Advanced

A mutation in factor I that is associated with atypical hemolytic uremic syndrome does not affect the function of factor I in complement regulation.

Nilsson, Sara LU ; Karpman, Diana LU ; Vaziri Sani, Fariba LU ; Kristoffersson, Ann-Charlotte LU ; Salomon, Rémi; Provot, Francois; Fremeaux-Bacchi, Veronique; Trouw, Leendert LU and Blom, Anna LU (2007) In Molecular Immunology 44(8). p.1835-1844
Abstract
Factor I (FI) is the major complement inhibitor that degrades Ob and C4b in the presence of cofactors such as factor H (FH) and membrane cofactor protein (MCP). Recently, mutations and polymorphisms in complement regulator molecules FH and MCP but also in FI have been associated with atypical hemolytic uremic syndrome (aHUS). HUS is a disorder characterized by hemolytic anemia, thrombocytopenia and acute renal failure. In this study, we report three unrelated patients with an identical heterozygous mutation, G261D, in the FI heavy chain who developed severe aHUS at different time points in their lives. Two of the patients also have polymorphisms in FH previously associated with risk of developing aHUS. Testing in particular one patient and... (More)
Factor I (FI) is the major complement inhibitor that degrades Ob and C4b in the presence of cofactors such as factor H (FH) and membrane cofactor protein (MCP). Recently, mutations and polymorphisms in complement regulator molecules FH and MCP but also in FI have been associated with atypical hemolytic uremic syndrome (aHUS). HUS is a disorder characterized by hemolytic anemia, thrombocytopenia and acute renal failure. In this study, we report three unrelated patients with an identical heterozygous mutation, G261D, in the FI heavy chain who developed severe aHUS at different time points in their lives. Two of the patients also have polymorphisms in FH previously associated with risk of developing aHUS. Testing in particular one patient and control serum samples we did not observe major differences in complement hemolytic activity, FI plasma levels or the capability to degrade C4b or Ob. A recombinant protein was produced in order to analyze the functional consequences of the mutation. Mutant FI had a slightly different migration pattern during electrophoresis under reducing conditions. An alteration due to alternative splicing or glycosylation was ruled out, thus the altered migration may be due to proximity of the mutation to a cysteine residue. The recombinant mutant FI degraded Ob and C4b in a manner comparable to wild-type protein. In conclusion, despite the association between the heterozygous mutation in FI and aHUS we did not observe any abnormalities in the function of FI regarding complement regulation. (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
aHUS, factor I, complement, kidney, regulation
in
Molecular Immunology
volume
44
issue
8
pages
1835 - 1844
publisher
Pergamon
external identifiers
  • wos:000244351500003
  • scopus:39049183685
ISSN
1872-9142
DOI
10.1016/j.molimm.2006.10.005
language
English
LU publication?
yes
id
385d8800-2d49-49eb-9473-2dc11efbab4d (old id 163428)
alternative location
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=17084897&dopt=Abstract
date added to LUP
2007-07-23 16:41:28
date last changed
2017-07-02 04:31:24
@article{385d8800-2d49-49eb-9473-2dc11efbab4d,
  abstract     = {Factor I (FI) is the major complement inhibitor that degrades Ob and C4b in the presence of cofactors such as factor H (FH) and membrane cofactor protein (MCP). Recently, mutations and polymorphisms in complement regulator molecules FH and MCP but also in FI have been associated with atypical hemolytic uremic syndrome (aHUS). HUS is a disorder characterized by hemolytic anemia, thrombocytopenia and acute renal failure. In this study, we report three unrelated patients with an identical heterozygous mutation, G261D, in the FI heavy chain who developed severe aHUS at different time points in their lives. Two of the patients also have polymorphisms in FH previously associated with risk of developing aHUS. Testing in particular one patient and control serum samples we did not observe major differences in complement hemolytic activity, FI plasma levels or the capability to degrade C4b or Ob. A recombinant protein was produced in order to analyze the functional consequences of the mutation. Mutant FI had a slightly different migration pattern during electrophoresis under reducing conditions. An alteration due to alternative splicing or glycosylation was ruled out, thus the altered migration may be due to proximity of the mutation to a cysteine residue. The recombinant mutant FI degraded Ob and C4b in a manner comparable to wild-type protein. In conclusion, despite the association between the heterozygous mutation in FI and aHUS we did not observe any abnormalities in the function of FI regarding complement regulation.},
  author       = {Nilsson, Sara and Karpman, Diana and Vaziri Sani, Fariba and Kristoffersson, Ann-Charlotte and Salomon, Rémi and Provot, Francois and Fremeaux-Bacchi, Veronique and Trouw, Leendert and Blom, Anna},
  issn         = {1872-9142},
  keyword      = {aHUS,factor I,complement,kidney,regulation},
  language     = {eng},
  number       = {8},
  pages        = {1835--1844},
  publisher    = {Pergamon},
  series       = {Molecular Immunology},
  title        = {A mutation in factor I that is associated with atypical hemolytic uremic syndrome does not affect the function of factor I in complement regulation.},
  url          = {http://dx.doi.org/10.1016/j.molimm.2006.10.005},
  volume       = {44},
  year         = {2007},
}