Novel homozygous CD46 variant with C‐isoform expression affects C3b inactivation in atypical hemolytic uremic syndrome

Abstract

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.

Genetic investigation of Nordic patients with complement-mediated kidney diseases

“…This was, however, not specifically demonstrated for the variants presented herein, as, for example, the aHUS-associated variant G261D did not exhibit complement dysregulation ( 64 ). CD46 variants may also cause loss-of-function by reduced expression on cell surfaces, as shown for c.286 + 2T>G and S201L ( 70 ), decreased cofactor activity, or affect C3b/C4b binding capacity ( 72 , 86 ). Likewise, thrombomodulin inhibits complement activation by promoting C3b inactivation and mutated variants have exhibited less C3b inactivation to iC3b on cell surfaces, as shown for the P501L variant ( 11 ).…”