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Ueda Y , Mohammed I , Song D , Gullipalli D , Zhou L , Sato S , Wang Y , Gupta S , Cheng Z , Wang H , Bao J , Mao Y , Brass L , Zheng XL , Miwa T , Palmer M , Dunaief J , Song WC
Murine systemic thrombophilia and hemolytic uremic syndrome from a factor H point mutation
Blood. 2017 Mar 2;129(9) :1184-1196
PMID: 28057640    PMCID: PMC5374733   
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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.
1528-0020 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 R01 AI117410/AI/NIAID NIH HHS/United States R01 HL115187/HL/NHLBI NIH HHS/United States R01 HL126724/HL/NHLBI NIH HHS/United States R01 AI085596/AI/NIAID NIH HHS/United States R01 AI044970/AI/NIAID NIH HHS/United States R01 EY023709/EY/NEI NIH HHS/United States Journal Article Research Support, N.I.H., Extramural United States Blood. 2017 Mar 2;129(9):1184-1196. doi: 10.1182/blood-2016-07-728253. Epub 2017 Jan 5.