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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Harley, John B. Zidovetzki, Raphael Wagner-weiner, Linda Ming, Wenyu Klein-gitelman, Marisa Dinauer, Mary C. Myones, Barry L. Jacob, Chaim O. Liu, Qiang Quismorio, Francesco P. Langefeld, Carl D. Gaffney, Patrick M. Mccurdy, Deborah Armstrong, Don L. Reiff, Andreas Vyse, Timothy J. Eisenstein, Miriam Kaufman, Kenneth M. Silverman, Earl John, Sutha Kimberly, Robert P. Moser, Kathy L. |
| Spatial Coverage | California |
| Description | Author Affiliation: Jacob CO ( The Lupus Genetic Group, Department of Medicine, University of Southern California, Los Angeles, CA 90089, USA. jacob@usc.edu); |
| Abstract | Systemic lupus erythematosus (SLE), the prototypic systemic autoimmune disease, is a debilitating multisystem autoimmune disorder characterized by chronic inflammation and extensive immune dysregulation in multiple organ systems, resulting in significant morbidity and mortality. Here, we present a multidisciplinary approach resulting in the identification of neutrophil cytosolic factor 2 (NCF2) as an important risk factor for SLE and the detailed characterization of its causal variant. We show that NCF2 is strongly associated with increased SLE risk in two independent populations: childhood-onset SLE and adult-onset SLE. The association between NCF2 and SLE can be attributed to a single nonsynonymous coding mutation in exon 12, the effect of which is the substitution of histidine-389 with glutamine (H389Q) in the PB1 domain of the NCF2 protein, with glutamine being the risk allele. Computational modeling suggests that the NCF2 H389Q mutation reduces the binding efficiency of NCF2 with the guanine nucleotide exchange factor Vav1. The model predicts that NCF2/H389 residue interacts with Vav1 residues E509, N510, E556, and G559 in the ZF domain of Vav1. Furthermore, replacing H389 with Q results in 1.5 kcal/mol weaker binding. To examine the effect of the NCF2 H389Q mutation on NADPH oxidase function, site-specific mutations at the 389 position in NCF2 were tested. Results show that an H389Q mutation causes a twofold decrease in reactive oxygen species production induced by the activation of the Vav-dependent Fcγ receptor-elicited NADPH oxidase activity. Our study completes the chain of evidence from genetic association to specific molecular function. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 2 |
| Volume Number | 109 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2012-01-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Genetic Predisposition To Disease Genetics Genetic Variation Lupus Erythematosus, Systemic Models, Molecular Multiprotein Complexes NADPH Oxidase Metabolism Amino Acid Sequence Genotype Molecular Sequence Data Chemistry Mutation, Missense Plasmids Polymorphism, Single Nucleotide Principal Component Analysis Protein Binding Proto-Oncogene Proteins C-vav Reactive Oxygen Species Rac1 GTP-Binding Protein Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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