotic recombination by its novel interactor C19ORF57/BRME1
A missense in HSF2BP causing primary ovarian insufficiency affects meiotic recombination by its novel interactor C19ORF57/BRME1
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DOI：
10.7554/elife.56996
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发表时间：
2020-08-26
期刊：
影响因子：
7.7
通讯作者：
Pendas, Alberto M.
中科院分区：
文献类型：
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作者：
Felipe-Medina, Natalia;Caburet, Sandrine;Pendas, Alberto M.
原发卵巢功能不全(POI)是不孕症的主要原因之一，但其病因尚不清楚。通过对一个POI家系进行全外显子组测序，我们在一个重要的减数分裂基因HSF2BP中确定了候选错义突变S167L。对HSF2BP-S167L变异体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，它表现为亚型等位基因。Hsf2bp(S167L/S167)L母猪产仔数较少，生育力下降。为了获得机制上的见解，我们确定C19ORF57/BRME1是HSF2BP的强相互作用和稳定剂，并表明BRME1/HSF2BP蛋白复合体与BRCA2、RAD51、RPA和PALB2免疫共沉淀。携带HSF2BP-S167L变异体的小细胞在重组结节处HSF2BP和BRME1的染色明显减少，重组酶RAD51/DMC1形成的病灶数量减少，从而导致交叉频率降低。我们的结果为HSF2BP-S167L在人类卵巢功能不全和亚(弱)生育中的分子机制提供了深入的认识。
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/S167)L 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.