title: A functional SNP in the regulatory region of the decay-accelerating factor gene associates with extraocular muscle pareses in myasthenia gravis.
abstract: 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.
authors.affiliation: Neurology Research Group, Department of Medicine, University of Cape Town, Cape Town, South Africa. jeanine.heckmann@uct.ac.za
authors.forename: J M
authors.initials: JM
authors.lastname: Heckmann
authors.forename: H
authors.initials: H
authors.lastname: Uwimpuhwe
authors.forename: R
authors.initials: R
authors.lastname: Ballo
authors.forename: M
authors.initials: M
authors.lastname: Kaur
authors.forename: V B
authors.initials: VB
authors.lastname: Bajic
authors.forename: S
authors.initials: S
authors.lastname: Prince
mesh_terms: D000818:Animals; D044383:Black People / Q000235:genetics; D018958:CD55 Antigens / Q000096:biosynthesis / Q000235:genetics*; D019556:COS Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D003171:Complement Pathway, Classical / Q000235:genetics*; D005260:Female; D006801:Humans; D007165:Immunosuppression Therapy; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D009157:Myasthenia Gravis / Q000235:genetics* / Q000378:metabolism / Q000628:therapy; D010291:Paresis; D020641:Polymorphism, Single Nucleotide; D020218:Response Elements / Q000235:genetics*; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics
chemical_list: D018958:CD55 Antigens; D008070:Lipopolysaccharides
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