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

Ueda, Yoshiyasu; Mohammed, Imran; 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; Song, Wen-Chao

Authors

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

Wen-Chao Song



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.

Citation

Ueda, Y., Mohammed, I., Song, D., Gullipalli, D., Zhou, L., Sato, S., …Song, W. (2017). Murine systemic thrombophilia and hemolytic uremic syndrome from a factor H point mutation. Blood, 129(9), 1184-1196. https://doi.org/10.1182/blood-2016-07-728253

Journal Article Type Article
Acceptance Date Dec 22, 2016
Online Publication Date Jan 5, 2017
Publication Date Mar 2, 2017
Deposit Date Sep 11, 2018
Publicly Available Date Mar 29, 2024
Journal Blood
Print ISSN 0006-4971
Electronic ISSN 1528-0020
Publisher American Society of Hematology
Peer Reviewed Peer Reviewed
Volume 129
Issue 9
Pages 1184-1196
DOI https://doi.org/10.1182/blood-2016-07-728253
Public URL https://nottingham-repository.worktribe.com/output/1070488
Publisher URL http://www.bloodjournal.org/content/129/9/1184.long?sso-checked=true
Additional Information This research was originally published in Blood. 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. Murine systemic thrombophilia and hemolytic uremic syndrome from a factor H point mutation. Blood. ;2017 Vol 129: 1184-1196. © the American Society of Hematology.