A functional SNP in the regulatory region of the decay-accelerating factor gene associates with extraocular muscle pareses in myasthenia gravis
KAUST DepartmentComputational Bioscience Research Center (CBRC)
MetadataShow full item record
AbstractComplement activation in myasthenia gravis (MG) may damage muscle endplate and complement regulatory proteins such as decay-accelerating factor (DAF) or CD55 may be protective. We hypothesize that the increased prevalence of severe extraocular muscle (EOM) dysfunction among African MG subjects reported earlier may result from altered DAF expression. To test this hypothesis, we screened the DAF gene sequences relevant to the classical complement pathway and found an association between myasthenics with EOM paresis and the DAF regulatory region c.-198CG SNP (odds ratio8.6; P0.0003). This single nucleotide polymorphism (SNP) results in a twofold activation of a DAF 5?-flanking region luciferase reporter transfected into three different cell lines. Direct matching of the surrounding SNP sequence within the DAF regulatory region with the known transcription factor-binding sites suggests a loss of an Sp1-binding site. This was supported by the observation that the c.-198CG SNP did not show the normal lipopolysaccharide-induced DAF transcriptional upregulation in lymphoblasts from four patients. Our findings suggest that at critical periods during autoimmune MG, this SNP may result in inadequate DAF upregulation with consequent complement-mediated EOM damage. Susceptible individuals may benefit from anti-complement therapy in addition to immunosuppression. © 2010 Macmillan Publishers Limited. All rights reserved.
CitationHeckmann JM, Uwimpuhwe H, Ballo R, Kaur M, Bajic VB, et al. (2010) A functional SNP in the regulatory region of the decay-accelerating factor gene associates with extraocular muscle pareses in myasthenia gravis. Genes and Immunity 11: 1-10. doi:10.1038/gene.2009.61.
JournalGenes and Immunity
PubMed Central IDPMC2834500
The following license files are associated with this item:
Except where otherwise noted, this item's license is described as This work is licensed under the Creative Commons Attribution-NonCommercial-No Derivative Works 3.0 Licence. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/3.0/
- The effects of prednisone and steroid-sparing agents on decay accelerating factor (CD55) expression: implications in myasthenia gravis.
- Authors: Auret J, Abrahams A, Prince S, Heckmann JM
- Issue date: 2014 Jun
- The African-387 C>T TGFB1 variant is functional and associates with the ophthalmoplegic complication in juvenile myasthenia gravis.
- Authors: Nel M, Buys JM, Rautenbach R, Mowla S, Prince S, Heckmann JM
- Issue date: 2016 Apr
- Complement regulators in extraocular muscle and experimental autoimmune myasthenia gravis.
- Authors: Kaminski HJ, Li Z, Richmonds C, Lin F, Medof ME
- Issue date: 2004 Oct
- Constitutive expression of murine decay-accelerating factor 1 is controlled by the transcription factor Sp1.
- Authors: Cauvi DM, Cauvi G, Pollard KM
- Issue date: 2006 Sep 15
- Associations between decay-accelerating factor polymorphisms and allergic respiratory diseases.
- Authors: Kawai T, Takeshita S, Imoto Y, Matsumoto Y, Sakashita M, Suzuki D, Shibasaki M, Tamari M, Hirota T, Arinami T, Fujieda S, Noguchi E
- Issue date: 2009 Oct