Mutations in factor H reduce binding affinity to C3b and heparin and surface attachment to endothelial cells in hemolytic uremic syndrome

J Clin Invest. 2003 Apr;111(8):1181-90. doi: 10.1172/JCI16651.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Complement C3b / metabolism*
  • Complement Factor H / genetics*
  • Complement Factor H / metabolism
  • Endothelium, Vascular / metabolism*
  • Flow Cytometry
  • Fluorescent Antibody Technique
  • Hemolytic-Uremic Syndrome / genetics*
  • Heparin / metabolism*
  • Humans
  • Mutation*
  • Protein Isoforms
  • Recombinant Proteins / metabolism

Substances

  • Protein Isoforms
  • Recombinant Proteins
  • complement factor H, human
  • Complement C3b
  • Complement Factor H
  • Heparin