title: Murine systemic thrombophilia and hemolytic uremic syndrome from a factor H point mutation.
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.
authors.affiliation: Department of Systems Pharmacology and Translational Therapeutics.
authors.forename: Yoshiyasu
authors.initials: Y
authors.lastname: Ueda
authors.affiliation: Department of Systems Pharmacology and Translational Therapeutics.
authors.forename: Imran
authors.initials: I
authors.lastname: Mohammed
authors.affiliation: Department of Ophthalmology, and.
authors.forename: Delu
authors.initials: D
authors.lastname: Song
authors.affiliation: Department of Systems Pharmacology and Translational Therapeutics.
authors.forename: Damodar
authors.initials: D
authors.lastname: Gullipalli
authors.affiliation: Department of Systems Pharmacology and Translational Therapeutics.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Department of Systems Pharmacology and Translational Therapeutics.
authors.forename: Sayaka
authors.initials: S
authors.lastname: Sato
authors.affiliation: Department of Systems Pharmacology and Translational Therapeutics.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
authors.forename: Shuchi
authors.initials: S
authors.lastname: Gupta
authors.affiliation: Department of Pharmacology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA.
authors.forename: Zhongjian
authors.initials: Z
authors.lastname: Cheng
authors.affiliation: Department of Pharmacology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA.
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA.
authors.forename: Jialing
authors.initials: J
authors.lastname: Bao
authors.affiliation: Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA.
authors.forename: Yingying
authors.initials: Y
authors.lastname: Mao
authors.affiliation: Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Brass
authors.affiliation: Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA.|Division of Laboratory Medicine, Department of Pathology, University of Alabama at Birmingham, Birmingham, AL; and.
authors.forename: X Long
authors.initials: XL
authors.lastname: Zheng
authors.affiliation: Department of Systems Pharmacology and Translational Therapeutics.
authors.forename: Takashi
authors.initials: T
authors.lastname: Miwa
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Palmer
authors.affiliation: Department of Ophthalmology, and.
authors.forename: Joshua
authors.initials: J
authors.lastname: Dunaief
authors.affiliation: Department of Systems Pharmacology and Translational Therapeutics.
authors.forename: Wen-Chao
authors.initials: WC
authors.lastname: Song
mesh_terms: D000818:Animals; D015153:Blotting, Western; D017242:Complement Factor H / Q000235:genetics*; D004195:Disease Models, Animal; D006463:Hemolytic-Uremic Syndrome / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017354:Point Mutation; D019851:Thrombophilia / Q000235:genetics*
chemical_list: D017242:Complement Factor H