Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Disease of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu, China.
Clinical Laboratory, West China Second University Hospital, Sichuan University, Chengdu, China.
Nat Struct Mol Biol. 2024 Nov;31(11):1798-1807. doi: 10.1038/s41594-024-01396-2. Epub 2024 Oct 8.
The functionally conserved subcortical maternal complex (SCMC) is essential for early embryonic development in mammals. Reproductive disorders caused by pathogenic variants in NLRP5, TLE6 and OOEP, three core components of the SCMC, have attracted much attention over the past several years. Evaluating the pathogenicity of a missense variant in the SCMC is limited by the lack of information on its structure, although we recently solved the structure of the mouse SCMC and proposed that reproductive disorders caused by pathogenic variants are related to the destabilization of the SCMC core complex. Here we report the cryogenic electron microscopy structure of the human SCMC and uncover that the pyrin domain of NLRP5 is essential for the stability of SCMC. By combining prediction of SCMC stability and in vitro reconstitution, we provide a method for identifying deleterious variants, and we successfully identify a new pathogenic variant of TLE6 (p.A396T). Thus, on the basis of the structure of the human SCMC, we offer a strategy for the diagnosis of reproductive disorders and the discovery of new infertility-associated variants.
功能保守的皮质下母性复合物（SCMC）对于哺乳动物的早期胚胎发育至关重要。过去几年，NLRP5、TLE6 和 OOEP 这三个 SCMC 的核心组成部分的致病变体引起的生殖障碍引起了广泛关注。尽管我们最近解决了小鼠 SCMC 的结构，并提出由致病性变体引起的生殖障碍与 SCMC 核心复合物的不稳定性有关，但评估 SCMC 中错义变体的致病性受到其结构信息缺乏的限制。在这里，我们报告了人类 SCMC 的低温电子显微镜结构，并揭示了 NLRP5 的吡咯啉-6 结构域对于 SCMC 稳定性的重要性。通过结合 SCMC 稳定性的预测和体外重建，我们提供了一种识别有害变体的方法，并成功鉴定了 TLE6 的一种新的致病性变体（p.A396T）。因此，基于人类 SCMC 的结构，我们为生殖障碍的诊断和新的不孕相关变体的发现提供了一种策略。
