Mutations in NLRP2 and NLRP5 cause female infertility characterised by early embryonic arrest
Mutations in NLRP2 and NLRP5 cause female infertility characterised by early embryonic arrest
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DOI：
10.1136/jmedgenet-2018-105936
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发表时间：
2019-07-01
影响因子：
4
通讯作者：
Wang, Lei
中科院分区：
文献类型：
--
作者：
Mu, Jian;Wang, Wenjing;Wang, Lei
背景人类成功的生殖需要正常的精子发生、卵子发生、受精和早期胚胎发育，而这些过程中的任何一个过程的异常都会导致不育。早期胚胎停滞通常见于辅助生殖技术(ART)反复失败的不孕不育患者。然而，早期胚胎停滞的遗传基础在很大程度上是未知的。目的探讨以早期胚胎停滞为特征的不孕症患者的遗传原因。方法我们对一个先证者进行了外显子组测序，该先证者来自一个血缘家庭。我们通过桑格测序进一步筛选了496名被诊断为早期胚胎停滞的个体中的候选基因。研究了突变对HeLa细胞、卵母细胞和胚胎的影响。结果我们鉴定了5个携带NLRP2双等位基因突变的独立个体。我们还发现来自两个家庭的三个人携带NLRP5的双等位基因突变。NLRP2和NLRP5的这些突变导致了体外以及卵母细胞和胚胎中蛋白质表达的减少。结论NLRP2和NLRP5是导致人类早期胚胎停滞的新突变基因。这一发现为ART复发性失败患者提供了更多潜在的诊断标记物，并帮助我们更好地理解以早期胚胎停滞为特征的女性不孕症的遗传学基础。
Background Successful human reproduction requires normal spermatogenesis, oogenesis, fertilisation and early embryonic development, and abnormalities in any of these processes will result in infertility. Early embryonic arrest is commonly observed in infertile patients with recurrent failure of assisted reproductive technology (ART). However, the genetic basis for early embryonic arrest is largely unknown. Objective We aim to identify genetic causes of infertile patients characterised by early embryonic arrest. Methods We pursued exome sequencing in a proband with embryonic arrest from the consanguineous family. We further screened candidate genes in a cohort of 496 individuals diagnosed with early embryonic arrest by Sanger sequencing. Effects of mutations were investigated in HeLa cells, oocytes and embryos. Results We identified five independent individuals carrying biallelic mutations in NLRP2. We also found three individuals from two families carrying biallelic mutations in NLRP5. These mutations in NLRP2 and NLRP5 caused decreased protein expression in vitro and in oocytes and embryos. Conclusions NLRP2 and NLRP5 are novel mutant genes responsible for human early embryonic arrest. This finding provides additional potential diagnostic markers for patients with recurrent failure of ART and helps us to better understand the genetic basis of female infertility characterised by early embryonic arrest.