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Murine systemic thrombophilia and hemolytic uremic syndrome from a factor H point mutation

Yoshiyasu Ueda, Imran Mohammed, Delu Song, Damodar Gullipalli, Lin Zhou, Sayaka Sato, Yuan Wang, Shuchi Gupta, Zhongjian Cheng, Hong Wang, Jialing Bao, Yingying Mao, Lawrence Brass, X. Long Zheng, Takashi Miwa, Matthew Palmer, Joshua Dunaief and Wen-chao Song

Key points

  • A point mutation in murine factor H (W1206R) impairs its interaction with host cells but does not affect its complement regulating activity

  • W1206R mutant mice develop complement-mediated systemic thrombotic angiopathy leading to renal failure, stroke and retinopathy

Abstract

Complement plays a key role in host defense but its dysregulation can cause autologous tissue injury. Complement activation is normally controlled by regulatory proteins including factor H (FH) in plasma and membrane cofactor protein (MCP) on the cell surface. Mutations in FH and MCP are linked to atypical hemolytic uremic syndrome, a type of thrombotic microangiopathy (TMA) that causes renal failure in patients. We describe here that disruption of FH function on the cell surface can also lead to disseminated complement-dependent macrovascular thrombosis. By gene targeting, we introduced a point mutation (W1206R) into murine FH that impaired its interaction with host cells but did not affect its plasma complement-regulating activity. Homozygous mutant mice carrying this mutation developed renal TMA as well as systemic thrombophilia involving large blood vessels in multiple organs including liver, lung, spleen and kidney. About 30% of mutant mice displayed symptoms of stroke and ischemic retinopathy and 48% died prematurely. Genetic deficiency of complement C3 and factor D prevented both the systemic thrombophilia and renal TMA phenotypes. These results demonstrate a causal relationship between complement dysregulation and systemic angiopathy and suggest that complement activation may contribute to various human thrombotic disorders involving both the micro- and macro-vasculature.

  • Submitted July 15, 2016.
  • Accepted December 22, 2016.