Department of Biomedicine, Aarhus University, Aarhus C, Denmark.
Department of Clinical Genetics, Aarhus University Hospital, Aarhus N, Denmark.
Eur J Immunol. 2022 Oct;52(10):1610-1619. doi: 10.1002/eji.202249838. Epub 2022 Aug 31.
Atypical hemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy that may lead to organ failure. Dysregulation of the complement system can cause aHUS, and various disease-related variants in the complement regulatory protein CD46 are described. We here report a pediatric patient with aHUS carrying a hitherto unreported homozygous variant in CD46 (NM_172359.3:c.602C>T p.(Ser201Leu)). In our functional analyses, this variant caused complement dysregulation through three separate mechanisms. First, CD46 surface expression on the patient's blood cells was significantly reduced. Second, stably expressing CD46(Ser201Leu) cells bound markedly less to patterns of C3b than CD46 WT cells. Third, the patient predominantly expressed the rare isoforms of CD46 (C dominated) instead of the more common isoforms (BC dominated). Using BC1 and C1 expressing cell lines, we found that the C1 isoform bound markedly less C3b than the BC1 isoform. These results highlight the coexistence of multiple mechanisms that may act synergistically to disrupt CD46 function during aHUS development.
非典型溶血尿毒症综合征（aHUS）是一种血栓性微血管病，可导致器官衰竭。补体系统失调可导致 aHUS，并且已描述了补体调节蛋白 CD46 中的各种与疾病相关的变异体。我们在此报告了一名患有 aHUS 的儿科患者，其携带 CD46 中迄今未报道的纯合变异体（NM_172359.3:c.602C>T p.(Ser201Leu)）。在我们的功能分析中，该变异体通过三种独立的机制引起补体失调。首先，患者血细胞表面的 CD46 表达显著降低。其次，稳定表达 CD46(Ser201Leu)的细胞与 CD46 WT 细胞相比，与 C3b 的结合明显减少。第三，患者主要表达罕见的 CD46 同工型（C 为主），而不是更常见的同工型（BC 为主）。使用表达 BC1 和 C1 的细胞系，我们发现 C1 同工型与 BC1 同工型相比，与 C3b 的结合明显减少。这些结果强调了多种机制可能协同作用破坏 aHUS 发展过程中 CD46 功能的共存。
