Advanced

Mutations in complement factor I as found in atypical hemolytic uremic syndrome lead to either altered secretion or altered function of factor I

Nilsson, Sara LU ; Kalchishkova, Nikolina LU ; Trouw, Leendert A.; Fremeaux-Bacchi, Veronique; Villoutreix, Bruno O. and Blom, Anna LU (2010) In European Journal of Immunology 40(1). p.172-185
Abstract
The complement system is regulated by inhibitors such as factor I (FI), a serine protease that degrades activated complement factors C4b and C3b in the presence of specific cofactors. Mutations and polymorphisms in FI and its cofactors are associated with atypical hemolytic uremic syndrome (aHUS). All 14 complement factor I mutations associated with aHUS analyzed in this study were heterozygous and generated premature stop codons (six) or amino acid substitutions (eight). Almost all of the mutants were expressed by human embryonic kidney 293 cells but only six mutants were secreted into the medium, three of which were at lower levels than WT. The remaining eight mutants were not secreted but sensitive to deglycosylation with... (More)
The complement system is regulated by inhibitors such as factor I (FI), a serine protease that degrades activated complement factors C4b and C3b in the presence of specific cofactors. Mutations and polymorphisms in FI and its cofactors are associated with atypical hemolytic uremic syndrome (aHUS). All 14 complement factor I mutations associated with aHUS analyzed in this study were heterozygous and generated premature stop codons (six) or amino acid substitutions (eight). Almost all of the mutants were expressed by human embryonic kidney 293 cells but only six mutants were secreted into the medium, three of which were at lower levels than WT. The remaining eight mutants were not secreted but sensitive to deglycosylation with endoglycosidase H, indicating that they were retained early in the secretory pathway. Six secreted mutants were purified and five of them were functionally altered in degradation of C4b/C3b in the fluid-phase in the presence of various cofactors and on endothelial cells. Three mutants cleaved surface-bound C3b less efficiently than WT. The D501N mutant was severely impaired both in solution and on surface irrespective of the cofactor used. in conclusion, mutations in complement factor I affect both secretion and function of FI, which leads to impaired regulation of the complement system in aHUS. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Atypical hemolytic uremic syndrome, Complement, Factor I
in
European Journal of Immunology
volume
40
issue
1
pages
172 - 185
publisher
John Wiley & Sons
external identifiers
  • wos:000274041800020
  • pmid:19877009
  • scopus:74249114451
ISSN
1521-4141
DOI
10.1002/eji.200939280
language
English
LU publication?
yes
id
14f38f11-e2cb-4585-ad4f-fde0cea60c08 (old id 1546995)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/19877009?dopt=Abstract
date added to LUP
2010-02-25 10:30:08
date last changed
2018-05-29 09:54:37
@article{14f38f11-e2cb-4585-ad4f-fde0cea60c08,
  abstract     = {The complement system is regulated by inhibitors such as factor I (FI), a serine protease that degrades activated complement factors C4b and C3b in the presence of specific cofactors. Mutations and polymorphisms in FI and its cofactors are associated with atypical hemolytic uremic syndrome (aHUS). All 14 complement factor I mutations associated with aHUS analyzed in this study were heterozygous and generated premature stop codons (six) or amino acid substitutions (eight). Almost all of the mutants were expressed by human embryonic kidney 293 cells but only six mutants were secreted into the medium, three of which were at lower levels than WT. The remaining eight mutants were not secreted but sensitive to deglycosylation with endoglycosidase H, indicating that they were retained early in the secretory pathway. Six secreted mutants were purified and five of them were functionally altered in degradation of C4b/C3b in the fluid-phase in the presence of various cofactors and on endothelial cells. Three mutants cleaved surface-bound C3b less efficiently than WT. The D501N mutant was severely impaired both in solution and on surface irrespective of the cofactor used. in conclusion, mutations in complement factor I affect both secretion and function of FI, which leads to impaired regulation of the complement system in aHUS.},
  author       = {Nilsson, Sara and Kalchishkova, Nikolina and Trouw, Leendert A. and Fremeaux-Bacchi, Veronique and Villoutreix, Bruno O. and Blom, Anna},
  issn         = {1521-4141},
  keyword      = {Atypical hemolytic uremic syndrome,Complement,Factor I},
  language     = {eng},
  number       = {1},
  pages        = {172--185},
  publisher    = {John Wiley & Sons},
  series       = {European Journal of Immunology},
  title        = {Mutations in complement factor I as found in atypical hemolytic uremic syndrome lead to either altered secretion or altered function of factor I},
  url          = {http://dx.doi.org/10.1002/eji.200939280},
  volume       = {40},
  year         = {2010},
}