Mutations in factor H reduce binding affinity to C3b and heparin and surface attachment to endothelial cells in hemolytic uremic syndrome.
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.
Manuelian
Tamara
T
Hans Knoell Institute for Natural Products Research, Beutenbergstrasse 11a, D-07745 Jena, Germany.
Hellwage
Jens
J
Meri
Seppo
S
Caprioli
Jessica
J
Noris
Marina
M
Heinen
Stefan
S
Jozsi
Mihaly
M
Neumann
Hartmut P H
HP
Remuzzi
Giuseppe
G
Zipfel
Peter F
PF
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
C493495:CFH protein, human; D020033:Protein Isoforms; D011994:Recombinant Proteins; D003179:Complement C3b; D017242:Complement Factor H; D006493:Heparin