The C3 p.Ile1157Thr mutation associated with atypical hemolytic uremic syndrome, particularly in Japan, does not lead to disease development in several mouse models.

BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy characterized by dysregulation of the complement system due to genetic mutations and polymorphisms in complement activators and regulators. In Japan, C3 is the gene most frequently implicated in aHUS, with approximately three-quarters of the mutations reported for C3 corresponding to p.Ile1157Thr (p.I1157T). Patients with the C3 p.I1157T mutation are notable for their favorable prognosis despite the high frequency of aHUS relapse compared with other C3 mutations; however, some cases progress to end-stage renal disease, and clinical heterogeneity in individuals carrying the C3 p.I1157T mutation has been documented. In vitro studies suggest that impaired inactivation of C3b carrying the p.I1157T mutation by complement regulators may contribute to aHUS pathogenesis, but in vivo evidence remains scarce.

OBJECTIVES: To evaluate the phenotype of mice carrying the C3 p.I1157T mutation.

METHODS: We generated knock-in mice homozygous for the C3 p.I1157T mutation (C3T/T).

RESULTS: The mice developed normally, displayed phenotypes largely indistinguishable from wild-type mice, and did not develop aHUS even under lipopolysaccharide-induced stress. Moreover, C3T/T mice with homozygous deficiency in Adamts-13 also remained asymptomatic, without evidence of C3 overactivation. Thus, the C3 p.I1157T mutation did not promote thrombotic microangiopathy under the conditions tested in mice.

CONCLUSION: The phenotypic differences between humans and mice may reflect species-specific features of the complement system or indicate that additional factors are required for the development of aHUS. C3T/T mice may provide a useful model for studying the potential pathophysiological roles of the C3 p.I1157T mutation.