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.-198C4G SNP (odds ratio ¼ 8.6; P ¼ 0.0003). This single nucleotide polymorphism (SNP) results in a twofold activation of a DAF 5 0 -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.-198C4G 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.

The characteristics of juvenile myasthenia gravis among South Africans

“…3 Sixty of the generalised MG subjects, of whom the majority were post-pubertal children with more severe disease, underwent thymectomy; the histological examination showed the expected preponderance of thymic hyperplasia. 6 A previous report which suggested that African-American children had a lower remission rate after thymectomy (≈20%) compared with those of European ancestry (≈58%) 9 is not supported by our data, which comprised predominantly children with African genetic ancestry (in whom there was ≈45% remission). Although we showed a trend towards more remissions after thymectomy (p=0.057), a sub-analysis of the Cape Town cohort with longer patient follow-up did not reveal a difference in remission rate between those that did and those that did not have thymectomy (p=0.51; data not shown).…”

“…The majority of these children had already developed either partial or complete ophthalmoplegia at the time of generalised MG symptom presentation, whereas the remainder developed it after treatment initiation. Research into the molecular basis 9 and the optimal management of this complication is ongoing. Juvenile MG accounts for less than 10 -15% of all MG cases, with an incidence of 1 -5 per million per year.…”

The tag SNP rs10746463 in decay-accelerating factor is associated with the susceptibility to gastric cancer

“…However, several studies have examined the function of genetic variants of DAF. Heckmann et al (2010) reported that −198 C > G polymorphism (rs28371586) in the upstream regulatory region of DAF elevated the promoter activity of gene and specifically the ability to induce DAF expression in response to Lipopolysaccharides (LPS). DAF rs2564978 T > C polymorphism is located in the promoter of DAF.…”

Complement and cytokine based therapeutic strategies in myasthenia gravis

“…Interestingly, inhibition of the complement cascade by a C5 antibody does not reduce the complement deposition at the extraocular muscles, while it does in other muscles [23,40]. The significance of complement regulators in MG pathogenesis is substantiated by a recent study suggesting that extraocular muscle involvement in MG might be associated with inadequate DAF upregulation due to a single nucleotide polymorphism in the regulatory region of the DAF gene [41].…”