Structural and functional characterization of factor H mutations associated with atypical hemolytic uremic syndrome

Am J Hum Genet. 2002 Dec;71(6):1285-95. doi: 10.1086/344515. Epub 2002 Nov 6.

Abstract

Genetic studies have demonstrated the involvement of the complement regulator factor H in nondiarrheal, nonverocytotoxin (i.e., atypical) cases of hemolytic uremic syndrome. Different factor H mutations have been identified in 10%-30% of patients with atypical hemolytic uremic syndrome (aHUS), and most of these mutations alter single amino acids in the C-terminal region of factor H. Although these mutations are considered to be responsible for the disease, the precise role that factor H plays in the pathogenesis of aHUS is unknown. We report here the structural and functional characterization of three different factor H proteins purified from the plasma of patients with aHUS who carry the factor H mutations W1183L, V1197A, or R1210C. Structural anomalies in factor H were found only in R1210C carriers; these individuals show, in their plasma, a characteristic high-molecular-weight factor H protein that results from the covalent interaction between factor H and human serum albumin. Most important, all three aHUS-associated factor H proteins have a normal cofactor activity in the proteolysis of fluid-phase C3b by factor I but show very low binding to surface-bound C3b. This functional impairment was also demonstrated in recombinant mutant factor H proteins expressed in COS7 cells. These data support the hypothesis that patients with aHUS carry a specific dysfunction in the protection of cellular surfaces from complement activation, offering new possibilities to improve diagnosis and develop appropriate therapies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • COS Cells
  • Complement C3b / metabolism
  • Complement Factor H / chemistry
  • Complement Factor H / genetics*
  • Complement Factor H / isolation & purification
  • Complement Factor H / metabolism*
  • DNA Mutational Analysis
  • Female
  • Fibrinogen / metabolism
  • Hemolytic-Uremic Syndrome / genetics*
  • Hemolytic-Uremic Syndrome / metabolism
  • Heterozygote
  • Humans
  • Male
  • Molecular Sequence Data
  • Molecular Weight
  • Mutation / genetics*
  • Pedigree
  • Protein Binding

Substances

  • complement factor H, human
  • Complement C3b
  • Complement Factor H
  • Fibrinogen

Associated data

  • OMIM/134370
  • OMIM/235400