title: Mutations in factor H reduce binding affinity to C3b and heparin and surface attachment to endothelial cells in hemolytic uremic syndrome.
abstract: Hemolytic uremic syndrome (HUS) is a disease characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. Recent studies have identified a factor H-associated form of HUS, caused by gene mutations that cluster in the C-terminal region of the complement regulator factor H. Here we report how three mutations (E1172Stop, R1210C, and R1215G; each of the latter two identified in three independent cases from different, unrelated families) affect protein function. All three mutations cause reduced binding to the central complement component C3b/C3d to heparin, as well as to endothelial cells. These defective features of the mutant factor H proteins explain progression of endothelial cell and microvascular damage in factor H-associated genetic HUS and indicate a protective role of factor H for tissue integrity during thrombus formation.
authors.affiliation: Hans Knoell Institute for Natural Products Research, Beutenbergstrasse 11a, D-07745 Jena, Germany.
authors.forename: Tamara
authors.initials: T
authors.lastname: Manuelian
authors.forename: Jens
authors.initials: J
authors.lastname: Hellwage
authors.forename: Seppo
authors.initials: S
authors.lastname: Meri
authors.forename: Jessica
authors.initials: J
authors.lastname: Caprioli
authors.forename: Marina
authors.initials: M
authors.lastname: Noris
authors.forename: Stefan
authors.initials: S
authors.lastname: Heinen
authors.forename: Mihaly
authors.initials: M
authors.lastname: Jozsi
authors.forename: Hartmut P H
authors.initials: HP
authors.lastname: Neumann
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Remuzzi
authors.forename: Peter F
authors.initials: PF
authors.lastname: Zipfel
mesh_terms: D000818:Animals; D003179:Complement C3b / Q000378:metabolism*; D017242:Complement Factor H / Q000235:genetics* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006463:Hemolytic-Uremic Syndrome / Q000235:genetics*; D006493:Heparin / Q000378:metabolism*; D006801:Humans; D009154:Mutation; D020033:Protein Isoforms; D011994:Recombinant Proteins / Q000378:metabolism
chemical_list: C493495:CFH protein, human; D020033:Protein Isoforms; D011994:Recombinant Proteins; D003179:Complement C3b; D017242:Complement Factor H; D006493:Heparin