title: 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.
abstract: 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.
authors.affiliation: Lund University, Department of Laboratory Medicine, Malmö University Hospital, Malmö, Sweden.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Blom
authors.forename: Frida
authors.initials: F
authors.lastname: Bergström
authors.forename: Matthew
authors.initials: M
authors.lastname: Edey
authors.forename: Martha
authors.initials: M
authors.lastname: Diaz-Torres
authors.forename: David
authors.initials: D
authors.lastname: Kavanagh
authors.forename: Anne
authors.initials: A
authors.lastname: Lampe
authors.forename: Judith A
authors.initials: JA
authors.lastname: Goodship
authors.forename: Lisa
authors.initials: L
authors.lastname: Strain
authors.forename: Nadeem
authors.initials: N
authors.lastname: Moghal
authors.forename: Mary
authors.initials: M
authors.lastname: McHugh
authors.forename: Carol
authors.initials: C
authors.lastname: Inward
authors.forename: Charles
authors.initials: C
authors.lastname: Tomson
authors.forename: Véronique
authors.initials: V
authors.lastname: Frémeaux-Bacchi
authors.forename: Bruno O
authors.initials: BO
authors.lastname: Villoutreix
authors.forename: Timothy H J
authors.initials: TH
authors.lastname: Goodship
mesh_terms: 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
chemical_list: C055609:C4BPA protein, human; C497857:CD46 protein, human; D050716:Complement C4b-Binding Protein; D006649:Histocompatibility Antigens; D051916:Membrane Cofactor Protein; D017242:Complement Factor H