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A functional SNP in the regulatory region of the decay-accelerating factor gene associates with extraocular muscle pareses in myasthenia gravis
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A functional SNP in the regulatory region of the decay-accelerating factor gene associates with extraocular muscle pareses in myasthenia gravis
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A functional SNP in the regulatory region of the decay-accelerating factor gene associates with extraocular muscle pareses in myasthenia gravis
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Journal Article
A functional SNP in the regulatory region of the decay-accelerating factor gene associates with extraocular muscle pareses in myasthenia gravis
2010
Overview
Complement 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.-198C>G SNP (odds ratio=8.6;
P
=0.0003). 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.-198C>G 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.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
African Continental Ancestry Group - genetics
/ Animals
/ Biomedical and Life Sciences
/ CD55 Antigens - biosynthesis
/ Complement Pathway, Classical - genetics
/ Disease
/ Female
/ Genes
/ Humans
/ Lipopolysaccharides - pharmacology
/ Male
/ Mice
/ Myasthenia Gravis - genetics
/ Myasthenia Gravis - metabolism
/ Original
/ Paresis
/ Polymorphism, Single Nucleotide
/ Response Elements - genetics
/ Single nucleotide polymorphisms
