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Journal of Human Genetics , (3 December 2015) | doi:10.1038/jhg.2015.146
The African−387 C>T TGFB1 variant is functional and associates with the ophthalmoplegic complication in juvenile myasthenia gravis
Melissa Nel, Joy-Mari Buys, Robyn Rautenbach, Shaheen Mowla, Sharon Prince and Jeannine M Heckmann
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.