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Positioning of a Polymorphic Quantitative Trait Nucleotide in the Ncf1 Gene Controlling Oxidative Burst Response and Arthritis Severity in Rats.

Hultqvist, Malin LU ; Sareila, Outi; Vilhardt, Frederik; Norin, Ulrika; Olsson, Lina LU ; Olofsson, Peter; Hellman, Ulf and Holmdahl, Rikard LU (2011) In Antioxidants & Redox Signaling 14(12). p.2373-2383
Abstract
The Ncf1 gene, encoding the P47PHOX protein that regulates production of reactive oxygen species (ROS) by the phagocyte NADPH oxidase complex, is associated with autoimmunity and arthritis severity in rats. We have now identified that the single nucleotide polymorphism (SNP) resulting in an M153T amino acid substitution mediates arthritis resistance and thus explains the molecular polymorphism underlying the earlier identified Ncf1 gene effect. We identified the SNP in position 153 to regulate ROS production using COSPHOX cells transfected with mutated Ncf1. To determine the role of this SNP for control of arthritis we used the Wistar strain, identified to carry only the postulated arthritis resistant SNP in position 153. When this Ncf1... (More)
The Ncf1 gene, encoding the P47PHOX protein that regulates production of reactive oxygen species (ROS) by the phagocyte NADPH oxidase complex, is associated with autoimmunity and arthritis severity in rats. We have now identified that the single nucleotide polymorphism (SNP) resulting in an M153T amino acid substitution mediates arthritis resistance and thus explains the molecular polymorphism underlying the earlier identified Ncf1 gene effect. We identified the SNP in position 153 to regulate ROS production using COSPHOX cells transfected with mutated Ncf1. To determine the role of this SNP for control of arthritis we used the Wistar strain, identified to carry only the postulated arthritis resistant SNP in position 153. When this Ncf1 allele was backcrossed to the arthritis susceptible DA strain, both granulocyte ROS production and arthritis resistance was restored. Position 153 is located in the hinge region between the PX and SH3 domains of P47PHOX. Mutational analysis of this position revealed a need for an -OH group in the side chain but we found no evidence for phosphorylation. The polymorphism did not affect assembly of the P47PHOX/P67PHOX complex in the cytosol nor membrane localization but is likely to operate downstream of assembly, affecting activity of the membrane NOX2 complex. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Antioxidants & Redox Signaling
volume
14
issue
12
pages
2373 - 2383
publisher
Mary Ann Liebert, Inc.
external identifiers
  • wos:000290783700005
  • pmid:21275845
  • scopus:79957475372
ISSN
1557-7716
DOI
10.1089/ars.2010.3440
language
English
LU publication?
yes
id
2df5b4aa-53dd-46f6-9fa0-95b72ac52483 (old id 1832625)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/21275845?dopt=Abstract
date added to LUP
2012-01-19 10:31:23
date last changed
2017-11-19 03:21:36
@article{2df5b4aa-53dd-46f6-9fa0-95b72ac52483,
  abstract     = {The Ncf1 gene, encoding the P47PHOX protein that regulates production of reactive oxygen species (ROS) by the phagocyte NADPH oxidase complex, is associated with autoimmunity and arthritis severity in rats. We have now identified that the single nucleotide polymorphism (SNP) resulting in an M153T amino acid substitution mediates arthritis resistance and thus explains the molecular polymorphism underlying the earlier identified Ncf1 gene effect. We identified the SNP in position 153 to regulate ROS production using COSPHOX cells transfected with mutated Ncf1. To determine the role of this SNP for control of arthritis we used the Wistar strain, identified to carry only the postulated arthritis resistant SNP in position 153. When this Ncf1 allele was backcrossed to the arthritis susceptible DA strain, both granulocyte ROS production and arthritis resistance was restored. Position 153 is located in the hinge region between the PX and SH3 domains of P47PHOX. Mutational analysis of this position revealed a need for an -OH group in the side chain but we found no evidence for phosphorylation. The polymorphism did not affect assembly of the P47PHOX/P67PHOX complex in the cytosol nor membrane localization but is likely to operate downstream of assembly, affecting activity of the membrane NOX2 complex.},
  author       = {Hultqvist, Malin and Sareila, Outi and Vilhardt, Frederik and Norin, Ulrika and Olsson, Lina and Olofsson, Peter and Hellman, Ulf and Holmdahl, Rikard},
  issn         = {1557-7716},
  language     = {eng},
  number       = {12},
  pages        = {2373--2383},
  publisher    = {Mary Ann Liebert, Inc.},
  series       = {Antioxidants & Redox Signaling},
  title        = {Positioning of a Polymorphic Quantitative Trait Nucleotide in the Ncf1 Gene Controlling Oxidative Burst Response and Arthritis Severity in Rats.},
  url          = {http://dx.doi.org/10.1089/ars.2010.3440},
  volume       = {14},
  year         = {2011},
}