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.
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) alpha-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 (chi2 = 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.
Blom
Anna M
AM
Lund University, Department of Laboratory Medicine, Malmö University Hospital, Malmö, Sweden.
Bergström
Frida
F
Edey
Matthew
M
Diaz-Torres
Martha
M
Kavanagh
David
D
Lampe
Anne
A
Goodship
Judith A
JA
Strain
Lisa
L
Moghal
Nadeem
N
McHugh
Mary
M
Inward
Carol
C
Tomson
Charles
C
Frémeaux-Bacchi
Véronique
V
Villoutreix
Bruno O
BO
Goodship
Timothy H J
TH
D058186:Acute Kidney Injury / Q000235:genetics* / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D019943:Amino Acid Substitution; D002648:Child; D015331:Cohort Studies; D050716:Complement C4b-Binding Protein; D017242:Complement Factor H / Q000235:genetics / Q000378:metabolism; D003170:Complement Pathway, Alternative / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D006463:Hemolytic-Uremic Syndrome / Q000235:genetics* / Q000378:metabolism; D006579:Heterozygote; D006649:Histocompatibility Antigens / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D051916:Membrane Cofactor Protein / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D011110:Polymorphism, Genetic
C055609:C4BPA protein, human; C497857:CD46 protein, human; D050716:Complement C4b-Binding Protein; D006649:Histocompatibility Antigens; D051916:Membrane Cofactor Protein; D017242:Complement Factor H