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* Lund University, Department of Laboratory Medicine, Malmö University Hospital, Malmö, Sweden;
Insitute of Human Genetics, Newcastle University;
Northern Molecular Genetics Service and
Department of Paediatric Nephrology, Newcastle upon Tyne Hospitals National Health Service Foundation Trust, Newcastle upon Tyne;
¶ Department of Nephrology, City Hospitals Sunderland National Health Service Foundation Trust, Sunderland;
|| Department of Paediatric Nephrology, Bristol Royal Hospital for Children;
# Department of Renal Medicine, Southmead Hospital, Bristol, United Kingdom;
** Institut National de la Santé et de la Recherche Médicale U255, Cordeliers Biomedical Research Center and Laboratory of Immunology, Georges-Pompidou European Hospital; and
Institut National de la Santé et de la Recherche Médicale U648, University of Paris V, Paris, France
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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by U.S. Immunodeficiency Network (to A.B.). T.H.J.G. is supported by Grants from the Foundation for Children with atypical Hemolytic Uremic Syndrome, the Robin Davis Trust, the Newcastle Healthcare Charity, the Peel Medical Research Trust, and the Mason Medical Research Foundation. M.E. is supported by a Fellowship from the Northern Counties Kidney Research Fund. D.K. is supported by a Fellowship from Kidney Research U.K.
2 Address correspondence and reprint requests to Dr. Anna Blom, Lund University, Department of Laboratory Medicine, Medical Protein Chemistry, Malmö University Hospital, The Wallenberg Laboratory floor 4, SE-205 02 Malmö, Sweden. E-mail address: anna.blom{at}med.lu.se
3 Abbreviations used in this paper: aHUS, atypical hemolytic uremic syndrome; C4BP, C4b-binding protein; CCP, complement control protein (domain); FH, factor H; FI, factor I; MCP, membrane cofactor protein; wt, wild type.
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  M-A Dragon-Durey, C Blanc, F Marliot, C Loirat, J Blouin, C Sautes-Fridman, W H Fridman, and V Fremeaux-Bacchi The high frequency of complement factor H related CFHR1 gene deletion is restricted to specific subgroups of patients with atypical haemolytic uraemic syndrome J. Med. Genet., July 1, 2009; 46(7): 447 - 450. [Abstract] [Full Text] [PDF]
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