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

Blom, Anna M., Bergstrom, Frida, Edey, Matthew, Diaz-Torres, Martha, Kavanagh, David, Lampe, Anne, Goodship, Judith A., Strain, Lisa, Moghal, Nadeem, McHugh, Mary, Inward, Carol, Tomson, Charles, Fremeaux-Bacchi, Veronique, Villoutreix, Bruno O. and Goodship, Timothy H. J. (2008) 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. The Journal of Immunology, 180 9: 6385-6391.


Author Blom, Anna M.
Bergstrom, Frida
Edey, Matthew
Diaz-Torres, Martha
Kavanagh, David
Lampe, Anne
Goodship, Judith A.
Strain, Lisa
Moghal, Nadeem
McHugh, Mary
Inward, Carol
Tomson, Charles
Fremeaux-Bacchi, Veronique
Villoutreix, Bruno O.
Goodship, Timothy H. J.
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
Journal name The Journal of Immunology   Check publisher's open access policy
ISSN 1550-6606
0022-1767
Publication date 2008-05-01
Sub-type Critical review of research, literature review, critical commentary
Volume 180
Issue 9
Start page 6385
End page 6391
Total pages 7
Place of publication Bethesda, MD, United States
Publisher American Association of Immunologists
Language eng
Subject 11 Medical and Health Sciences
1117 Public Health and Health Services
Formatted 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) -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 (2 = 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.
Keyword Atypical hemolytic uremic syndrome (aHUS)
Haemolytic anaemia
Polymorphism
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Unknown

Document type: Journal Article
Sub-type: Critical review of research, literature review, critical commentary
Collections: Excellence in Research Australia (ERA) - Collection
School of Medicine Publications
 
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Created: Thu, 04 Feb 2010, 00:17:17 EST by Ms May Balasaize on behalf of Faculty Of Health Sciences