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

P Sánchez-Corral, D Pérez-Caballero, O Huarte… - The American Journal of …, 2002 - cell.com
P Sánchez-Corral, D Pérez-Caballero, O Huarte, AM Simckes, E Goicoechea…
The American Journal of Human Genetics, 2002cell.com
Genetic studies have demonstrated the involvement of the complement regulator factor H in
nondiarrheal, nonverocytotoxin (ie, 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 …
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.
cell.com