Biallelic variants in ZFP36L2 cause female infertility characterised by recurrent preimplantation embryo arrest
Biallelic variants in ZFP36L2 cause female infertility characterised by recurrent preimplantation embryo arrest
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DOI：
10.1136/jmedgenet-2021-107933
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发表时间：
2021-10
影响因子：
4
通讯作者：
Wei Zheng;Qian-Qian Sha-Qian;Huiling Hu;Fei Meng;Qinwei Zhou;Xueqin Chen;Shuoping Zhang;Y. Gu
中科院分区：
文献类型：
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作者：
Wei Zheng;Qian-Qian Sha-Qian;Huiling Hu;Fei Meng;Qinwei Zhou;Xueqin Chen;Shuoping Zhang;Y. Gu
背景：复发性植入前胚胎发育停滞（RPEA）是与已确定的遗传异常相关的辅助生殖技术治疗失败的最常见原因。已知母体基因的变异只能占这些病例的20%-30%。其他受影响个体的潜在遗传原因仍然未知。方法对100例RPEA患者进行全外显子测序。通过桑格测序、生物信息学和体外功能分析以及合子的单细胞RNA测序来验证所鉴定的候选致病变体的功能表征。结果ZFP 36 L2基因的双等位基因变异与RPEA相关，重复变异（p.Ser308_Ser310del）阻止了受精卵和HeLa细胞中母体mRNA的降解。结论这些发现强调了母体mRNA衰变与人类植入前胚胎发育之间的相关性，并突出了一个新的可能负责RPEA的基因，这可能有助于遗传诊断。
Background Recurrent preimplantation embryo developmental arrest (RPEA) is the most common cause of assisted reproductive technology treatment failure associated with identified genetic abnormalities. Variants in known maternal genes can only account for 20%–30% of these cases. The underlying genetic causes for the other affected individuals remain unknown. Methods Whole exome sequencing was performed for 100 independent infertile females that experienced RPEA. Functional characterisations of the identified candidate disease-causative variants were validated by Sanger sequencing, bioinformatics and in vitro functional analyses, and single-cell RNA sequencing of zygotes. Results Biallelic variants in ZFP36L2 were associated with RPEA and the recurrent variant (p.Ser308_Ser310del) prevented maternal mRNA decay in zygotes and HeLa cells. Conclusion These findings emphasise the relevance of the relationship between maternal mRNA decay and human preimplantation embryo development and highlight a novel gene potentially responsible for RPEA, which may facilitate genetic diagnoses.