RT Journal Article
SR Electronic
T1 A Novel Non-Synonymous Polymorphism (p.Arg240His) in C4b-Binding Protein Is Associated with Atypical Hemolytic Uremic Syndrome and Leads to Impaired Alternative Pathway Cofactor Activity
JF The Journal of Immunology
JO J. Immunol.
FD American Association of Immunologists
SP 6385
OP 6391
DO 10.4049/jimmunol.180.9.6385
VO 180
IS 9
A1 Blom, Anna M.
A1 Bergström, Frida
A1 Edey, Matthew
A1 Diaz-Torres, Martha
A1 Kavanagh, David
A1 Lampe, Anne
A1 Goodship, Judith A.
A1 Strain, Lisa
A1 Moghal, Nadeem
A1 McHugh, Mary
A1 Inward, Carol
A1 Tomson, Charles
A1 Frémeaux-Bacchi, Véronique
A1 Villoutreix, Bruno O.
A1 Goodship, Timothy H. J.
YR 2008
UL http://www.jimmunol.org/content/180/9/6385.abstract
AB Atypical hemolytic uremic syndrome (aHUS) is a disorder characterized by hemolytic anemia, thrombocytopenia, and acute renal failure. Mutations, polymorphisms, and copy number variation in complement factors and inhibitors are associated with aHUS. In this study, we report the first functional non-synonymous polymorphism in the complement inhibitor C4b-binding protein (C4BP) α-chain (c.719G>A; p.Arg240His), which is associated with aHUS. This heterozygous change was found in 6/166 aHUS patients compared with 5/542 normal (χ2 = 6.021; p = 0.014), which was replicated in a second cohort of aHUS patients in which we found 5/170 carriers. The polymorphism does not decrease expression efficiency of C4BP. p.Arg240His is equally efficient as the wild type in binding and supporting degradation of C4BP but its ability to bind C3b and act as cofactor to its degradation both in fluid phase and on surfaces is impaired. This observation supports the hypothesis that dysregulation of the alternative pathway of complement is pivotal for aHUS. Three of the patients carry also mutations in membrane cofactor protein and factor H strengthening the hypothesis that individuals may carry multiple susceptibility factors with an additive effect on the risk of developing aHUS.