The African −387 C>T TGFB1 variant is functional and associates with the ophthalmoplegic complication in juvenile myasthenia gravis

Although extraocular muscles are commonly affected by myasthenia gravis (mg) at presentation, a treatment-resistant ophthalmoplegic complication of mg (op-mg) occurs in younger patients with african-genetic ancestry. in mg, pathogenic antibodies activate complement-mediated muscle damage and this may be potentiated in some op-mg cases because of relative deficiency of decay-accelerating factor/cd55. extending this argument, we hypothesized that op-mg individuals may harbor african-specific polymorphisms in key genes influencing extraocular muscle remodeling. we screened the regulatory region of the transforming growth factor beta-1 (tgfb1) gene encoding the cytokine pivotal in muscle healing responses. we show the frequency of an african-specific polymorphism tgfb1 c.−387 t (rs11466316) among south africans with african-genetic ancestry is higher than 1000 genomes african controls (17.2% vs 4.8%; p<1 × 10−7), and associates with juvenile op-mg (28%; p=0.043). further, tgfb1 −387 c>t is functional because it represses the tgfb1 promoter construct basal activity by fivefold, and op-mg fibroblasts (−387 c/t or t/t) have lower basal tgfb1 mrna transcripts compared with controls (−387 c/c)(p=0.001). co-transfections with sp1 show less responsiveness of the −387 t promoter compared with wild-type −387 c (p=0.015). our findings suggest that population-specific alleles may lower tgfb1 expression, thereby influencing op-mg susceptibility by inhibiting extraocular muscle cd55 upregulation and/or altered endplate remodeling.