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

Ueda, Yoshiyasu, Mohammed, Imran ORCID: https://orcid.org/0000-0002-8412-0768, Song, Delu, Gullipalli, Damodar, Zhou, Lin, Sato, Sayaka, Wang, Yuan, Gupta, Shuchi, Cheng, Zhongjian, Wang, Hong, Bao, Jialing, Mao, Yingying, Brass, Lawrence, Zheng, X.Long, Miwa, Takashi, Palmer, Matthew, Dunaief, Joshua and Song, Wen Chao 2017. Murine systemic thrombophilia and hemolytic uremic syndrome from a factor h point mutation. Blood 129 (9) , pp. 1184-1196. 10.1182/blood-2016-07-728253

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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. 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. Approximately 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 macrovasculature.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Optometry and Vision Sciences
Publisher:	American Society of Hematology
ISSN:	0006-4971
Date of Acceptance:	22 December 2016
Last Modified:	11 Nov 2022 09:02
URI:	https://orca.cardiff.ac.uk/id/eprint/152708

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