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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; Mohlin, Frida LU ; Edey, Matthew; Diaz-Torres, Martha; Kavanagh, David; Lampe, Anne; Goodship, Judith A; Strain, Lisa; Moghal, Nadeem and McHugh, Mary, et al. (2008) In Journal of Immunology 180(9). p.6385-6391
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... (More)
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. (Less)
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Journal of Immunology
volume
180
issue
9
pages
6385 - 6391
publisher
American Association of Immunologists
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  • WOS:000257507000074
  • PMID:18424762
  • Scopus:44449103295
ISSN
1550-6606
language
English
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yes
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0fd11553-c682-4f4a-9d59-96f1adc14c31 (old id 1147224)
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http://www.ncbi.nlm.nih.gov/pubmed/18424762?dopt=Abstract
date added to LUP
2008-05-06 09:26:12
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2016-10-23 04:32:58
@misc{0fd11553-c682-4f4a-9d59-96f1adc14c31,
  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.},
  author       = {Blom, Anna M and Mohlin, Frida and Edey, Matthew and Diaz-Torres, Martha and Kavanagh, David and Lampe, Anne and Goodship, Judith A and Strain, Lisa and Moghal, Nadeem and McHugh, Mary and Inward, Carol and Tomson, Charles and Frémeaux-Bacchi, Véronique and Villoutreix, Bruno O and Goodship, Timothy H J},
  issn         = {1550-6606},
  language     = {eng},
  number       = {9},
  pages        = {6385--6391},
  publisher    = {ARRAY(0x98bdc08)},
  series       = {Journal of Immunology},
  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.},
  volume       = {180},
  year         = {2008},
}