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Genetic, molecular and functional analyses of complement factor I deficiency.

Nilsson, Sara LU ; Trouw, Leendert LU ; Renault, Nicolas; Miteva, Maria A; Genel, Ferah; Zelazko, Marta; Marquart, Hanne; Muller, Klaus; Sjöholm, Anders LU and Truedsson, Lennart LU , et al. (2009) In European Journal of Immunology 39(1). p.310-323
Abstract
Complete deficiency of complement inhibitor factor I (FI) results in secondary complement deficiency due to uncontrolled spontaneous alternative pathway activation leading to susceptibility to infections. Current genetic examination of two patients with near complete FI deficiency and three patients with no detectable serum FI and also close family members revealed homozygous or compound heterozygous mutations in several domains of FI. These mutations were introduced into recombinant FI and the resulting proteins were purified for functional studies, while transient transfection was used to analyze expression and secretion. The G170V mutation resulted in a protein that was not expressed, whereas the mutations Q232K, C237Y, S250L, I339M and... (More)
Complete deficiency of complement inhibitor factor I (FI) results in secondary complement deficiency due to uncontrolled spontaneous alternative pathway activation leading to susceptibility to infections. Current genetic examination of two patients with near complete FI deficiency and three patients with no detectable serum FI and also close family members revealed homozygous or compound heterozygous mutations in several domains of FI. These mutations were introduced into recombinant FI and the resulting proteins were purified for functional studies, while transient transfection was used to analyze expression and secretion. The G170V mutation resulted in a protein that was not expressed, whereas the mutations Q232K, C237Y, S250L, I339M and H400L affected secretion. Furthermore, the C237Y and the S250L mutants did not degrade C4b and C3b as efficiently as the WT. The truncated Q336x mutant could be expressed, in vitro, but was not functional because it lacks the serine protease domain. Furthermore, this truncated FI was not detected in serum of the patient. Structural investigations using molecular modeling were performed to predict the potential impact the mutations have on FI structure. This is the first study that investigates, at the functional level, the consequences of molecular defects identified in patients with full FI deficiency. (Less)
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Contribution to journal
publication status
published
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in
European Journal of Immunology
volume
39
issue
1
pages
310 - 323
publisher
John Wiley & Sons
external identifiers
  • wos:000262889900028
  • pmid:19065647
  • scopus:60549095970
ISSN
1521-4141
DOI
10.1002/eji.200838702
language
English
LU publication?
yes
id
65755303-7a9a-46f9-b963-616c1c4e76ff (old id 1276315)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/19065647?dopt=Abstract
date added to LUP
2009-01-09 11:34:50
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2017-11-19 04:19:06
@article{65755303-7a9a-46f9-b963-616c1c4e76ff,
  abstract     = {Complete deficiency of complement inhibitor factor I (FI) results in secondary complement deficiency due to uncontrolled spontaneous alternative pathway activation leading to susceptibility to infections. Current genetic examination of two patients with near complete FI deficiency and three patients with no detectable serum FI and also close family members revealed homozygous or compound heterozygous mutations in several domains of FI. These mutations were introduced into recombinant FI and the resulting proteins were purified for functional studies, while transient transfection was used to analyze expression and secretion. The G170V mutation resulted in a protein that was not expressed, whereas the mutations Q232K, C237Y, S250L, I339M and H400L affected secretion. Furthermore, the C237Y and the S250L mutants did not degrade C4b and C3b as efficiently as the WT. The truncated Q336x mutant could be expressed, in vitro, but was not functional because it lacks the serine protease domain. Furthermore, this truncated FI was not detected in serum of the patient. Structural investigations using molecular modeling were performed to predict the potential impact the mutations have on FI structure. This is the first study that investigates, at the functional level, the consequences of molecular defects identified in patients with full FI deficiency.},
  author       = {Nilsson, Sara and Trouw, Leendert and Renault, Nicolas and Miteva, Maria A and Genel, Ferah and Zelazko, Marta and Marquart, Hanne and Muller, Klaus and Sjöholm, Anders and Truedsson, Lennart and Villoutreix, Bruno O and Blom, Anna M},
  issn         = {1521-4141},
  language     = {eng},
  number       = {1},
  pages        = {310--323},
  publisher    = {John Wiley & Sons},
  series       = {European Journal of Immunology},
  title        = {Genetic, molecular and functional analyses of complement factor I deficiency.},
  url          = {http://dx.doi.org/10.1002/eji.200838702},
  volume       = {39},
  year         = {2009},
}