Department of Laboratory Medicine, Lund University, Malmö, Sweden.
Eur J Immunol. 2013 Jun;43(6):1617-29. doi: 10.1002/eji.201243196. Epub 2013 Apr 23.
Since a tightly regulated complement system is needed for a successful pregnancy, we hypothesized that alterations in complement inhibitors may be associated with idiopathic, recurrent miscarriage. We sequenced all exons coding for three complement inhibitors: C4b-binding protein (C4BP), CD46, and CD55 in 384 childless women with at least two miscarriages that could not be explained by known risk factors. Several alterations were found in C4BPA, of which the R120H, I126T, and the G423T mutations affected the expression level and/or the ability of recombinant C4BP to serve as cofactor for factor I. The only variant in C4BPB was located in the C-terminal part, and did not impair the polymerization of the molecule. Our results identify for the first time alterations in C4BP in women experiencing recurrent miscarriages. We also found four CD46 alterations in individual patients that were not found in healthy controls. One of the rare variants, P324L, showed decreased expression, whereas N213I resulted in deficient protein processing as well as an impaired cofactor activity in the degradation of both C4b and C3b. The identified alterations may result in in vivo consequences and contribute to the disorder but the degree of association must be evaluated in larger cohorts.
由于成功妊娠需要一个受到严格调控的补体系统，我们推测补体抑制剂的改变可能与特发性、复发性流产有关。我们对编码三种补体抑制剂（C4 结合蛋白[C4BP]、CD46 和 CD55）的所有外显子在 384 名至少经历过两次无法用已知风险因素解释的流产的无子女性中进行了测序。在 C4BPA 中发现了几个改变，其中 R120H、I126T 和 G423T 突变影响了重组 C4BP 作为因子 I 辅助因子的表达水平和/或能力。C4BPB 中唯一的变体位于 C 末端，不影响分子的聚合。我们的研究结果首次在经历复发性流产的女性中发现了 C4BP 的改变。我们还在个别患者中发现了四个 CD46 改变，而在健康对照组中没有发现这些改变。其中一个罕见的变体 P324L 表现出表达降低，而 N213I 导致蛋白加工缺陷以及 C4b 和 C3b 降解的辅助因子活性受损。鉴定出的改变可能导致体内后果并导致该疾病，但必须在更大的队列中评估其关联程度。
