Advanced

A Novel C3 Mutation Causing Increased Formation of the C3 Convertase in Familial Atypical Hemolytic Uremic Syndrome.

Sartz, Lisa LU ; Olin, Anders LU ; Kristoffersson, Ann-Charlotte LU ; Ståhl, Anne-lie LU ; Johansson, Martin E; Westman, Kerstin LU ; Fremeaux-Bacchi, Veronique; Nilsson, Kristina and Karpman, Diana LU (2012) In Journal of immunology (Baltimore, Md. : 1950) 188(4). p.2030-2037
Abstract
Atypical hemolytic uremic syndrome has been associated with dysregulation of the alternative complement pathway. In this study, a novel heterozygous C3 mutation was identified in a factor B-binding region in exon 41, V1636A (4973 T > C). The mutation was found in three family members affected with late-onset atypical hemolytic uremic syndrome and symptoms of glomerulonephritis. All three patients exhibited increased complement activation detected by decreased C3 levels and glomerular C3 deposits. Platelets from two of the patients had C3 and C9 deposits on the cell surface. Patient sera exhibited more C3 cleavage and higher levels of C3a. The C3 mutation resulted in increased C3 binding to factor B and increased net formation of the C3... (More)
Atypical hemolytic uremic syndrome has been associated with dysregulation of the alternative complement pathway. In this study, a novel heterozygous C3 mutation was identified in a factor B-binding region in exon 41, V1636A (4973 T > C). The mutation was found in three family members affected with late-onset atypical hemolytic uremic syndrome and symptoms of glomerulonephritis. All three patients exhibited increased complement activation detected by decreased C3 levels and glomerular C3 deposits. Platelets from two of the patients had C3 and C9 deposits on the cell surface. Patient sera exhibited more C3 cleavage and higher levels of C3a. The C3 mutation resulted in increased C3 binding to factor B and increased net formation of the C3 convertase, even after decay induced by decay-accelerating factor and factor H, as assayed by surface plasmon resonance. Patient sera incubated with washed human platelets induced more C3 and C9 deposition on the cell surface in comparison with normal sera. More C3a was released into serum over time when washed platelets were exposed to patient sera. Results regarding C3 and C9 deposition on washed platelets were confirmed using purified patient C3 in C3-depleted serum. The results indicated enhanced convertase formation leading to increased complement activation on cell surfaces. Previously described C3 mutations showed loss of function with regard to C3 binding to complement regulators. To our knowledge, this study presents the first known C3 mutation inducing increased formation of the C3 convertase, thus explaining enhanced activation of the alternative pathway of complement. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of immunology (Baltimore, Md. : 1950)
volume
188
issue
4
pages
2030 - 2037
publisher
American Association of Immunologists
external identifiers
  • WOS:000300139000050
  • PMID:22250080
  • Scopus:84856863401
ISSN
1550-6606
DOI
10.4049/jimmunol.1100319
language
English
LU publication?
yes
id
0ba867c7-a2ec-49a8-8f57-a132729004fa (old id 2336347)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/22250080?dopt=Abstract
http://www.research.med.lu.se/sv_projektdetaljer.php?Proj=17
date added to LUP
2012-02-01 21:34:54
date last changed
2016-11-01 10:16:40
@misc{0ba867c7-a2ec-49a8-8f57-a132729004fa,
  abstract     = {Atypical hemolytic uremic syndrome has been associated with dysregulation of the alternative complement pathway. In this study, a novel heterozygous C3 mutation was identified in a factor B-binding region in exon 41, V1636A (4973 T > C). The mutation was found in three family members affected with late-onset atypical hemolytic uremic syndrome and symptoms of glomerulonephritis. All three patients exhibited increased complement activation detected by decreased C3 levels and glomerular C3 deposits. Platelets from two of the patients had C3 and C9 deposits on the cell surface. Patient sera exhibited more C3 cleavage and higher levels of C3a. The C3 mutation resulted in increased C3 binding to factor B and increased net formation of the C3 convertase, even after decay induced by decay-accelerating factor and factor H, as assayed by surface plasmon resonance. Patient sera incubated with washed human platelets induced more C3 and C9 deposition on the cell surface in comparison with normal sera. More C3a was released into serum over time when washed platelets were exposed to patient sera. Results regarding C3 and C9 deposition on washed platelets were confirmed using purified patient C3 in C3-depleted serum. The results indicated enhanced convertase formation leading to increased complement activation on cell surfaces. Previously described C3 mutations showed loss of function with regard to C3 binding to complement regulators. To our knowledge, this study presents the first known C3 mutation inducing increased formation of the C3 convertase, thus explaining enhanced activation of the alternative pathway of complement.},
  author       = {Sartz, Lisa and Olin, Anders and Kristoffersson, Ann-Charlotte and Ståhl, Anne-lie and Johansson, Martin E and Westman, Kerstin and Fremeaux-Bacchi, Veronique and Nilsson, Kristina and Karpman, Diana},
  issn         = {1550-6606},
  language     = {eng},
  number       = {4},
  pages        = {2030--2037},
  publisher    = {ARRAY(0xb3f8950)},
  series       = {Journal of immunology (Baltimore, Md. : 1950)},
  title        = {A Novel C3 Mutation Causing Increased Formation of the C3 Convertase in Familial Atypical Hemolytic Uremic Syndrome.},
  url          = {http://dx.doi.org/10.4049/jimmunol.1100319},
  volume       = {188},
  year         = {2012},
}