Pregnancy associated atypical hemolytic uremic syndrome (p-aHUS) is a disease with a triad of hemolytic anemia, thrombocytopenia and acute renal failure, which might be attributed to the uncontrolled complement activation. Herein, we sequenced a postpartum-aHUS patient and found the two missense variants of CD46, a novel mutation (c.403G > C, p.G135R) from her father and a once reported mutation (c.293C > T, p.T98I) without expressional and functional tests from her mother. The G135R mutation caused a significantly reduced membrane expression of CD46 in peripheral blood lymphocyte and renal cells. The T98I mutation caused a mild decrease membrane expression of CD46 in peripheral blood lymphocyte cells. Moreover, the expressed G135R protein was in precursor form, indicating that this mutant was retained intracellularly. The C3b binding ability of T98I mutant was slightly decreased while the C4b binding ability is not significantly changed. The cofactor ability of the two mutants for factor I in the degradation of C3b was demonstrated to be impaired. This study reported the first case of a four-generation postpartum-aHUS pedigree with isolated CD46 variants and the detailed disease progression, treatment, and prognosis provided more meaningful information for the understanding the disease.

中文翻译：

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遗传和功能分析CD46中的两个错义突变易患产后非典型溶血性尿毒症综合征。

妊娠相关的非典型溶血性尿毒症综合征（p-aHUS）是一种溶血性贫血，血小板减少症和急性肾衰竭的三联征，可能归因于补体激活不受控制。在这里，我们对一名产后aHUS患者进行了测序，发现了两个CD46的错义变体，一个来自她父亲的新突变（c.403G> C，p.G135R）和一个曾经报道的突变（c.293C> T，p.T98I）。 ），没有经过母亲的表情和功能测试。G135R突变导致外周血淋巴细胞和肾细胞中CD46的膜表达明显降低。T98I突变导致外周血淋巴细胞中CD46的膜表达轻度降低。而且，表达的G135R蛋白是前体形式，表明该突变体保留在细胞内。T98I突变体的C3b结合能力略有下降，而C4b结合能力没有明显改变。已证明这两个突变体在降解C3b方面对I因子的辅助因子能力受损。这项研究报告了首例四代产后aHUS谱系，带有分离的CD46变异，详细的疾病进展，治疗和预后为了解疾病提供了更有意义的信息。