Genetic and functional analysis of two missense mutations in CD46 predispose to postpartum atypical hemolytic uremic...

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.